ORCID Profile
0000-0002-4140-8139
Current Organisation
University of Queensland
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Publisher: Springer Science and Business Media LLC
Date: 12-09-2017
DOI: 10.1038/S41598-017-10440-9
Abstract: Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery s le identified significant evidence for association with coding variants in single-variant (rs1801232- CUBN ) and gene-level ( CIITA and PARP4 ) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 ( P = 2.3 × 10 −9 ) in GREB1 at 2p25.1 — a locus previously identified in a GWA meta-analysis of European and Japanese s les. Despite sufficient power, our results did not identify any protein-modifying variants (MAF 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2004
Publisher: Elsevier BV
Date: 05-2008
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Publisher: Springer Science and Business Media LLC
Date: 08-12-2011
Publisher: Springer Science and Business Media LLC
Date: 12-06-2015
DOI: 10.1038/NCOMMS8208
Publisher: Informa UK Limited
Date: 02-11-2018
Publisher: Springer Science and Business Media LLC
Date: 02-12-2015
DOI: 10.1038/MP.2014.133
Publisher: Springer Science and Business Media LLC
Date: 16-05-2009
DOI: 10.1007/S10519-009-9276-X
Abstract: Mitochondria are central to optimal functioning of the nervous system and disruption of mitochondrial function is known to lead to cognitive impairment. However, there has been little focus on whether common mitochondrial DNA polymorphisms contribute to normal variation in cognitive phenotypes. In this study, we use methodology for carrying out whole mitochondrial association studies in family cohorts to test whether 69 common mitochondrial variants and 10 common European haplogroups are associated with a number of measures of cognition, including information processing, word recognition and general cognitive ability, in a s le of Australian adolescent twins and their singleton/non-twin siblings. With data from 1,385 in iduals from 665 families, this is by far the largest mitochondrial association study of cognition undertaken to date. We find that there is no significant evidence that either common European mitochondrial SNPs or haplogroups are associated with variation in cognitive performance. In spite of the associations not reaching significance, several of the most highly associated SNPs are in mitochondrial genes that have previously been identified as potentially playing a role in cognitive performance in mice. These genes warrant further investigation in both functional and association studies with larger cohorts.
Publisher: Cold Spring Harbor Laboratory
Date: 21-10-2022
DOI: 10.1101/2022.10.20.22281201
Abstract: In clinical practice, the co-existence of endometriosis and gastrointestinal symptoms is often observed however, the factors driving this link remain largely unknown. Here, using large-scale multifaceted data including observational, genetic, and pharmaceutical datasets, we report a positive phenotypic and genetic association of endometriosis with peptic ulcer disease (PUD), gastro-oesophageal reflux disease (GORD), a combined GORD/PUD Medicated (GPM) phenotype and irritable bowel syndrome (IBS), but not with inflammatory bowel disease (IBD). Mendelian randomization analysis identified a causal effect of the GPM phenotype on endometriosis and a bidirectional causal association between endometriosis and IBS. Cross-trait meta-analysis and colocalization along with comprehensive functional annotation confirmed two shared genetic loci ( FN1, TACSTD2 ) for endometriosis with IBS and twelve loci ( ETAA1, HOXC4, RERG, SEMA3F, SPAG16, HIST1H2BC, RAB5B, CCKBR and PDE4B ) with GORD and PUD. Shared genetic loci may contribute to risk of both endometriosis and digestive disorders through the involvement of DNA damage, estrogen regulated cell-proliferation and inflammation, and barrier dysfunction. Analyses of medication usage identified a higher use of drugs for IBS, GORD and PUD in women diagnosed with endometriosis as well as a higher use of hormone therapies in women diagnosed with IBS, GORD and PUD but not for IBD, which strongly supports the co-occurrence of these conditions and highlights the potential for drug repositioning and caution around drug contraindications in clinical practice. Taken together, the combined evidence robustly suggests a shared disease aetiology and provides important clinical implications for diagnostic and treatment decisions for endometriosis and digestive disorders. Both endometriosis and gastrointestinal disorders affect a large proportion of people worldwide and the co-existence of endometriosis and gastrointestinal symptoms (eg, abnormal pain, bloating, constipation) is often observed in clinical practice. The association of these two diseases was supported but also limited to previous observational evidence which highlights a three-fold increase in the prevalence of irritable bowel syndrome (IBS) in women with endometriosis. Observational study is easily subject to measurement error, confounding and reverse causation. Therefore, it is important to assess the association using multidimensional datasets and more accurate approaches, such as the use of genetic data in a mendelian randomisation framework as well as the analysis from a perspective of medication usage. Genetic risk factors for endometriosis and gastrointestinal disorders, two leading causes of discomfort and chronic pelvic pain, are correlated. Mendelian randomisation analyses supported a causal relationship between genetic predisposition to gastrointestinal disorders (gastro-oesophageal reflux disease (GORD) and peptic ulcer diseases (PUD)) and endometriosis risk, and evidence for a bidirectional causal relationship between endometriosis and IBS, which might explain in part the co-occurrence of these diseases. The identification of shared risk loci highlighted biological pathways that may contribute to the pathogenesis of both diseases, including estrogen regulation and inflammation, as well as potential therapeutic drug targets such as CCKBR and PDE4B . The higher use of drugs for IBS, GORD and PUD in women diagnosed with endometriosis as well as the higher use of hormone therapies in women diagnosed with IBS, GORD and PUD, support the co-occurrence of these conditions and shared disease aetiology but also highlights the potential for drug repositioning and caution around drug contraindications.
Publisher: Oxford University Press (OUP)
Date: 29-05-2013
DOI: 10.1093/HMG/DDT239
Publisher: Springer Science and Business Media LLC
Date: 11-2005
DOI: 10.1007/S10519-005-6187-3
Abstract: Prenatal exposure to testosterone has been hypothesised to effect lateralization by influencing cell death in the foetal brain. Testosterone binds to the X chromosome linked androgen receptor, which contains a polymorphic polyglutamine CAG repeat, the length of which is positively correlated with testosterone levels in males, and negatively correlated in females. To determine whether the length of the androgen receptor mediates the effects of testosterone on laterality, we examined the association between the number of CAG repeats in the androgen receptor gene and handedness for writing. Association was tested by adding regression terms for the length of the androgen receptor alleles to a multi-factorial-threshold model of liability to left-handedness. In females we found the risk of left-handedness was greater in those with a greater number of repeats (p=0.04), this finding was replicated in a second independent s le of female twins (p=0.014). The length of the androgen receptor explained 6% of the total variance and 24% of the genetic variance in females. In males the risk of left-handedness was greater in those with fewer repeats (p=0.02), with variation in receptor length explaining 10% of the total variance and 24% of the genetic variance. Thus, consistent with Witelson's theory of testosterone action, in all three s les the likelihood of left handedness increased in those in iduals with variants of the androgen receptor associated with lower testosterone levels.
Publisher: Oxford University Press (OUP)
Date: 09-05-2023
Abstract: Endometriosis remains a poorly understood disease, despite its high prevalence and debilitating symptoms. The overlap in symptoms and the increased risk of multiple other traits in women with endometriosis is becoming increasingly apparent through epidemiological data. Genetic studies offer a method of investigating these comorbid relationships through the assessment of causal relationships with Mendelian randomization (MR), as well as identification of shared genetic variants and genes involved across traits. This has the capacity to identify risk factors for endometriosis as well as provide insight into the aetiology of disease. We aim to review the current literature assessing the relationship between endometriosis and other traits using genomic data, primarily through the methods of MR and genetic correlation. We critically examine the limitations of these studies in accordance with the assumptions of the utilized methods. The PubMed database was used to search for peer-reviewed original research articles using the terms ‘Mendelian randomization endometriosis’ and ‘“genetic correlation” endometriosis’. Additionally, a Google Scholar search using the terms ‘“endometriosis” “mendelian randomization” “genetic correlation”’ was performed. All relevant publications (n = 21) published up until 7 October 2022 were included in this review. Upon compilation of all traits with published MR and/or genetic correlation with endometriosis, additional epidemiological and genetic information on their comorbidity with endometriosis was sourced by searching for the trait in conjunction with ‘endometriosis’ on Google Scholar. The association between endometriosis and multiple pain, gynaecological, cancer, inflammatory, gastrointestinal, psychological, and anthropometric traits has been assessed using MR analysis and genetic correlation analysis. Genetic correlation analyses provide evidence that genetic factors contributing to endometriosis are shared with multiple traits: migraine, uterine fibroids, subtypes of ovarian cancer, melanoma, asthma, gastro-oesophageal reflux disease, gastritis/duodenitis, and depression, suggesting the involvement of multiple biological mechanisms in endometriosis. The assessment of causality with MR has revealed several potential causes (e.g. depression) and outcomes (e.g. ovarian cancer and uterine fibroids) of a genetic predisposition to endometriosis however, interpretation of these results requires consideration of potential violations of the MR assumptions. Genomic studies have demonstrated that there is a molecular basis for the co-occurrence of endometriosis with other traits. Dissection of this overlap has identified shared genes and pathways, which provide insight into the biology of endometriosis. Thoughtful MR studies are necessary to ascertain causality of the comorbidities of endometriosis. Given the significant diagnostic delay of endometriosis of 7–11 years, determining risk factors is necessary to aid diagnosis and reduce the disease burden. Identification of traits for which endometriosis is a risk factor is important for holistic treatment and counselling of the patient. The use of genomic data to disentangle the overlap of endometriosis with other traits has provided insights into the aetiology of endometriosis.
Publisher: Elsevier BV
Date: 08-2014
Publisher: Wiley
Date: 06-11-2015
DOI: 10.1002/IJC.29280
Publisher: Oxford University Press (OUP)
Date: 08-04-2010
Publisher: Hindawi Limited
Date: 12-07-2011
DOI: 10.1002/HUMU.21536
Abstract: We recently mapped a quantitative trait locus for monocyte counts to chromosome 9q31 (rs7023923). Here we extend this work by showing with two independent approaches that rs7023923 regulates the expression levels of the nearby LPAR1 gene (P<0.0001), specifically implicating this gene in monocyte development. Furthermore, we tested 10 additional loci identified in the original analysis for replication in 1,122 in iduals and confirm that rs6740847 near the alpha-4-integrin gene (ITGA4) associates with variation in monocyte counts (combined P=2.7×10(-10)). This variant is in complete linkage disequilibrium (r(2) =1) with a previously reported eQTL for ITGA4 (rs2124440), indicating that this is the likely causal gene in the region. Our results indicate that rs7023923 and rs6740847 respectively upregulate LPAR1 and downregulate ITGA4 expression and this increases the number of monocytes circulating in the peripheral blood. Further studies that investigate the downstream mechanism involved and the impact on immune function are warranted.
Publisher: Elsevier BV
Date: 2009
Publisher: Bioscientifica
Date: 08-1989
Abstract: Blood s les were obtained from adult female Weddell seals in McMurdo Sound, Antarctica, utilizing four different seals every 2 h for 24 h on two occasions in November 1987. Plasma levels of melatonin were mostly near zero, whereas the values for cortisol were high (2101 ±54 and 1908 ± 108 ( s.e.m. ) nmol/l, n = 52). For both hormones there was no evidence of a diurnal pattern of secretion. Juvenile seals s led in December 1985 also had no evidence of a diurnal secretion pattern of melatonin, but blood levels of melatonin were higher than in adults. The results indicate that secretion of melatonin in adult Weddell seals ceases during the Antarctic summer. Journal of Endocrinology (1989) 122, 445–449
Publisher: Springer Science and Business Media LLC
Date: 12-05-2015
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1086/510885
Publisher: Wiley
Date: 24-01-2015
DOI: 10.1111/JGH.12674
Abstract: The etiology of Crohn's disease (CD) implicates both genetic and environmental factors. Smoking behavior is one environmental risk factor to play a role in the development of CD. The study aimed to assess the contribution of the interleukin 23 receptor (IL23R) in determining disease susceptibility in two independent cohorts of CD, and to investigate the interactions between IL23R variants, smoking behavior, and CD-associated genes, NOD2 and ATG16L1. Ten IL23R single-nucleotide polymorphisms (SNPs) were genotyped in 675 CD cases, and 1255 controls from Brisbane, Australia (dataset 1). Six of these SNPs were genotyped in 318 CD cases and 533 controls from Canterbury, New Zealand (dataset 2). Case-control analysis of genotype and allele frequencies, and haplotype analysis for all SNPs was conducted. We demonstrate a strong increased CD risk for smokers in both datasets (odds ratio 3.77, 95% confidence interval 2.88-4.94), and an additive interaction between IL23R SNPs and cigarette smoking. Ileal involvement was a consistent marker of strong SNP-CD association (P ≤ 0.001), while the lowest minor allele frequencies for location were found in those with colonic CD (L2). Three haplotype blocks were identified across the 10 IL23R SNPs conferring different risk of CD. Haplotypes conferred no further risk of CD when compared with single SNP analyses. IL23R gene variants determine CD susceptibility in the Australian and New Zealand population, particularly ileal CD. A strong additive interaction exists between IL23R SNPs and smoking behavior resulting in a dramatic increase in disease risk depending upon specific genetic background.
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1086/432960
Publisher: Oxford University Press (OUP)
Date: 11-06-2007
Abstract: Endometriosis has a genetic component, and significant linkage has been found to a region on chromosome 10q. Two candidate genes, EMX2 and PTEN, implicated in both endometriosis and endometrial cancer, lie on chromosome 10q. We hypothesized that variation in EMX2 and/or PTEN could contribute to the risk of endometriosis and may account for some of the linkage signal on 10q. We genotyped single nucleotide polymorphisms (SNPs) in a case-control design to evaluate association between endometriosis and common variations in these two genes. The genotyping and statistical analysis were based on s les collected from Australian volunteers. The cases were 768 unrelated women with surgically confirmed endometriosis selected from affected sister pair (ASP) families participating in the Australian Genes behind Endometriosis Study. The controls were 768 female participants in twin studies who, based on screening questions, did not have a diagnosis of endometriosis. Genotypes of 22 SNPs in the EMX2 gene and 15 SNPs in the PTEN gene were the main outcome measures. Statistical analysis provided measures of linkage disequilibrium and association. Permutation testing showed no globally significant association between any SNPs or haplotypes and endometriosis for either gene. It is unlikely that the EMX2 or PTEN gene variants investigated contribute to risk for initiation and/or development of endometriosis.
Publisher: Public Library of Science (PLoS)
Date: 07-04-0004
Publisher: Elsevier BV
Date: 10-2012
Publisher: Elsevier BV
Date: 10-2004
DOI: 10.1016/J.JACI.2004.05.060
Abstract: Eosinophils are granulocytic white blood cells implicated in asthma and atopic disease. The degree of eosinophilia in the blood of patients with asthma correlates with the severity of asthmatic symptoms. Quantitative trait loci (QTL) linkage analysis of eosinophil count may be a more powerful strategy of mapping genes involved in asthma than linkage analysis using affected relative pairs. To identify QTLs responsible for variation in eosinophil count in adolescent twins. We measured eosinophil count longitudinally in 738 pairs of twins at 12, 14, and 16 years of age. We typed 757 highly polymorphic microsatellite markers at an average spacing of approximately 5 centimorgans across the genome. We then used multipoint variance components linkage analysis to test for linkage between marker loci and eosinophil concentrations at each age across the genome. We found highly significant linkage on chromosome 2q33 in 12-year-old twins (logarithm of the odds=4.6 P=.000002) and suggestive evidence of linkage in the same region in 14-year-olds (logarithm of the odds=1.0 P=.016). We also found suggestive evidence of linkage at other areas of the genome, including regions on chromosomes 2, 3, 4, 8, 9, 11, 12, 17, 20, and 22. A QTL for eosinophil count is present on chromosome 2q33. This QTL might represent a gene involved in asthma pathophysiology.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2009
DOI: 10.1038/NG.410
Publisher: Elsevier BV
Date: 08-2013
Publisher: Wiley
Date: 24-07-2013
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.BIOPSYCH.2007.03.007
Abstract: KIAA0319 (6p22.2) has recently been implicated as a susceptibility gene for dyslexia. We aimed to find further support for this gene by examining its association with reading and spelling ability in adolescent twins and their siblings unselected for dyslexia. Ten single nucleotide polymorphisms (SNPs) in or near the KIAA0319 gene were typed in 440 families with up to five offspring who had been tested on reading and spelling tasks. Family-based association analyses were performed, including a univariate analysis of the principal component reading and spelling score derived from the Components of Reading Examination (CORE) test battery and a bivariate analysis of whole-word reading tests measured in a slightly larger s le. Significant association with rs2143340 (TTRAP) and rs6935076 (KIAA0319) and with a three-SNP haplotype spanning KIAA0319 and TTRAP was observed. The association with rs2143340 was found in both analyses, although the effect was in the opposite direction to that previously reported. The effect of rs6935076 on the principal component was in the same direction as past findings. Two of the three significant in idual haplotypes showed effects in the opposite direction to the two prior reports. These results suggest that a multilocus effect in or near KIAA0319 may influence variation in reading ability.
Publisher: Cambridge University Press (CUP)
Date: 12-2004
Publisher: Oxford University Press (OUP)
Date: 15-02-2023
DOI: 10.1093/HMG/DDAD028
Abstract: Testing the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An alternative approach is to investigate the effect of rare genetic variants on DNA methylation (DNAm) as effect sizes are expected to be larger for molecular traits compared with complex traits. Here, we investigate DNAm in healthy ageing populations—the Lothian Birth Cohorts of 1921 and 1936—and identify both transient and stable outlying DNAm levels across the genome. We find an enrichment of rare genetic single nucleotide polymorphisms (SNPs) within 1 kb of DNAm sites in in iduals with stable outlying DNAm, implying genetic control of this extreme variation. Using a family-based cohort, the Brisbane Systems Genetics Study, we observed increased sharing of DNAm outliers among more closely related in iduals, consistent with these outliers being driven by rare genetic variation. We demonstrated that outlying DNAm levels have a functional consequence on gene expression levels, with extreme levels of DNAm being associated with gene expression levels toward the tails of the population distribution. This study demonstrates the role of rare SNPs in the phenotypic variation of DNAm and the effect of extreme levels of DNAm on gene expression.
Publisher: Oxford University Press (OUP)
Date: 06-2011
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Wiley
Date: 06-05-2013
DOI: 10.1111/ADB.12062
Publisher: Springer Science and Business Media LLC
Date: 06-07-2023
DOI: 10.1007/S00439-023-02582-W
Abstract: Comorbid conditions can be driven by underlying pleiotropic and causal mechanisms that can provide insights into shared molecular and biological processes contributing to disease risk. Endometriosis is a chronic condition affecting one in nine women of reproductive age and poses many challenges including lengthy diagnostic delays and limited treatment efficacy owing to poor understanding of disease aetiology. To shed light on the underlying biological mechanisms and to identify potential risk factors, we examine the epidemiological and genomic relationship between endometriosis and its comorbidities. In the UK Biobank 292 ICD10 codes were epidemiologically correlated with endometriosis diagnosis, including gynaecological, immune, infection, pain, psychiatric, cancer, gastrointestinal, urinary, bone and cardiovascular traits. A subset of the identified comorbidities ( n = 76) underwent follow-up genetic analysis. Whilst Mendelian randomisation suggested causality was not responsible for most comorbid relationships, 22 traits were genetically correlated with endometriosis, including pain, gynaecological and gastrointestinal traits, suggestive of a shared genetic background. Pleiotropic genetic variants and genes were identified using gene-based and colocalisation analysis. Shared genetic risk factors and potential target genes suggest a erse collection of biological systems are involved in these comorbid relationships including coagulation factors, development of the female reproductive tract and cell proliferation. These findings highlight the ersity of traits with epidemiological and genomic overlap with endometriosis and implicate a key role for pleiotropy in the comorbid relationships.
Publisher: Springer Science and Business Media LLC
Date: 04-1995
DOI: 10.1007/BF00352421
Publisher: BMJ
Date: 29-08-2013
Publisher: S. Karger AG
Date: 1996
DOI: 10.1159/000134425
Abstract: Two yeast artificial chromosomes (YACs 48B6 and 88F7) that span the ovine cystic fibrosis transmembrane conductance regulator (CFTR) gene locus have been isolated. These YAC clones have been physically assigned to the interval 4q23→q25 on sheep chromosome 4, using fluorescence in situ hybridization. A sequence polymorphism in exon 7 of the CFTR gene was identified in Merino sheep and present at a low frequency. This polymorphism segregated in several flocks. Linkage analysis confirmed the location of CFTR on sheep chromosome 4. The most likely location is within a 13.7-cM region close to markers MAF70 and TGLA116.
Publisher: Cambridge University Press (CUP)
Date: 10-2011
Abstract: Genes in the TGF9 signaling pathway play important roles in the regulation of ovarian follicle growth and ovulation rate. Mutations in three genes in this pathway, growth differentiation factor 9 ( GDF9 ), bone morphogenetic protein 15 ( BMP15 ) and the bone morphogenetic protein receptor B 1 ( BMPRB1 ), influence dizygotic (DZ) twinning rates in sheep. To date, only variants in GDF9 and BMP15 , but not their receptors transforming growth factor ß receptor 1 ( TGFBR1 ), bone morphogenetic protein receptor 2 ( BMPR2 ) and BMPR1B , have been investigated with respect to their roles in human DZ twinning. We screened for rare and novel variants in TGFBR1, BMPR2 and BMPR1B in mothers of dizygotic twins (MODZT) from twin-dense families, and assessed association between genotyped and imputed variants and DZ twinning in another large s le of MODZT. Three novel variants were found: a deep intronic variant in BMPR2 , and one intronic and one non-synonymous exonic variant in BMPRB1 which would result in the replacement of glutamine by glutamic acid at amino acid position 294 (p.Gln294Glu). None of these variants were predicted to have major impacts on gene function. However, the p.Gln294Glu variant changes the same amino acid as a sheep BMPR1B functional variant and may have functional consequences. Six BMPR1B variants were marginally associated with DZ twinning in the larger case-control s le, but these were no longer significant once multiple testing was taken into account. Our results suggest that variation in the TGF9 signaling pathway type II receptors has limited effects on DZ twinning rates in humans.
Publisher: Elsevier BV
Date: 04-2010
Publisher: Springer Science and Business Media LLC
Date: 06-10-2023
Publisher: Oxford University Press (OUP)
Date: 05-06-2015
DOI: 10.1093/HMG/DDV211
Abstract: Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a s le of 1029 in iduals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent s les from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a s le of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).
Publisher: Springer Science and Business Media LLC
Date: 03-08-2015
DOI: 10.1038/NG.3373
Publisher: Oxford University Press (OUP)
Date: 16-02-2019
Abstract: Endometriotic lesions are composed in part of endometrial-like stromal cells, however, there is a shortage of immortalized human endometrial stromal cultures available for research. As genetic factors play a role in endometriosis risk, it is important that genotype is also incorporated into analysis of pathological mechanisms. Human telomerase reverse transcriptase (hTERT) immortalization (using Lenti-hTERT-green fluorescent protein virus) took place following genotype selection 13 patients homozygous for either the risk or non-risk 'other' allele for one or more important endometriosis risk single nucleotide polymorphism on chromosome 1p36.12 (rs3820282, rs56318008, rs55938609, rs12037376, rs7521902 or rs12061255). Short tandem repeat DNA profiling validated that donor tissue matched that of the immortalized cell lines and confirmed that cultures were genetically novel. Expression of morphological markers (vimentin and cytokeratin) and key genes of interest (telomerase, estrogen and progesterone receptors and LINC00339) were examined and functional assays for cell proliferation, steroid hormone and inflammatory responses were performed for 7/13 cultures. All endometrial stromal cell lines maintained their fibroblast-like morphology (vimentin-positive) and homozygous endometriosis-risk genotype following introduction of hTERT. Furthermore, the new stromal cultures demonstrated positive and erse responses to hormones (proliferation and decidualisation changes) and inflammation (dose-dependent response), while maintaining hormone receptor expression. In conclusion, we successfully developed a range of human endometrial stromal cell lines that carry important endometriosis-risk alleles. The wider implications of this approach go beyond advancing endometriosis research these cell lines will be valuable tools for multiple endometrial pathologies offering a level of genetic and phenotypic ersity not previously available.
Publisher: Elsevier BV
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 05-2011
DOI: 10.1038/NG.824
Abstract: We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 in iduals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010 rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68 rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.
Publisher: Springer Science and Business Media LLC
Date: 21-05-2008
Abstract: A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability in 5000 7-year-old children from the Twins Early Development Study (TEDS). Four of these SNPs were identified through a 10 K microarray analysis and one was identified through a targeted analysis of brain-expressed genes. The present study tested this association with general cognitive ability in six population s les of varying size and age from Australia, the UK (Scotland and England) and the Netherlands. Results from the largest s le (N=1310) approached significance (P=0.06) in the direction of the original finding, but results from the other s les (N=205-758) were mixed. A meta-analysis of the results--allowing for effect size heterogeneity between s les--yielded a non-significant correlation (r=-0.01, P=0.57), indicating that this SNP set was not associated with general cognitive ability in the populations studied.
Publisher: Oxford University Press (OUP)
Date: 09-2006
DOI: 10.1373/CLINCHEM.2006.070169
Abstract: Background: The BRAF gene is frequently somatically altered in malignant melanoma. A majority of variations are at the valine 600 residue leading to a V600E substitution that constitutively activates the kinase. We screened 4000 patient and control DNAs for germ-line variations at the valine 600 residue. Methods: We developed a novel assay by adapting single-base variation assays and software for MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry to screen for all 5 reported variants at codon 600 of the BRAF gene. We screened a case-control collection comprising s les from 1082 melanoma patients and 154 of their unaffected relatives from 1278 families and from 2744 in iduals from 659 unselected twin families with no history of melanoma. A panel of 66 melanoma cell lines was used for variation-positive controls. Results: All melanoma cell lines that we had found previously to carry a codon 600 variation were verified in this study. Three of the 4 possible variants (V600E n = 47, V600K n = 2, V600R n = 1) were detected, but no case of V600D was available. No germ-line variants were found in the s les from the 3980 melanoma patients or from the control in iduals. Conclusions: This new assay is a high-throughput, automated alternative to standard sequencing and can be used as a rapid initial screen for somatic variants associated with melanoma. Germ-line variants at valine 600 are unlikely to exist and do not contribute to the reported role of the BRAF gene in melanoma predisposition.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2011
DOI: 10.1038/NATURE10630
Publisher: Springer Science and Business Media LLC
Date: 11-06-2013
DOI: 10.1038/MP.2013.72
Publisher: Elsevier BV
Date: 04-2011
Publisher: Oxford University Press (OUP)
Date: 23-07-2008
Abstract: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein suspected to be involved in the pathogenesis of endometriosis by establishing a new blood supply to the human exfoliated endometrium. Several transcription factor-binding sites are found in the VEGF 5'-untranslated region and variation within the region increases the transcriptional activity. Six previous studies which tested between one and three single nucleotide polymorphisms (SNPs) in s les comprising 105-215 cases and 100-219 controls have produced conflicting evidence for association between the SNPs in the VEGF region and endometriosis. To further investigate the reported association between VEGF variants and endometriosis, we tested the four VEGF polymorphisms (-2578 A/C, rs699947 -460 T/C, rs833061 +405 G/C, rs2010963 and +936 C/T, rs3025039) in a large Australian s le of 958 familial endometriosis cases and 959 controls. We also conducted a literature-based review of all relevant association studies of these VEGF SNPs in endometriosis and performed a meta-analysis. There was no evidence for association between endometriosis and the VEGF polymorphisms genotyped in our study. Combined association results from a meta-analysis did not provide any evidence for either genotypic or allelic association with endometriosis. Our detailed review and meta-analysis of the VEGF polymorphisms suggests that genotyping assay problems may underlie the previously reported associations between VEGF variants and endometriosis.
Publisher: Oxford University Press (OUP)
Date: 11-12-2007
Abstract: Endometriosis is a common disease with a heritable component. The collaborative International Endogene Study consists of two data sets (Oxford and Australia) comprising 1176 families with multiple affected. The aim was to investigate whether the apparent concentration of cases in a proportion of families could be explained by one or more rare variants with (near-)Mendelian autosomal inheritance. Linkage analyses (aimed at finding chromosomal regions harbouring disease-predisposing genes) were conducted in families with three or more affected (Oxford: n = 52 Australia: n = 196). In the Oxford data set, a non-parametric linkage score (Kong & Cox (K&C) Log of ODds (LOD)) of 3.52 was observed on chromosome 7p (genome-wide significance P = 0.011). A parametric MOD score (equal to maximum LOD maximized over 357 possible inheritance models) of 3.89 was found at 65.72 cM (D7S510) for a dominant model with reduced penetrance. After including the Australian data set, the non-parametric K&C LOD of the combined data set was 1.46 at 57.3 cM the parametric analysis found an MOD score of 3.30 at D7S484 (empirical significance: P = 0.035) for a recessive model with high penetrance. Critical recombinant analysis narrowed the probable region of linkage down to overlapping 6.4 Mb and 11 Mb intervals containing 48 and 96 genes, respectively. This is the first report to suggest that there may be one or more high-penetrance susceptibility loci for endometriosis with (near-)Mendelian inheritance.
Publisher: Cambridge University Press (CUP)
Date: 12-2008
Abstract: The genetic basis of cardiovascular disease (CVD) is complex and still largely elusive. Plasma lipid concentrations are well-established risk factors for cardiovascular disease (CVD), and have adult heritabilities ranging from 0.48 to 0.87. Estimates for adolescents are slightly higher (range 0.71 to 0.82). To identify loci affecting lipid concentrations across adolescence, we analyzed longitudinal lipid data in a s le of 134 monozygotic and 626 dizygotic twin pairs at ages twelve, fourteen and sixteen, and their siblings, from 760 Australian families. Univariate linkage analysis for each phenotype and time point was supplemented by multivariate analysis across the time points. A genome-wide association scan was also performed on a subset of the subjects ( N = 441). The strongest linkage was seen for triglycerides on chromosome 6p24.3 (multivariate –log 10 p = 6.81 equivalent LOD = 6.13 p = 1.55 × 10 –7 ). Significant linkage was also found for LDL cholesterol on chromosome 2q35 (multivariate –log 10 p = 5.59 equivalent LOD = 4.53 p = 2.57 × 10 –6 ). In the association analysis, rs10503840 on 8p21.1 was significantly associated with total cholesterol levels at age fourteen ( p = 8.24 × 10 –7 , estimated significance threshold 2.45 × 10 –6 ). Association at p 2.25 × 10 –6 was also found between triglycerides at age 12 and rs10507266, in an intron of THRAP2 (MIM 608771) on 12q24.21 and between HDL-C at age 14 and rs10506325 in an intergenic region of 12q13.13. Suggestive evidence of association at ages twelve and fourteen was found between HDL-C and rs10492859 on 16q23 ( p = 2.42 × 10 –5 and 2.77 × 10 –4 , respectively). Further longitudinal genetic studies of cardiovascular risk factors, focused on critical periods of development or change, are needed.
Publisher: Public Library of Science (PLoS)
Date: 31-05-2012
Publisher: Springer Science and Business Media LLC
Date: 30-07-2018
DOI: 10.1038/S41598-018-29462-Y
Abstract: Gene expression varies markedly across the menstrual cycle and expression levels for many genes are under genetic control. We analyzed gene expression and mapped expression quantitative trait loci (eQTLs) in endometrial tissue s les from 229 women and then analyzed the overlap of endometrial eQTL signals with genomic regions associated with endometriosis and other reproductive traits. We observed a total of 45,923 cis -eQTLs for 417 unique genes and 2,968 trans -eQTLs affecting 82 unique genes. Two eQTLs were located in known risk regions for endometriosis including LINC00339 on chromosome 1 and VEZT on chromosome 12 and there was evidence for eQTLs that may be target genes in genomic regions associated with other reproductive diseases. Dynamic changes in expression of in idual genes across cycle include alterations in both mean expression and transcriptional silencing. Significant effects of cycle stage on mean expression levels were observed for (2,427/15,262) probes with detectable expression in at least 90% of s les and for (2,877/9,626) probes expressed in some, but not all s les. Pathway analysis supports similar biological control of both altered expression levels and transcriptional silencing. Taken together, these data identify strong genetic effects on genes with erse functions in human endometrium and provide a platform for better understanding genetic effects on endometrial-related pathologies.
Publisher: Wiley
Date: 17-09-2008
Publisher: Springer Science and Business Media LLC
Date: 29-10-2010
Abstract: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes. An extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P -values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of 0.05 was considered statistically significant. No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found. These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.BPOBGYN.2018.01.012
Abstract: Developments in high-throughput genotyping technology have driven discovery of genomic regions associated with an increased risk of endometriosis. In all, 16 genomic regions have been associated with risk of endometriosis in one or more populations. The latest meta-analysis including 17,045 endometriosis cases identified 14 genomic regions supported by results from multiple studies. No independent associations were identified from direct genotyping of common and low-frequency protein-coding variants. This suggests that the most common genetic factors that contribute to endometriosis risk are located in regulatory DNA sequences and alter the regulation of gene transcription. Evidence from different methods is essential to identify the target genes and transcripts that contribute to altered disease risk. Potential target genes in three chromosome regions showing altered gene regulation include LINC00339 and CDC42 on chromosome 1, CDKN2A-AS1 on chromosome 9, and VEZT on chromosome 12. Further functional studies are needed to confirm the causal genes in these and other regions to understand pathways that increase endometriosis risk and help identify novel targets for interventions to improve diagnosis and treatment.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2014
DOI: 10.1038/MP.2014.107
Publisher: Cambridge University Press (CUP)
Date: 05-08-2003
Publisher: Springer Science and Business Media LLC
Date: 17-04-2011
DOI: 10.1038/NG.812
Publisher: Elsevier BV
Date: 12-2008
Publisher: Springer Science and Business Media LLC
Date: 12-12-2011
DOI: 10.1038/NG.731
Publisher: Cambridge University Press (CUP)
Date: 02-2003
DOI: 10.1375/136905203762687861
Abstract: For zygosity diagnosis in the absence of genotypic data, or in the recruitment phase of a twin study where only single twins from same-sex pairs are being screened, or to provide a test for s le duplication leading to the false identification of a dizygotic pair as monozygotic, the appropriate analysis of respondents' answers to questions about zygosity is critical. Using data from a young adult Australian twin cohort (N = 2094 complete pairs and 519 singleton twins from same-sex pairs with complete responses to all zygosity items), we show that application of latent class analysis (LCA), fitting a 2-class model, yields results that show good concordance with traditional methods of zygosity diagnosis, but with certain important advantages. These include the ability, in many cases, to assign zygosity with specified probability on the basis of responses of a single informant (advantageous when one zygosity type is being overs led) and the ability to quantify the probability of misassignment of zygosity, allowing prioritization of cases for genotyping as well as identification of cases of probable laboratory error. Out of 242 twins (from 121 like-sex pairs) where genotypic data were available for zygosity confirmation, only a single case was identified of incorrect zygosity assignment by the latent class algorithm. Zygosity assignment for that single case was identified by the LCA as uncertain (probability of being a monozygotic twin only 76%), and the co-twin's responses clearly identified the pair as dizygotic (probability of being dizygotic 100%). In the absence of genotypic data, or as a safeguard against s le duplication, application of LCA for zygosity assignment or confirmation is strongly recommended.
Publisher: Cold Spring Harbor Laboratory
Date: 20-03-2008
Abstract: The application of genetic association studies to detect mitochondrial variants responsible for phenotypic variation has recently been demonstrated. However, the only power estimates currently available are based on the use of mitochondrial haplogroups, which can only tag a small fraction of the common variation in the mitochondrial genome. Here, power estimates are derived for a SNP-based study design for both disease (case-control) and quantitative trait mapping studies. Power is estimated using simulations based on a collection of publicly available mitochondrial sequences of European origin. The power when testing all common mitochondrial SNPs is shown to be equivalent to that when testing only tagging SNPs, despite the relatively high ratio of tagging SNPs to total SNPs resulting from the tagging of all SNPs with a minor allele frequency greater than 1%. The s le size requirements of mitochondrial genome association studies are compared with that of nuclear whole-genome studies. Remarkably, the trade off between the number of tests being performed and the proportion of phenotypic variance explained for a fixed effect size results in approximately equal s le sizes required for both study types, although the per in idual cost for the mitochondrial association study is much less. To test the representation of the sequences used in the power simulations, a s le of 3839 in iduals from 1037 Australian families was genotyped for 69 tagging SNPs. The strong concordance in allele frequencies and linkage disequilibrium between the European sequences and the Australian s le indicates that the results presented here are transferable across populations of European descent.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2014
DOI: 10.1038/MP.2014.51
Publisher: Elsevier BV
Date: 12-2005
Publisher: Public Library of Science (PLoS)
Date: 06-06-2013
Publisher: Public Library of Science (PLoS)
Date: 19-07-2012
Publisher: Public Library of Science (PLoS)
Date: 16-05-2013
Publisher: Oxford University Press (OUP)
Date: 20-09-2016
DOI: 10.1093/HMG/DDW320
Abstract: Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 in iduals and endometrial tissue from 136 in iduals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 in iduals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk (P = 1.84 × 10−5, OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of LINC00339 (also known as HSPC157) and increasing expression of CDC42 (P = 2.0 ×10−54 and 4.5x10−4 respectively). The largest effects were for two LINC00339 probes (P = 2.0 ×10−54 1.0 × 10−34). The eQTL for LINC00339 was also observed in endometrial tissue (P = 2.4 ×10−8) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for WNT4. Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both LINC00339 and CDC4 and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for CDC42 and the risk allele increases expression of CDC42. However, no effect of rs3820282 was observed in the LINC00339 expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both LINC00339 and CDC42.
Publisher: Cambridge University Press (CUP)
Date: 10-2011
Abstract: An evolving hypothesis postulates that melanomas may arise through ‘nevus-associated’ and ‘chronic sun exposure’ pathways. We explored this hypothesis by examining associations between nevus-associated loci and melanoma risk across strata of body site and histological subtype. We genotyped 1028 invasive case patients and 1469 controls for variants in methylthioadenosine phosphorylase (MTAP), phospholipase A2, group VI (PLA2G6) , and Interferon regulatory factor 4 (IRF4) , and compared allelic frequencies globally and by anatomical site and histological subtype of melanoma. Odds-ratios (ORs) and 95% confidence intervals (CIs) were calculated using classical and multinomial logistic regression models. Among controls, MTAP rs10757257, PLA2G6 rs132985 and IRF4 rs12203592 were the variants most significantly associated with number of nevi. In adjusted models, a significant association was found between MTAP rs10757257 and overall melanoma risk (OR = 1.32, 95% CI = 1.14–1.53), with no evidence of heterogeneity across sites ( Phomogeneity =.52). In contrast, MTAP rs10757257 was associated with superficial spreading/nodular melanoma (OR = 1.34, 95% CI = 1.15– 1.57), but not with lentigo maligna melanoma (OR = 0.79, 95% CI = 0.46–1.35) ( Phomogeneity =.06), the subtype associated with chronic sun exposure. Melanoma was significantly inversely associated with rs12203592 in children (OR = 0.35, 95% CI = 0.16–0.77) and adolescents (OR = 0.61, 95% CI = 0.42–0.91), but not in adults ( Phomogeneity =.0008). Our results suggest that the relationship between MTAP and melanoma is subtype-specific, and that the association between IRF4 and melanoma is more evident for cases with a younger age at onset. These findings lend some support to the ‘ ergent pathways’ hypothesis and may provide at least one candidate gene underlying this model. Further studies are warranted to confirm these findings and improve our understanding of these relationships.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2015
DOI: 10.1038/TP.2015.159
Abstract: Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippoc al neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P -values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499 , miR-708 and miR-1908 . Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499 , four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2 . First results of functional analyses in rat hippoc al neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.
Publisher: Oxford University Press (OUP)
Date: 27-03-2015
DOI: 10.1093/HMG/DDV112
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1086/513703
Publisher: Springer Science and Business Media LLC
Date: 09-08-2018
DOI: 10.1038/S41467-018-05427-7
Abstract: Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins ( SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
Publisher: Cambridge University Press (CUP)
Date: 04-2008
Abstract: Multiple reports have identified variation in the GABRA2 gene as contributing to the genetic susceptibility to alcohol dependence. However, both the mechanism behind this association, and the range of alcohol-related phenotypes affected by variation in this gene, are currently undefined. Other data suggest that the risk of alcohol dependence is increased by relative insensitivity to alcohol's intoxicating effects. We have therefore tested whether GABRA2 variation is associated with variation in the subjective and objective effects of a standard dose of alcohol in humans. Data on responses to alcohol from the Alcohol Challenge Twin Study (Martin et al., 1985) have been tested against allelic and haplotype information obtained by typing 41 single-nucleotide polymorphisms in or close to the GABRA2 gene. Nominally significant allelic associations ( p .05, without correction for multiple testing) were found for body sway, motor coordination, pursuit rotor and arithmetical computation tasks, and for the personality dimension of Neuroticism. Because of the large number of phenotypes tested, these possibly significant findings will need to be confirmed in further studies.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2010
DOI: 10.1038/NG.608
Publisher: Elsevier BV
Date: 11-2013
Publisher: Springer Science and Business Media LLC
Date: 04-12-2018
DOI: 10.1038/S41598-018-35871-W
Abstract: DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation from whole blood measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n = 614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1 Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5′ UTR regions. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1 × 10 −10 ), ulcerative colitis (p = 2 × 10 −5 ), Crohn’s disease (p = 6 × 10 −8 ) and coronary artery disease (p = 5.5 × 10 −6 ) when compared to a random s le of SNPs with matched minor allele frequency, although this enrichment is explained by the genomic location of the mQTL SNPs.
Publisher: Bioscientifica
Date: 08-1984
Abstract: The plasma concentrations of LH and prolactin and various parameters of ovarian function were examined in cows on known days of the oestrous cycle during May and June (autumn and winter) and during October (spring). Luteinizing hormone peak frequency and plasma prolactin concentrations were significantly higher in October than during the May–June period (LH, P ·05 prolactin, P ·01). The mean diameters of large healthy follicles (≥8 mm diameter) and the dominant oestrogen-secreting follicles were significantly larger ( P ·01 for both follicle types) and each follicle contained more granulosa cells (both P ·01) in May–June than in October. The LH responsiveness of theca interna with respect to androstenedione production and the levels of aromatase activity in granulosa cells did not differ with time of year. The corpora lutea were heavier ( P ·05) and secreted more progesterone ( P ·01) in May–June than in October. It is concluded that seasonal differences in ovarian activity exist in cows and that these differences are probably the consequence of seasonal differences in gonadotrophin secretion. J. Endocr. (1984) 102 , 189–198
Publisher: Springer Science and Business Media LLC
Date: 17-02-2013
DOI: 10.1007/S10519-013-9587-9
Abstract: There is increasing evidence for the role of rare copy-number variation (CNV) in the development of neuropsychiatric disorders. It is likely that such variants also have an effect on the variation of cognition in what is considered the "normal" phenotypic range. The role of rare CNV (>20 KB in length frequency <5 %) on general cognitive ability is investigated in a s le of 800 in iduals (mean age = 16.5, SD = 1.2) using copy-number variants called from the Illumina 610K SNP genotyping array with the software QuantiSNP. We assessed three measures of CNV burden--total CNV length, number of CNV and average CNV length--for both deletions and duplications in combination and separately. No correlation was found between any of the measures of CNV burden and IQ, or when comparing the top and bottom 10 % of the s le for IQ, both on a genome-wide scale and at in idual positions across the genome.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2012
DOI: 10.1038/NPP.2012.49
Publisher: Cold Spring Harbor Laboratory
Date: 16-09-2021
DOI: 10.1101/2021.09.13.21263503
Abstract: Opioid addiction (OA) has strong heritability, yet few genetic variant associations have been robustly identified. Only rs1799971, the A118G variant in OPRM1 , has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data and published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective s le size of 88,114 in iduals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r g 0.9). We observed the strongest evidence to date for OPRM1 : lead SNP rs9478500 ( p =2.56×10 −9 ). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN . Variants within these loci appear to be pleiotropic for addiction and related traits.
Publisher: Oxford University Press (OUP)
Date: 21-10-2015
Publisher: Wiley
Date: 17-07-2007
Publisher: S. Karger AG
Date: 1997
DOI: 10.1159/000134670
Abstract: Three genes—parathyroid hormone-like hormone (PTHLH), insulin-like growth factor 1 (IGF1), and retinoic acid receptor γ (RARG)—have been mapped to sheep i (Ovis aries) /i chromosome 3 (OAR 3). The order and genetic distances between loci on OAR 3 are similar to those on cattle i (Bos taurus) /i chromosome 5, as expected from their close evolutionary relationship. The OAR 3 linkage map shows conserved synteny with human chromosome 12, but there are at least two rearrangements in gene order between the species.
Publisher: Bioscientifica
Date: 09-1987
Abstract: An experiment was conducted to measure LH pulse frequencies in bilaterally adrenalectomized Ile-de-France ewes during the mid-anoestrous season. Seven ewes were adrenalectomized under general anaesthesia and maintained on daily injections of 3 mg deoxycorticosterone acetate (DOCA). Adrenalectomy did not affect the patterns of LH release and the mean intervals between pulses in the adrenalectomized and sham-operated control ewes were 48 and 52 min respectively. Small implants of oestradiol significantly reduced the frequency of LH pulses in both groups and, in the presence of oestradiol, there were no differences in LH release between adrenalectomized and sham-operated ewes, with the mean interpulse intervals being 91 and 89 min respectively. In a second experiment, designed to assess the effects of DOCA on LH release, the mean interpulse intervals in unoperated control ewes (46 min) and unoperated ewes given daily injections of 3 mg DOCA (47 min) were similar to those observed in adrenalectomized and sham-operated ewes. In the presence of small implants of oestradiol, the combination of DOCA and oestradiol decreased the pulse frequency significantly more than oestradiol alone (mean interpulse intervals of 85 and 65 min respectively) suggesting that DOCA may act as a progestagen in sheep. Thus alternative treatments to DOCA for the maintenance of adrenalectomized sheep must be found for future studies on the role of adrenal steroids in the reproductive system. It appears that adrenal steroids do not play a major role in the seasonal changes in LH release in the ewe. J. Endocr. (1987) 114, 437–442
Publisher: Springer Science and Business Media LLC
Date: 21-09-2022
Publisher: Springer Science and Business Media LLC
Date: 09-07-2008
Abstract: There is an increasing recognition of the potential role of variants in mitochondrial DNA and nuclear-encoded mitochondrial proteins in modifying disease risk. This has led to a rise in the number of mitochondrial association studies being undertaken. The unique inheritance pattern of mitochondria makes mitochondrial DNA variation susceptible to having geographical structure. Such a structure may have a dramatic impact on mitochondrial association studies, particularly in heterogeneous populations. By combining self-reported ancestry data and mitochondrial genotype data for a s le of 3839 in iduals from 1037 Australian families, population substructure is tested by looking for evidence of differences in mitochondrial haplogroup and single nucleotide polymorphism (SNP) frequencies between different ancestral groups in Australia. In addition, the substructure within ancestral groups is tested by comparing the similarity of mates to randomly drawn pairs of in iduals from the same ancestral group. It is shown that there are significant differences in the frequency of variants both between European and non-European groups, and within Europe. This agrees with previous studies of European mitochondrial variation. No evidence was found for structure within ancestral groups. These results have implications for future association studies in the Australian population, and other populations of heterogeneous ancestry.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2250
Publisher: Oxford University Press (OUP)
Date: 14-09-2006
Abstract: Endometriosis is a common gynaecological disease with symptoms of pelvic pain and infertility which affects 7-10% of women in their reproductive years. Activation of an oncogenic allele of Kirsten rat sarcoma viral oncogene homologue (KRAS) in the reproductive tract of mice resulted in the development of endometriosis. We hypothesized that variation in KRAS may influence risk of endometriosis in humans. Thirty tagSNPs spanning a region of 60.7 kb across the KRAS locus were genotyped using iPLEX chemistry on a MALDI-TOF MassARRAY platform in 959 endometriosis cases and 959 unrelated controls, and data were analysed for association with endometriosis. Genotypes were obtained for most in iduals with a mean completion rate of 99.1%. We identified six haplotype blocks across the KRAS locus in our s le. There were no significant differences between cases and controls in the frequencies of in idual single-nucleotide polymorphisms (SNPs) or haplotypes. We also developed a rapid method to screen for 11 common KRAS and BRAF mutations on the Sequenom MassARRAY system. The assay detected all mutations previously identified by direct sequencing in a panel of positive controls. No germline variants for KRAS or BRAF were detected. Our results demonstrate that any risk of endometriosis in women because of common variation in KRAS must be very small.
Publisher: Oxford University Press (OUP)
Date: 22-05-2019
DOI: 10.1534/GENETICS.119.302091
Abstract: Expression QTL (eQTL) detection has emerged as an important tool for unraveling the relationship between genetic risk factors and disease or clinical phenotypes. Most studies are predicated on the assumption that only a single causal variant explains the association signal in each interval. This greatly simplifies the statistical modeling, but is liable to biases in scenarios where multiple local causal-variants are responsible. Here, our primary goal was to address the prevalence of secondary cis-eQTL signals regulating peripheral blood gene expression locally, utilizing two large human cohort studies, each & s les with accompanying whole genome genotypes. The CAGE (Consortium for the Architecture of Gene Expression) dataset is a compendium of Illumina microarray studies, and the Framingham Heart Study is a two-generation Affymetrix dataset. We also describe Bayesian colocalization analysis of the extent of sharing of cis-eQTL detected in both studies as well as with the BIOS RNAseq dataset. Stepwise conditional modeling demonstrates that multiple eQTL signals are present for ∼40% of over 3500 eGenes in both microarray datasets, and that the number of loci with additional signals reduces by approximately two-thirds with each conditioning step. Although & % of the peak signals across platforms fine map to the same credible interval, the colocalization analysis finds that as many as 50–60% of the primary eQTL are actually shared. Subsequently, colocalization of eQTL signals with GWAS hits detected 1349 genes whose expression in peripheral blood is associated with 591 human phenotype traits or diseases, including enrichment for genes with regulatory functions. At least 10%, and possibly as many as 40%, of eQTL-trait colocalized signals are due to nonprimary cis-eQTL peaks, but just one-quarter of these colocalization signals replicated across the gene expression datasets. Our results are provided as a web-based resource for visualization of multi-site regulation of gene expression and its association with human complex traits and disease states.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2010
DOI: 10.1038/NG.717
Publisher: Springer Science and Business Media LLC
Date: 18-08-2013
Publisher: Springer Science and Business Media LLC
Date: 21-11-2010
DOI: 10.1038/NG.714
Publisher: Cambridge University Press (CUP)
Date: 04-2004
Publisher: Wiley
Date: 16-11-2008
DOI: 10.1111/J.1751-1097.2007.00237.X
Abstract: Eumelanin (brown/black melanin) and pheomelanin (red/yellow melanin) in human hair can be quantified using chemical methods or approximated using spectrophotometric methods. Chemical methods consume greater resources, making them less attractive for epidemiological studies. This investigation sought to identify the spectrophotometric measures that best explain the light-dark continuum of hair color and the measure that is best able to distinguish red hair from nonred hair. Genetic analysis was performed on these two measures to determine the proportion of genetic and environmental influences on variation in these traits. Reflectance curves along the visible spectrum and subjective ratings of hair color were collected from 1730 adolescent twin in iduals. Discriminant class analyses were performed to determine the spectrophotometric measure that could best proxy for eumelanin and pheomelanin quantities. The ratio of light reflected in the green portion of the spectrum to that reflected in the red portion of the spectrum was best able to distinguish red hair from nonred hair. Melanocortin 1 receptor (MC1R) genotype explained some, but not all, variation in this measure. Light absorbed in the red portion of the spectrum was best able to explain the light-dark continuum of hair color. Variance components analysis showed that there were qualitatively different genetic influences between males and females for the light-dark continuum of hair. Our results show that spectrophotometric measures approximating variation in eumelanin and pheomelanin may be considered as an alternative to chemical methods in larger epidemiological studies.
Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/RD9890299
Abstract: Concentrations of FSH were measured in new-born lambs in Booroola Merino x Romney and Booroola Merino flocks where the Booroola F gene was segregating, and in progeny from sires of a prolific strain of Romney sheep. FSH concentrations increased with age and liveweight in Booroola Merino x Romney ewe lambs to reach peak concentrations at 4-6 weeks of age. Significantly higher mean concentrations were recorded in ewe lambs homozygous for the Booroola gene (FF) compared with non-carrier (+ +) ewe lambs. Concentrations in heterozygous (F+) ewe lambs were intermediate. Maximum differences between the genotypes were recorded at 6 weeks of age. Significantly higher FSH concentrations were also recorded in F-gene-carrier female lambs when compared to non-carriers in two other flocks. FSH concentrations remained low in ram lambs up to 12 weeks of age, and there were no differences between Booroola genotypes. The progeny of one ram from the prolific Romney family had high ovulation rates at 18 months of age. The progeny of other related rams showed no increase in ovulation rates at 18 months of age. Concentrations of FSH in the high-ovulation-rate progeny at 3 and 5 weeks of age did not differ from those in the low-ovulation-rate progeny, but were lower than those in the progeny of an FF Booroola Merino x Romney ram. These results support the hypothesis that neonatal concentrations of FSH are higher in lambs carrying the Booroola F gene, but not in all prolific strains since high FSH concentrations were not recorded in daughters from a prolific Romney flock.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Oxford University Press (OUP)
Date: 26-08-2014
Publisher: Cambridge University Press (CUP)
Date: 08-2003
Publisher: Elsevier BV
Date: 1997
DOI: 10.1016/S0739-7240(96)00098-7
Abstract: Growth hormone (GH) gene expression was investigated in pituitaries of 14- to 15-month-old ram lambs from flocks selected for high (fat) or low (lean) back fat depth, which were also homozygous for a single GH gene allele, heterozygous or homozygous for a duplication in the GH gene. The pituitaries of lean sheep of all three GH genotypes were significantly heavier than those of fat sheep, but there were no pituitary weight differences between GH genotypes. No significant lean-fat selection line- or GH genotype-specific differences were measured in pituitary GH concentration. However there was a significant increase (P < 0.01) in the total pituitary content of GH in lean compared with fat animals and a significant interaction between GH genotype and lean-fat selection line (P < 0.05) was noted for GH content. No significant differences were measured in the relative concentration of GH mRNA, suggesting that the ratio of GH mRNA per mg total cellular RNA remained constant across lean-fat selection line and GH genotype. We conclude that the pituitary glands of Coopworth sheep selected for low backfat depth (lean) are bigger and have an increased GH content, but appear to contain similar concentrations of GH mRNA and immunoreactive GH as the pituitaries of fat sheep. The presence of the GH gene duplication in sheep has little measurable effect on the expression and storage of GH in the pituitary.
Publisher: Elsevier BV
Date: 02-2008
Publisher: Wiley
Date: 06-2006
DOI: 10.1111/J.1530-0277.2006.00128.X
Abstract: The low-activity variant of the aldehyde dehydrogenase 2 (ALDH2) gene found in East Asian populations leads to the alcohol flush reaction and reduces alcohol consumption and risk of alcohol dependence (AD). We have tested whether other polymorphisms in the ALDH2 gene have similar effects in people of European ancestry. Serial measurements of blood and breath alcohol, subjective intoxication, body sway, skin temperature, blood pressure, and pulse were obtained in 412 twins who took part in an alcohol challenge study. Participants provided data on alcohol reactions, alcohol consumption, and symptoms related to AD at the time of the study and subsequently. Haplotypes based on 5 single-nucleotide polymorphisms (SNPs) were used in tests of the effects of variation in the ALDH2 gene on alcohol metabolism and alcohol's effects. The typed SNPs were in strong linkage disequilibrium and 2 complementary haplotypes comprised 83% of those observed. Significant effects of ALDH2 haplotype were observed for breath alcohol concentration, with similar but smaller and nonsignificant effects on blood alcohol. Haplotype-related variation in responses to alcohol, and reported alcohol consumption, was small and not consistently in the direction predicted by the effects on alcohol concentrations. Genetic variation in ALDH2 affects alcohol metabolism in Europeans. However, the data do not support the hypothesis that this leads to effects on alcohol sensitivity, consumption, or risk of dependence.
Publisher: Wiley
Date: 18-02-2022
DOI: 10.1002/IJGO.14115
Abstract: To study clinical, surgical characteristics and the relationship between endometriosis lesion types and conception rate after surgery in infertile women with endometriosis. A prospective, multicenter cohort of 204 women (age 20–35 years) with endometriosis was followed up post‐surgery between November 2017 and February 2020 at three tertiary‐care hospitals. Based on the severity of endometriosis lesion type, deep infiltrating endometriosis (DIE) (81/204, 39.7%) was the most common lesion followed by ovarian endometriosis (OMA) (64/204, 31.4%), and superficial peritoneal endometriosis (SUP) (59/204, 28.9%). Endometriosis patients had a single lesion type (94/204, 46.1%), two lesion types (77/204, 37.7%), or three lesion types (33/204, 16.2%) with significant differences between regions ( P 0.001). Around 40% (37/95) of obese women had SUP ( P = 0.003) whereas 78% (14/18) of underweight women had DIE ( P 0.001). Significant differences in mean Endometriosis Fertility Index scores between endometriosis lesion types and patients with one, two, and three types of lesions were observed ( P 0.001). The majority (22/32, 68.8%) of the women conceived naturally after the surgery. Half (16/32 50%) of the women with a single lesion type conceived after the surgery of which most (13/16, 81.2%) had SUP, followed by OMA (2/16, 12.5%), and DIE (1/16, 6.3%). Women with SUP and only one type of endometriotic lesion were more likely to conceive post‐surgery.
Publisher: Oxford University Press (OUP)
Date: 27-07-2012
DOI: 10.1093/HMG/DDS304
Publisher: Wiley
Date: 09-04-2013
DOI: 10.1002/EAT.22133
Publisher: Cambridge University Press (CUP)
Date: 10-2004
Publisher: Elsevier BV
Date: 11-2014
Publisher: Springer Science and Business Media LLC
Date: 11-08-2021
Publisher: Cold Spring Harbor Laboratory
Date: 03-10-2009
Abstract: Genome-wide association studies (GWAS) have now successfully identified important genetic variants associated with many human traits and diseases. The high cost of genotyping arrays in large data sets remains the major barrier to wider utilization of GWAS. We have developed a novel method in which whole blood from cases and controls, respectively, is pooled prior to DNA extraction for genotyping. We demonstrate proof of principle by clearly identifying the associated variants for eye color, age-related macular degeneration, and pseudoexfoliation syndrome in cohorts not previously studied. Blood pooling has the potential to reduce GWAS cost by several orders of magnitude and dramatically shorten gene discovery time. This method has profound implications for translation of modern genetic approaches to a multitude of diseases and traits yet to be analyzed by GWAS, and will enable developing nations to participate in GWAS.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2009
DOI: 10.1038/MP.2008.81
Publisher: Oxford University Press (OUP)
Date: 06-2006
DOI: 10.1373/CLINCHEM.2005.065052
Abstract: Background: Plasma cholinesterase activity is known to be correlated with plasma triglycerides, HDL- and LDL-cholesterol, and other features of the metabolic syndrome. A role in triglyceride metabolism has been proposed. Genetic variants that decrease activity have been studied extensively, but the factors contributing to overall variation in the population are poorly understood. We studied plasma cholinesterase activity in a s le of 2200 adult twins to assess covariation with cardiovascular risk factors and components of the metabolic syndrome, to determine the degree of genetic effects on enzyme activity, and to search for quantitative trait loci affecting activity. Methods and Results: Cholinesterase activity was lower in women than in men before the age of 50, but increased to activity values similar to those in males after that age. There were highly significant correlations with variables associated with the metabolic syndrome: plasma triglyceride, HDL- and LDL-cholesterol, apolipoprotein B and E, urate, and insulin concentrations γ-glutamyltransferase and aspartate and alanine aminotransferase activities body mass index and blood pressure. The heritability of plasma cholinesterase activity was 65%. Linkage analysis with data from the dizygotic twin pairs showed suggestive linkage on chromosome 3 at the location of the cholinesterase (BCHE) gene and also on chromosome 5. Conclusions: Our results confirm and extend the connection between cholinesterase, cardiovascular risk factors, and metabolic syndrome. They establish a substantial heritability for plasma cholinesterase activity that might be attributable to variation near the structural gene and at an independent locus.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41467-018-06649-5
Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1 , PPARGC1B , HDAC4 , FAM208B, DOCK8 , and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Oxford University Press (OUP)
Date: 02-2013
Publisher: Springer Science and Business Media LLC
Date: 30-03-2011
DOI: 10.1038/EJHG.2011.21
Publisher: Oxford University Press (OUP)
Date: 2021
Abstract: The etiology and pathogenesis of endometriosis are complex with both genetic and environmental factors contributing to disease risk. Genome-wide association studies (GWAS) have identified multiple signals in the estrogen receptor 1 (ESR1) region associated with endometriosis and other reproductive traits and diseases. In addition, candidate gene association studies identified signals in the ESR1 region associated with endometriosis risk suggesting genetic regulation of genes in this region may be important for reproductive health. This study aimed to investigate hormonal and genetic regulation of genes in the ESR1 region in human endometrium. Changes in serum oestradiol and progesterone concentrations and expression of hormone receptors ESR1 and progesterone receptor (PGR) were assessed in endometrial s les from 135 women collected at various stages of the menstrual cycle. Correlation between hormone concentrations, receptor expression and expression of genes in the ESR1 locus was investigated. The effect of endometriosis risk variants on expression of genes in the region was analyzed to identify gene targets. Hormone concentrations and receptor expression varied significantly across the menstrual cycle. Expression of genes in the ESR1 region correlated with progesterone concentration however, they were more strongly correlated with expression of ESR1 and PGR suggesting coregulation of genes. There was no evidence that endometriosis risk variants directly regulated expression of genes in the region. Limited s le size and cellular heterogeneity in endometrial tissue may impact the ability to detect significant genetic effects on gene expression. Effects of these variants should be validated in a larger dataset and in relevant in idual cell types.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1086/522934
Publisher: Springer Science and Business Media LLC
Date: 07-1996
Abstract: Recent advances in biomedical machine learning demonstrate great potential for data-driven techniques in health care and biomedical research. However, this potential has thus far been h ered by both the scarcity of annotated data in the biomedical domain and the ersity of the domain's subfields. While unsupervised learning is capable of finding unknown patterns in the data by design, supervised learning requires human annotation to achieve the desired performance through training. With the latter performing vastly better than the former, the need for annotated datasets is high, but they are costly and laborious to obtain. This review explores a family of approaches existing between the supervised and the unsupervised problem setting. The goal of these algorithms is to make more efficient use of the available labeled data. The advantages and limitations of each approach are addressed and perspectives are provided.
Publisher: Springer Science and Business Media LLC
Date: 15-10-2011
DOI: 10.1007/S10519-010-9402-9
Abstract: The region containing ROBO1 (Chromosome 3p12.3) has been implicated as a susceptibility gene for reading disorder and language deficit by translocation and linkage data. No association studies have yet been reported supporting any candidate gene. Here we report the first association of this gene with language deficits, specifically with phonological buffer deficits (a phenotype implicated in language acquisition, Specific Language Impairment and Speech Sound Disorder) and dyslexia (reading and spelling ability traits) in an unselected s le of adolescent twins and their siblings. Family-based analyses were performed on 144 tag SNPs in ROBO1, typed in 538 families with up to five offspring and tested for association with a developmental marker of language impairment (phonological buffer capacity, assessed using non word repetition). A reading and spelling ability measure--based on validated measures of lexical processing (irregular word) and grapheme-phoneme decoding (pseudo word)--and measures of short-term and working memory were also analysed. Significant association for phonological buffer capacity was observed for 21 of 144 SNPs tested, peaking at 8.70 × 10(-05) and 9.30 × 10(-05) for SNPs rs6803202 and rs4535189 respectively for nonword repetition, values that survive correction for multiple testing. Twenty-two SNPs showed significant associations for verbal storage (forward digit span)--a trait linked to phonological span. By contrast, just 5 SNPs reached nominal significance for working-memory, not surviving correction, and, importantly, only one SNP in the 144 tested reached nominal significance (0.04) for association with reading and spelling ability. These results provide strong support for ROBO1 as a gene involved in a core trait underpinning language acquisition, with a specific function in supporting a short-term buffer for arbitrary phonological strings. These effects of ROBO1 appear to be unrelated to brain mechanisms underpinning reading ability, at least by adolescence. While replication will be critical, the present results strongly support ROBO1 as the first gene discovered to be associated with language deficits affecting normal variation in language ability. Its functional role in neuronal migration underlying bilateral symmetry and lateralization of neuronal function further suggests a role in the evolution of human language ability.
Publisher: Oxford University Press (OUP)
Date: 09-01-2013
DOI: 10.1093/HMG/DDS551
Publisher: SAGE Publications
Date: 09-2015
DOI: 10.2217/WHE.15.41
Abstract: Endometriosis is a heritable complex disorder that is influenced by multiple genetic and environmental factors. Identification of these genetic factors will aid a better understanding of the underlying biology of the disease. In this article, we describe different methods of studying genetic variation of endometriosis, summarize results from genetic studies performed to date and provide recommendations for future studies to uncover additional factors contributing to the heritable component of endometriosis.
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2020
DOI: 10.1101/2020.11.09.20228114
Abstract: Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses provided evidence of a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.
Publisher: Elsevier BV
Date: 02-2006
Abstract: Deterioration in stratum corneum reticular patterning (skin pattern or skin wrinkling) has been associated with increased rates of solar keratoses and skin cancer. A previous analysis of data from the twin s le used in this investigation has shown that 86% of the variation in skin pattern is genetic at age 12 and 62% in an adult s le (mean age = 47.5). Variation due to genetic influences is likely to be influenced by more than one locus. Here, we present results of a genome-wide linkage scan of skin pattern in adolescent twins and siblings from 428 nuclear twin families. Sib-pair linkage analysis was performed on skin pattern data collected from twins at age 12 (378 informative families) and 14 (316 families). Suggestive linkage was found at marker D12S397 (12p13.31, logarithm of the odds (lod) 1.94), when the effect of the trait locus was modelled to influence the skin pattern equally at both ages 12 and 14. In the same analysis, a peak was seen at 4q23 with a lod score of 1.55. A possible candidate for the peak at 12p13.31 is the protease inhibitor, alpha-2-macroglobulin.
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Publisher: Wiley
Date: 03-03-2008
DOI: 10.1002/AJMG.B.30741
Abstract: In a previous study we identified a relatively homogeneous subtype of schizophrenia characterized by pervasive cognitive deficit, which was the exclusive contributor to our findings of linkage to 6p25-p24. The 6p region contains Dysbindin (DTNBP1), considered to be one of the major schizophrenia candidate genes. While multiple studies have reported association between genetic variation in DTNBP1 and schizophrenia, the findings have been inconsistent and controversial, leading to recent calls for systematic re-examination and unambiguous evidence of association. To address this, we have undertaken a comprehensive survey of common genetic variation within DTNBP1 and its association with schizophrenia, using a HapMap-based gene-tagging approach. We genotyped 39 tSNPs in a s le of 336 cases and 172 controls of Anglo-Irish ancestry, with the phenotype defined as clinical schizophrenia, and as composite neurocognitive endophenotypes. Allele and haplotype frequencies, and LD structure in our control s le were similar to those in other European populations. Using multivariate generalized linear modeling, we observed no significant association between any tSNP and any outcome variable. Association with haplotypes was examined across the gene and in the previously associated 5' region. Neither global haplotype tests, nor specific analysis of the "risk" haplotype previously reported in an ethnically related population, the Irish high-density schizophrenia families, showed significant evidence of association with schizophrenia or with the neurocognitive endophenotypes in our s le. The framework and results of this study should facilitate further attempts at re-analysis of DTNBP1, in terms of standardized approaches to both phenotype definition and analysis of genetic variation.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2019
DOI: 10.1038/S41467-019-12536-4
Abstract: Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant ( P 5 × 10 −8 ) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 ( TERT ), 5q35.2 ( FGFR4 ) and 11q22.3 ( ATM ). Four loci identified in the meta-analysis are also associated with endometriosis risk an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2011
DOI: 10.1038/EJHG.2011.39
Publisher: Wiley
Date: 02-04-2008
DOI: 10.1002/AJMG.B.30744
Abstract: The Val158Met polymorphism of the gene encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with psychiatric disorders, but replication has been inconsistent including both sex limitation and heterogeneity of the associated allele. In this study we investigate the association between three SNPs from COMT and anxiety and depression disorders and neuroticism all measured within the same study s le. Participants were selected as sibling pairs (or multiples) that were either concordant or discordant for extreme neuroticism scores from a total s le of 18,742 Australian twin in iduals and their siblings. All participants completed the Composite International Diagnostic Interview (CIDI) from which diagnoses of DSM-IV depression and anxiety disorders were determined. Of the participants, 674 had a diagnosis of anxiety and/or depression from 492 families. Study participants (n = 2,045 from 987 families) plus, where possible, their parents were genotyped for rs737865, rs4680 (Val158Met), and rs165599. Using family based tests we looked for association between these variants and neuroticism, depression, anxiety, panic disorder and agarophobia (PDAG) and obsessive compulsive disorder. We found no convincing evidence for association either in allelic or genotypic tests for the total s le or when the s le was stratified by sex. Haplotype T-G-G showed weak association (P = 0.042) with PDAG before correction for multiple testing association between this haplotype and schizophrenia has been previously reported in an Australian s le.
Publisher: Springer Science and Business Media LLC
Date: 07-08-2015
DOI: 10.1007/S10689-015-9826-8
Abstract: Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.
Publisher: Oxford University Press (OUP)
Date: 07-12-2006
DOI: 10.1093/HMG/DDL441
Publisher: Wiley
Date: 08-10-2009
DOI: 10.1111/J.1398-9995.2009.02091.X
Abstract: Linkage studies have implicated the 2q33, 9p21, 11q13 and 20q13 regions in the regulation of allergic disease. The aim of this study was to test genetic variants in candidate genes from these regions for association with specific asthma traits. Ninety-five single nucleotide polymorphisms (SNP) located in eight genes (CD28, CTLA4, ICOS, ADAM23, ADAMTSL1, MS4A2, CDH26 and HRH3) were genotyped in >5000 in iduals from Australian (n = 1162), Dutch (n = 99) and Danish (n = 303) families. Traits tested included doctor-diagnosed asthma, atopy, airway obstruction, total serum immunoglobulin (Ig) E levels and eosinophilia. Association was tested using both multivariate and univariate methods, with gene-wide thresholds for significance determined through simulation. Gene-by-gene and gene-by-environment analyses were also performed. There was no overall evidence for association with seven of the eight genes tested when considering all genetic variation assayed in each gene. The exception was MS4A2 on chromosome 11q13, which showed weak evidence for association with IgE (gene-wide P < 0.05, rs502581). There were no significant gene-by-gene or gene-by-environment interaction effects after accounting for the number of tests performed. The in idual variants genotyped in the 2q33, 9p21 and 20q13 regions do not explain a large fraction of the variation in the quantitative traits tested or have a major impact on asthma or atopy risk. Our results are consistent with a weak effect of MS4A2 polymorphisms on the variation of total IgE levels.
Publisher: The Endocrine Society
Date: 09-2000
DOI: 10.1210/JC.85.9.3391
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
Publisher: Public Library of Science (PLoS)
Date: 26-04-2012
Publisher: Wiley
Date: 06-02-2023
DOI: 10.1111/JOG.15549
Abstract: Endometriosis is a serious, chronic disorder where endometrial tissue grows outside the uterus, causing severe pelvic pain and infertility. It affects 11% of women. Endometriosis is a multifactorial disorder of unclear etiology, although retrograde menstruation plays a major role. It has a genetic component with over 40 genetic risk factors mapped, although their mechanism of action is still emerging. New evidence suggests a role for retrograde menstruation of endometrial stem rogenitor cells, now that identifying markers of these cells are available. Recent lineage tracing and tissue clearing microscopy and 3D reconstruction has provided new understanding of endometrial glandular structure, particularly the horizontal orientation and interconnection of basalis glands. New sequencing technologies, particularly whole genome DNA sequencing are revealing somatic mutations, including in cancer driver genes, in normal and eutopic endometrium of patients with endometriosis, as well as ectopic endometriotic lesions. Methylome sequencing is offering insight into the regulation of genes and the role of the environmental factors. Single cell RNA sequencing reveals the transcriptome of in idual endometrial cells, shedding new light on the ersity and range of cellular subpopulations of the major cell types present in the endometrium and in endometriotic lesions. New endometrial epithelial organoid cultures replicating glandular epithelium are providing tractable models for studying endometriosis. Organoids derived from menstrual fluid offer a non‐invasive source of endometrial tissue and a new avenue for testing drugs and developing personalized medicine for treating endometriosis. These new approaches are rapidly advancing our understanding of endometriosis etiology.
Publisher: Oxford University Press (OUP)
Date: 15-04-2010
DOI: 10.1093/HMG/DDQ144
Publisher: Oxford University Press (OUP)
Date: 18-10-2012
DOI: 10.1093/HMG/DDR478
Publisher: Cold Spring Harbor Laboratory
Date: 23-09-2014
Abstract: Epigenetic mechanisms such as DNA methylation (DNAm) are essential for regulation of gene expression. DNAm is dynamic, influenced by both environmental and genetic factors. Epigenetic drift is the ergence of the epigenome as a function of age due to stochastic changes in methylation. Here we show that epigenetic drift may be constrained at many CpGs across the human genome by DNA sequence variation and by lifetime environmental exposures. We estimate repeatability of DNAm at 234,811 autosomal CpGs in whole blood using longitudinal data (2–3 repeated measurements) on 478 older people from two Scottish birth cohorts—the Lothian Birth Cohorts of 1921 and 1936. Median age was 79 yr and 70 yr, and the follow-up period was ∼10 yr and ∼6 yr, respectively. We compare this to methylation heritability estimated in the Brisbane Systems Genomics Study, a cross-sectional study of 117 families (offspring median age 13 yr parent median age 46 yr). CpG repeatability in older people was highly correlated (0.68) with heritability estimated in younger people. Highly heritable sites had strong underlying cis -genetic effects. Thirty-seven and 1687 autosomal CpGs were associated with smoking and sex, respectively. Both sets were strongly enriched for high repeatability. Sex-associated CpGs were also strongly enriched for high heritability. Our results show that a large number of CpGs across the genome, as a result of environmental and/or genetic constraints, have stable DNAm variation over the human lifetime. Moreover, at a number of CpGs, most variation in the population is due to genetic factors, despite some sites being highly modifiable by the environment.
Publisher: American Medical Association (AMA)
Date: 02-06-2008
Publisher: American Psychiatric Association Publishing
Date: 08-2011
Publisher: Informa UK Limited
Date: 02-11-2014
Publisher: BMJ
Date: 06-07-2007
Publisher: Springer Science and Business Media LLC
Date: 09-12-2008
DOI: 10.1038/MP.2008.125
Publisher: Springer Science and Business Media LLC
Date: 2001
Abstract: It has been hypothesized that numerous genes contribute to in idual variation in human cognition. An extensive search of the scientific literature was undertaken to identify candidate genes which might contribute to this complex trait. A list of over 150 candidate genes that may influence some aspect of cognition was compiled. Some genes are particularly strong candidates based on evidence for involvement in cognitive processes in humans, mice, and Drosophila melanogaster. This survey confirms that many genes are associated with cognitive variation and highlights the potential importance of animal models in the study of human cognition.
Publisher: Oxford University Press (OUP)
Date: 07-2010
DOI: 10.1086/653125
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 13-02-2013
Publisher: Springer Science and Business Media LLC
Date: 30-08-2011
DOI: 10.1038/MP.2011.101
Publisher: Springer Science and Business Media LLC
Date: 13-01-2010
Publisher: Oxford University Press (OUP)
Date: 04-02-2009
DOI: 10.1093/HMG/DDP060
Publisher: Springer Science and Business Media LLC
Date: 30-03-2011
DOI: 10.1038/EJHG.2011.48
Publisher: Springer Science and Business Media LLC
Date: 12-10-2018
DOI: 10.1038/S41525-018-0068-1
Abstract: Variation in reproductive lifespan and female fertility have implications for health, population size and ageing. Fertility declines well before general signs of menopause and is also adversely affected by common reproductive diseases, including polycystic ovarian syndrome (PCOS) and endometriosis. Understanding the factors that regulate the timing of puberty and menopause, and the relationships with fertility are important for in iduals and for policy. Substantial genetic variation exists for common traits associated with reproductive lifespan and for common diseases influencing female fertility. Genetic studies have identified mutations in genes contributing to disorders of reproduction, and in the last ten years, genome-wide association studies (GWAS) have transformed our understanding of common genetic contributions to these complex traits and diseases. These studies have made great progress towards understanding the genetic factors contributing to variation in traits and diseases influencing female fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. Many variants implicate DNA damage/repair genes in variation in the age at menopause with implications for follicle health and ageing. In addition to the discovery of in idual genes and pathways, the increasingly powerful studies on common genetic risk factors help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.EJOGRB.2019.11.012
Abstract: Endometriosis affects a large proportion of women during their reproductive years and is associated with pain and infertility, also affecting psychological wellbeing and quality of life. The pathogenesis of the disease remains unclear, although it is believed to be multifactorial. The endocannabinoid system (ECS) consists of a number of ligands, receptors and enzymes, and has gained interests in endometriosis research. This review aims to summarise all available evidence reporting the roles of the ECS in endometriosis. A literature search of the PubMed, EMBASE, and Web of Science electronic medical databases was performed. Original and review articles published in peer-reviewed journals were included. No publication date or publication status restrictions were imposed. Significant differences in the concentrations and expressions of the components of the ECS were reported in the eutopic and ectopic endometrium, and the systemic circulation of women with endometriosis compared to controls. Endometriosis appears to be associated with downregulation of CB1 receptors and upregulation of TRPV1 receptors. The role of CB1 and progesterone in anti-inflammatory action and the role of TRPV1 in inflammation and pain are of particular interests. Furthermore, the ECS has been reported to be involved in processes relevant to endometriosis, including cell migration, cell proliferation, apoptosis, inflammation, and interacts with sex steroid hormones. The ECS may play a role in disease establishment, progression, and pain in endometriosis. However, reports are based on studies of limited size and there are inconsistencies among the definition of their control groups. There are also conflicting reports regarding precise involvement of the ECS in endometriosis. Future research with larger numbers, strict inclusion and exclusion criteria and detailed clinical information is imperative.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2012
DOI: 10.1038/NG.2213
Publisher: Oxford University Press (OUP)
Date: 08-10-2014
DOI: 10.1093/HMG/DDU516
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Wiley
Date: 16-07-2009
DOI: 10.1002/AJMG.A.32973
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
DOI: 10.1038/AJG.2010.161
Abstract: Crohn's disease (CD MIM 266600) is one of the most common forms of inflammatory bowel disease (IBD), and represents a significant burden to health care in developed countries. Our aim was to determine whether a gene in the IBD linkage region on chromosome 19q13, with a role in Paneth cell secretion and T-cell activation, conferred genetic susceptibility to the development of CD. In total, 792 CD cases and 1,244 controls of Australian origin (Caucasian) were genotyped for seven single-nucleotide polymorphisms (SNPs) in the gene encoding the intermediate conductance calcium-activated potassium channel protein (KCNN4) at 19q13.2. CD cases were phenotyped using the Montreal classification. The replication set comprised an additional 326 CD cases and 951 population-based Caucasian controls. Analysis of the KCNN4 mRNA transcript was carried out using quantitative reverse transcriptase-PCR. KCNN4 SNP rs2306801 was associated with CD (primary P=0.0008, odds ratio (OR) (95% confidence interval (CI)): 0.76 (0.65-0.89) replication P=0.01, OR (95% CI): 0.77 (0.61-0.97). Stratification by disease location identified the association between SNP rs2306801 and ileal CD (P=0.01). Non-inflamed ileal mucosa from CD patients carrying any of the common disease-predisposing NOD2 variants (R702W, G908R, 1007fs) had significantly reduced levels of KCNN4 mRNA expression (P=0.001). KCNN4 protein expression was detected in Paneth cells, and in T cells in inflamed lamina propria. Our data implicate the role of KCNN4 in ileal CD. The dual roles of KCNN4 in Paneth cell secretion and T-cell activation and also its nature as a potassium channel make it an important and practical therapeutic target.
Publisher: Cambridge University Press (CUP)
Date: 04-09-2009
DOI: 10.1017/THG.2015.61
Abstract: Endometriosis is a complex disease that affects 6–10% of women in their reproductive years and 20–50% of women with infertility. Genome-wide and candidate-gene association studies for endometriosis have identified 10 independent risk loci, and of these, nine (rs7521902, rs13394619, rs4141819, rs6542095, rs1519761, rs7739264, rs12700667, rs1537377, and rs10859871) are polymorphic in European populations. Here we investigate the replication of nine SNP loci in 998 laparoscopically and histologically confirmed endometriosis cases and 783 disease-free controls from Belgium. SNPs rs7521902, rs13394619, and rs6542095 show nominally significant ( p .05) associations with endometriosis, while the directions of effect for seven SNPs are consistent with the original reports. Association of rs6542095 at the IL1A locus with ‘All’ ( p = .066) and ‘Grade_B’ ( p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population. Meta-analysis with the published results yields genome-wide significant evidence for rs7521902, rs13394619, rs6542095, rs12700667, rs7739264, and rs1537377. Notably, three coding variants in GREB1 (near rs13394619) and CDKN2B-AS1 (near rs1537377) also showed nominally significant associations with endometriosis. Overall, this study provides important replication in a uniquely characterized independent population, and indicates that the majority of the original genome-wide association findings are not due to chance alone.
Publisher: Wiley
Date: 17-07-2009
DOI: 10.1002/GEPI.20361
Publisher: Oxford University Press (OUP)
Date: 23-08-2011
DOI: 10.1093/HMG/DDR375
Publisher: Oxford University Press (OUP)
Date: 21-07-2005
DOI: 10.1093/NAR/GNI126
Publisher: BMJ
Date: 08-2021
DOI: 10.1136/BMJOPEN-2021-050844
Abstract: Endometriosis is one of the common, gynaecological disorders associated with chronic pelvic pain and subfertility affecting ~10% of reproductive age women. The clinical presentation, etiopathogenesis of endometriosis subtypes and associated risk factors are largely unknown. Genome-Wide Association (GWA) Studies (GWAS) provide strong evidence for the role of genetic risk factors contributing to endometriosis. However, no studies have investigated the association of the GWAS-identified single-nucleotide polymorphism (SNPs) with endometriosis risk in the Indian population therefore, one-sixth of the world’s population is not represented in the global genome consortiums on endometriosis. The Endometriosis Clinical and Genetic Research in India (ECGRI) study aims to broaden our understanding of the clinical phenotypes and genetic risks associated with endometriosis. ECGRI is a large-scale, multisite, case–control study of 2000 endometriosis cases and 2000 hospital controls to be recruited over 4 years at 15 collaborating study sites across India covering representative Indian population from east,north-east, north, central, west and southern geographical zones of India. We will use the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project (WERF-EPHect) data collection instruments for capturing information on clinical, epidemiological, lifestyle, environmental and surgical factors. WERF-EPHect standard operating procedures will be followed for the collection, processing and storage of biological s les. The principal analyses will be for main outcome measures of the incidence of endometriosis, disease subtypes and disease severity determined from the clinical data. This will be followed by GWAS within and across ethnic groups. The study is approved by the Institutional Ethics Committee of Indian Council of Medical Research-National Institute for Research in Reproductive Health and all participating study sites. The study is also approved by the Health Ministry Screening Committee of the Government of India. The results from this study will be actively disseminated through discussions with endometriosis patient groups, conference presentations and published manuscripts.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2015
DOI: 10.1038/NG.3412
Publisher: Springer Science and Business Media LLC
Date: 19-04-2011
DOI: 10.1038/MP.2011.32
Publisher: Springer Science and Business Media LLC
Date: 28-10-2012
DOI: 10.1038/NG.2445
Publisher: Oxford University Press (OUP)
Date: 18-03-2015
Abstract: Do DNA variants in the growth regulation by estrogen in breast cancer 1 (GREB1) region regulate endometrial GREB1 expression and increase the risk of developing endometriosis in women? We identified new single nucleotide polymorphisms (SNPs) with strong association with endometriosis at the GREB1 locus although we did not detect altered GREB1 expression in endometriosis patients with defined genotypes. Genome-wide association studies have identified the GREB1 region on chromosome 2p25.1 for increasing endometriosis risk. The differential expression of GREB1 has also been reported by others in association with endometriosis disease phenotype. Fine mapping studies comprehensively evaluated SNPs within the GREB1 region in a large-scale data set (>2500 cases and >4000 controls). Publicly available bioinformatics tools were employed to functionally annotate SNPs showing the strongest association signal with endometriosis risk. Endometrial GREB1 mRNA and protein expression was studied with respect to phases of the menstrual cycle (n = 2-45 per cycle stage) and expression quantitative trait loci (eQTL) analysis for significant SNPs were undertaken for GREB1 [mRNA (n = 94) and protein (n = 44) in endometrium]. Participants in this study are females who provided blood and/or endometrial tissue s les in a hospital setting. The key SNPs were genotyped using Sequenom MassARRAY. The functional roles and regulatory annotations for identified SNPs are predicted by various publicly available bioinformatics tools. Endometrial GREB1 expression work employed qRT-PCR, western blotting and immunohistochemistry studies. Fine mapping results identified a number of SNPs showing stronger association (0.004 < P < 0.032) with endometriosis risk than the original GWAS SNP (rs13394619) (P = 0.034). Some of these SNPs were predicted to have functional roles, for ex le, interaction with transcription factor motifs. The haplotype (a combination of alleles) formed by the risk alleles from two common SNPs showed significant association (P = 0.026) with endometriosis and epistasis analysis showed no evidence for interaction between the two SNPs, suggesting an additive effect of SNPs on endometriosis risk. In normal human endometrium, GREB1 protein expression was altered depending on the cycle stage (significantly different in late proliferative versus late secretory, P < 0.05) and cell type (glandular epithelium, not stromal cells). However, GREB1 expression in endometriosis cases versus controls and eQTL analyses did not reveal any significant changes. In silico prediction tools are generally based on cell lines different to our tissue and disease of interest. Functional annotations drawn from these analyses should be considered with this limitation in mind. We identified cell-specific and hormone-specific changes in GREB1 protein expression. The lack of a significant difference observed following our GREB1 expression studies may be the result of moderate power on mixed cell populations in the endometrial tissue s les. This study further implicates the GREB1 region on chromosome 2p25.1 and the GREB1 gene with involvement in endometriosis risk. More detailed functional studies are required to determine the role of the novel GREB1 transcripts in endometriosis pathophysiology. Funding for this work was provided by NHMRC Project Grants APP1012245, APP1026033, APP1049472 and APP1046880. There are no competing interests.
Publisher: Springer Science and Business Media LLC
Date: 11-03-2014
DOI: 10.1038/NCOMMS4339
Abstract: Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large s les are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a s le of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Cold Spring Harbor Laboratory
Date: 28-11-2022
DOI: 10.1101/2022.11.27.518106
Abstract: Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Identifying biologic and genetic effects on DNA methylation (DNAm) in endometrium increases understanding of mechanisms that influence gene regulation predisposing to endometriosis and offers an opportunity for novel therapeutic target discovery. Herein, we characterize variation in endometrial DNAm and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genome-wide genotype data and methylation at 759,345 DNAm sites in endometrial s les from 984 deeply-phenotyped participants. We identify significant differences in DNAm profiles between menstrual cycle phases and at four DNAm sites between stage III/IV endometriosis and controls. We estimate that 15.4% of the variation in endometriosis is captured by DNAm, and identify DNAm networks associated with endometriosis. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis -mQTL including some tissue-specific effects. We find significant differences in DNAm profiles between endometriosis sub- phenotypes and a significant association between genetic regulation of methylation in endometrium and disease risk, providing functional evidence for genomic targets contributing to endometriosis risk and pathogenesis.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 11-10-2012
Publisher: Springer Science and Business Media LLC
Date: 06-1999
Abstract: A number of genes in the human and mouse genomes are subject to genomic imprinting, with selective inactivation of one allele of a gene in a parent-of-origin specific manner. One of the first imprinted genes identified was the Insulin-like Growth Factor 2 gene (IGF2), which promotes growth of the fetus and is expressed from only the paternal allele in most tissues in both the mouse and human. The aim of this study was to establish the imprinting status of IGF2 in sheep (Ovis aries). Sheep provide an interesting model to study imprinting, owing to differences in their placental development and the fact that they have been subject to strong artificial selection for various production traits. We report the identification of a length polymorphism in the transcribed 3'-untranslated region of the ovine IGF2 gene. This polymorphism was used to map IGF2 to sheep Chromosome (Chr) 21 and demonstrate that IGF2 is indeed imprinted in sheep, being expressed from the paternal allele. We also report that the developmental switch from imprinted IGF2 expression in the fetal liver to biallelic IGF2 expression in the adult liver, which occurs in the human but not mouse, also occurs in sheep. Differences in male- and female-specific recombination values reported around the IGF2 locus in the human were also observed around the ovine IGF2 locus. The techniques developed in this study will enable the imprinting status of IGF2 to be assessed in a variety of tissues and stages of development in normal sheep.
Publisher: Public Library of Science (PLoS)
Date: 02-06-2011
Publisher: Oxford University Press (OUP)
Date: 05-02-2008
DOI: 10.1093/NAR/GKM1060
Publisher: Oxford University Press (OUP)
Date: 26-03-2012
DOI: 10.1093/HMG/DDS114
Publisher: Wiley
Date: 13-04-2012
Publisher: Springer Science and Business Media LLC
Date: 10-02-2013
DOI: 10.1038/NG.2554
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/NG.3401
Publisher: Springer Science and Business Media LLC
Date: 23-06-2013
DOI: 10.1038/NG.2676
Publisher: Oxford University Press (OUP)
Date: 2008
Publisher: American Association for Cancer Research (AACR)
Date: 04-2008
DOI: 10.1158/1055-9965.EPI-08-0023
Abstract: Rates of adenocarcinoma of the esophagus (EAC) and esophagogastric junction (EGJAC) have been rising rapidly in recent decades, in contrast to the declining rates of esophageal squamous cell carcinomas (ESCC). Obesity is a major risk factor for both EAC and EGJAC, but not ESCC, and there is speculation that obesity promotes adenocarcinoma development through endocrine and related pathways. We therefore compared the prevalence of 12 single nucleotide polymorphisms (SNPs) in nine candidate genes previously implicated in obesity pathways (LEP, LEPR, ADIPOQ, POMC, PPARα, PPARγ, RXRγ, GHRL, and INSIG2) in a large Australian case-control study comprising DNA s les from 260 EAC cases, 301 EGJAC cases, 213 ESCC cases, and 1,352 population controls. No SNPs were associated with EGJAC or ESCC. Although several SNPs seemed to be associated with EAC on crude analysis [ADIPOQ (rs1501299), LEP (5′-untranslated region), PPARγ (H447H), and GHRL (M72L)], effect sizes were modest and none of the associations was significant after correcting for multiple comparisons. Further, we found no consistent evidence that any of the genotypes were associated with risk of EAC or EGJAC within strata of body mass index (& .0 kg/m2, 25.0-29.9 kg/m2, & kg/m2). In conclusion, our data suggest that these SNPs do not play a major role in esophageal carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008 (4):1007–12)
Publisher: Georg Thieme Verlag KG
Date: 07-1980
Abstract: Pigs were fed alternately tryptophan deficient diet and the same diet supplemented with tryptophan. The deficient diet depressed food intake, caused changes in the pattern of plasma amino acids, increased plasma glucose levels and increased plasma urea levels per unit food intake. Plasma levels of insulin and growth hormone gave no indication that either hormone was involved in the suppression of food intake.
Publisher: Cambridge University Press (CUP)
Date: 12-2015
DOI: 10.1017/THG.2015.87
Abstract: Monozygotic (MZ) twins provide a natural system for investigating developmental plasticity and the potential epigenetic origins of disease. A major difference in the intrauterine environment between MZ pairs is whether they share a common placenta or have separate placentas. Using DNA methylation measured at ,000 points in the genome on the Illumina HumanMethylation450 array, we demonstrate that the co-twins of MZ pairs (average age of 14) that shared a common placenta ( n = 18 pairs) have more similar DNA methylation levels in blood throughout the genome relative to those with separate placentas ( n = 16 pairs). Functional annotation of the genomic regions that show significantly different correlation between monochorionic (MC) and dichorionic (DC) MZ pairs found an over-representation of genes involved in the regulation of transcription, neuronal development, and cellular differentiation. These results support the idea that prenatal environmental exposures may have a lasting effect on an in idual's epigenetic landscape, and the potential for these changes to have functional consequences.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2022
DOI: 10.1038/S41366-022-01202-3
Abstract: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. We pooled in idual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.
Publisher: Wiley
Date: 25-03-2009
Publisher: Springer Science and Business Media LLC
Date: 20-06-2022
DOI: 10.1038/S42003-022-03541-3
Abstract: Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not clear. Using isolated, purified and cultured endometrial cells of mesenchymal origin from 19 women with ( n = 10) and without ( n = 9) endometriosis we analysed the transcriptome of 33,758 in idual cells and compared these to clinical characteristics and in vitro growth profiles. We show purified mesenchymal cell cultures include a mix of mesenchymal stem cells and two endometrial stromal fibroblast subtypes with distinct transcriptomic signatures indicative of varied progression through the differentiation processes. The fibroblast subgroup characterised by incomplete differentiation was predominantly (81%) derived from women with endometriosis and exhibited an altered in vitro growth profile. These results uncover an inherent difference in endometrial cells of women with endometriosis and highlight the relevance of cellular differentiation and its potential to contribute to disease susceptibility.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2012
DOI: 10.1038/EJHG.2012.47
Publisher: Oxford University Press (OUP)
Date: 10-06-2011
DOI: 10.1093/HMG/DDR272
Publisher: Wiley
Date: 2001
DOI: 10.1002/AJMG.1255
Abstract: The tendency to dizygotic (DZ) twinning is inherited in both humans and sheep, and a fecundity gene in sheep (FecB) maps to sheep chromosome 6, syntenic with human 4q21-25. Our aim was to see whether a gene predisposing to human DZ twinning mapped to this region. DNA was collected from 169 pairs and 17 sets of 3 sisters (trios) from Australia and New Zealand who had each had spontaneous DZ twins, mostly before the age of 35, and from a replication s le of 111 families (92 affected sister pairs) from The Netherlands. Exclusion mapping was carried out after typing 26 markers on chromosome 4, of which 8 spanned the region likely to contain the human homologue of the sheep FecB gene. We used nonparametric affected sib pair methods for linkage analysis [ASPEX 2.2, Hinds and Risch, 1999]. Complete exclusion of linkage (lod 1.5) was obtained for all but the p terminus region on chromosome 4. Exclusion in the syntenic region was stronger, down to lambda(s) = 1.3. We concluded that if there is a gene influencing DZ twinning on chromosome 4, its effect must be minor.
Publisher: Massachusetts Medical Society
Date: 10-07-2003
DOI: 10.1056/NEJMOA030050
Publisher: Public Library of Science (PLoS)
Date: 05-08-2010
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1038/JID.2011.322
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.JAAC.2010.10.010
Abstract: Breast-fed C-allele carriers of the rs174575 single nucleotide polymorphism in the fatty acyl desaturase 2 (FADS2) gene have been reported to show a 6.4 to 7 IQ point advantage over formula-fed C-allele carriers, with no effect of breast-feeding in GG carriers. An Australian s le was examined to determine if an interaction between breast-feeding and the rs174575 single nucleotide polymorphism had any effect on IQ. This hypothesis was tested in more than 700 families of adolescent twins assessed for IQ and breast-feeding, birth weight, and FADS2 polymorphisms, and parental socioeconomic status and education, and maternal FADS2 status. No significant evidence for a moderating effect on IQ of rs174575 C-carrier status and breast-feeding was found, and there no effects of maternal FADS2 status on offspring IQ. In addition, no main effects of any FADS2 polymorphisms on IQ were found when the genotype was kept as two-homozygote and one-heterozygote categories and indeed no evidence for effects of breast-feeding on IQ scores after controlling for parental socioeconomic status and education. The investigation was extended to two additional FADS2 polymorphisms (rs1535 and rs174583), but again, although these polymorphisms code alleles affecting fatty acid metabolism, no main or interaction effects were found on IQ. These results support the view that apparent effects of breast-feeding on IQ reflect differential likelihood of breast-feeding as a function of parental education and did not support the predicted interaction effect of FADS2 and breast-feeding on IQ.
Publisher: Society for Neuroscience
Date: 20-06-2012
Publisher: Springer Science and Business Media LLC
Date: 06-11-2015
DOI: 10.1038/NCOMMS9804
Abstract: Eczema often precedes the development of asthma in a disease course called the ‘atopic march’. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27 P= 2.1 × 10 −8 ) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58 P= 5.3 × 10 −9 ). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
Publisher: Oxford University Press (OUP)
Date: 16-04-2015
Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 02-2020
Publisher: Research Square Platform LLC
Date: 21-06-2021
DOI: 10.21203/RS.3.RS-596345/V1
Abstract: Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not clear. Using isolated, purified and cultured endometrial cells of mesenchymal origin from 19 women with (n = 10) and without (n = 9) endometriosis we analysed the transcriptome of 33,758 in idual cells and compared these to clinical characteristics and in vitro growth profiles. We show purified mesenchymal cell cultures include a mix of mesenchymal stem cells and two endometrial stromal fibroblast subtypes with distinct transcriptomic signatures indicative of varied progression through the differentiation processes. The fibroblast subgroup characterised by incomplete differentiation was predominantly (81%) derived from women with endometriosis and exhibited an altered in vitro growth profile. These results uncover an inherent difference in endometrial cells of women with endometriosis and highlight the relevance of cellular differentiation and its potential to contribute to disease susceptibility.
Publisher: Oxford University Press (OUP)
Date: 28-11-2012
DOI: 10.1093/HMG/DDS491
Publisher: Elsevier BV
Date: 2016
Publisher: Springer Science and Business Media LLC
Date: 04-09-2009
DOI: 10.1007/S00125-009-1510-9
Abstract: There has been much focus on the potential role of mitochondria in the aetiology of type 2 diabetes and the metabolic syndrome, and many case-control mitochondrial association studies have been undertaken for these conditions. We tested for a potential association between common mitochondrial variants and a number of quantitative traits related to type 2 diabetes in a large s le of >2,000 healthy Australian adolescent twins and their siblings, many of whom were measured on more than one occasion. To the best of our knowledge, this is the first mitochondrial association study of quantitative traits undertaken using family data. The maternal inheritance pattern of mitochondria means established association methodologies are unsuitable for analysis of mitochondrial data in families. We present a methodology, implemented in the freely available program Sib-Pair for performing such an analysis. Despite our study having the power to detect variants with modest effects on these phenotypes, only one significant association was found after correction for multiple testing in any of four age groups. This was for mt14365 with triacylglycerol levels (unadjusted p = 0.0006). This association was not replicated in other age groups. We find little evidence in our s le to suggest that common European mitochondrial variants contribute to variation in quantitative phenotypes related to diabetes. Only one variant showed a significant association in our s le, and this association will need to be replicated in a larger cohort. Such replication studies or future meta-analyses may reveal more subtle effects that could not be detected here because of limitations of s le size.
Publisher: Oxford University Press (OUP)
Date: 27-02-2013
DOI: 10.1093/HMG/DDT104
Publisher: Environmental Health Perspectives
Date: 08-2007
DOI: 10.1289/EHP.8847
Publisher: Public Library of Science (PLoS)
Date: 16-05-2008
Publisher: Wiley
Date: 03-02-2010
DOI: 10.1111/J.1398-9995.2009.02135.X
Abstract: It is largely unknown whether epigenetic modifications of key genes may contribute to the reported maternal effects in atopy. The aim of this study was to characterize the methylation patterns of the membrane-spanning 4-domains, subfamily A, member 2 gene (MS4A2) (beta-chain of the IgE high-affinity receptor), a key gene in the allergic cascade. Mass spectrometry and bisulphite sequencing were used to measure the methylation of two potential substrates for epigenetic regulation of MS4A2, namely a predicted promoter and a CpG-rich AluSp repeat. Methylation was measured in DNA extracted from peripheral blood lymphocytes of 38 atopic cases and 37 controls. Cases were positive for atopy, asthma, bronchial hyper-responsiveness and had high IgE levels. Both parents of eight atopic cases were also tested. The AluSp element was highly methylated across all in iduals (mean 0.92, range 0.87-0.94), a pattern inconsistent with classical imprinting. Variation in methylation at this locus was not associated with age, sex, daily steroid use or atopic status, and there were no differences in methylation between mothers and fathers of atopic cases. Bisulphite sequencing analysis of the promoter region showed that it was also not imprinted, and there was no evidence for allele-specific methylation, but we were unable to test for association with atopy status. Methylation levels at the AluSp repeat analysed in MS4A2 were inconsistent with classical imprinting mechanisms and did not associate with atopy status. The promoter region was less methylated but further analysis of this region in larger cohorts is warranted to investigate its role in allergic disease.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Springer Science and Business Media LLC
Date: 14-06-2011
DOI: 10.1038/MP.2011.68
Publisher: Public Library of Science (PLoS)
Date: 06-05-2010
Publisher: Wiley
Date: 20-06-2013
DOI: 10.1111/GBB.12053
Publisher: Elsevier BV
Date: 02-2015
Publisher: Elsevier BV
Date: 10-2012
Publisher: Cambridge University Press (CUP)
Date: 27-05-2015
DOI: 10.1017/THG.2015.29
Abstract: For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m 2 ) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for in idual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin in iduals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
Publisher: Oxford University Press (OUP)
Date: 30-06-2014
Publisher: Springer Science and Business Media LLC
Date: 13-12-2007
DOI: 10.1007/S00439-006-0279-X
Abstract: Traditionally twins are classified as dizygous or fraternal and monozygous or identical (Hall Twinning, 362, 2003 and 735-743). We report a rare case of 46,XX/46,XY twins: Twin A presented with ambiguous genitalia and Twin B was a phenotypically normal male. These twins demonstrate a third, previously unreported mechanism for twinning. The twins underwent initial investigation with 17-hydroxyprogesterone and testosterone levels, pelvic ultrasound and diagnostic laparoscopy. Cytogenetic analysis was performed on peripheral blood cells and skin fibroblasts. Histological examination and Fluorescence in situ hybridization studies on touch imprints were performed on gonadal biopsies. DNA analysis using more than 6,000 DNA markers was performed on skin fibroblast s les from the twins and on peripheral blood s les from both parents. Twin A was determined to be a true hermaphrodite and Twin B an apparently normal male. Both twins had a 46,XX/46,XY chromosome complement in peripheral lymphocytes, skin fibroblasts, and gonadal biopsies. The proportion of XX to XY cells varied between the twins and the tissues evaluated. Most significantly the twins shared 100% of maternal alleles and approximately 50% of paternal alleles in DNA analysis of skin fibroblasts. The twins are chimeric and share a single genetic contribution from their mother but have two genetic contributions from their father thus supporting the existence of a third, previously unreported type of twinning.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
Publisher: Wiley
Date: 24-05-2012
DOI: 10.1002/AJMG.B.32072
Publisher: Springer Science and Business Media LLC
Date: 11-06-2013
DOI: 10.1038/TP.2013.45
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1038/NATURE14101
Publisher: Oxford University Press (OUP)
Date: 16-11-2008
Abstract: The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. Twins are relatively common and occur on average 13 times per 1000 maternities, though the twinning frequency varies over time and geographic location. This variation is mostly attributed to the differences in DZ twinning rate, since the monozygotic twinning rate is relatively constant. DZ twinning is in part under genetic control, with mothers of DZ twins reporting significantly more female family members with DZ twins than mothers of monozygotic twins. Maternal factors such as genetic history, advanced age and increased parity are known to increase the risk of DZ twins. Recent research confirmed that taller mothers and mothers with a high body mass index (30>) are at greater risk of DZ twinning. Seasonality, smoking, oral contraceptive use and folic acid show less convincing associations with twinning. Genetic analysis is beginning to identify genes contributing to the variation in twinning. Mutations in one of these genes (growth differentiation factor 9) are significantly more frequent in mothers of DZ twins. However, the mutations are rare and only account for a small part of the genetic contribution for twinning.
Publisher: The Endocrine Society
Date: 10-2008
DOI: 10.1210/JC.2007-2568
Abstract: Context: Age at menarche (AAM) is an important trait both biologically and socially, a clearly defined event in female pubertal development, and has been associated with many clinically significant phenotypes. Objective: The objective of the study was to identify genetic loci influencing variation in AAM in large population-based s les from three countries. Design/Participants: Recalled AAM data were collected from 13,697 in iduals and 4,899 pseudoindependent sister-pairs from three different populations (Australia, The Netherlands, and the United Kingdom) by mailed questionnaire or interview. Genome-wide variance components linkage analysis was implemented on each s le in idually and in combination. Results: The mean, sd, and heritability of AAM across the three s les was 13.1 yr, 1.5 yr, and 0.69, respectively. No loci were detected that reached genome-wide significance in the combined analysis, but a suggestive locus was detected on chromosome 12 (logarithm of the odds = 2.0). Three loci of suggestive significance were seen in the U.K. s le on chromosomes 1, 4, and 18 (logarithm of the odds = 2.4, 2.2 and 3.2, respectively). Conclusions: There was no evidence for common highly penetrant variants influencing AAM. Linkage and association suggest that one trait locus for AAM is located on chromosome 12, but further studies are required to replicate these results.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2013
DOI: 10.1038/NG.2506
Publisher: Wiley
Date: 11-2013
DOI: 10.1002/GEPI.21760
Publisher: Wiley
Date: 12-1999
DOI: 10.1046/J.1365-2052.1999.00548.X
Abstract: Microsatellite variation was analyzed in five Chinese indigenous goat breeds, which include four Cashmere breeds (Tibetan, Neimonggol, Liaoning, Taihang) and one Hubei local breed (Matou) used for meat production. Five ovine and one bovine microsatellites, selected from eight ovine microsatellites and five bovine microsatellites were suitable for use in this study. With these six microsatellites, allele frequencies, heterozygosity, polymorphism information content (PIC) and effective allele number were calculated. A neighbor-joining tree was constructed using Nei's standard genetic distance (1978). In the tree, Neimonggol and Liaoning were grouped together, then with Taihang while Tibetan and Matou in idually had their own branch. The genetic relationship of five breeds corresponds to their history and geographic origins.
Publisher: Elsevier BV
Date: 11-2008
Publisher: Oxford University Press (OUP)
Date: 08-07-2008
Publisher: Cold Spring Harbor Laboratory
Date: 07-03-2019
DOI: 10.1101/570614
Abstract: A variety of experimental and computational methods have been developed to demultiplex s les from pooled in iduals in a single-cell RNA sequencing (scRNA-Seq) experiment which either require adding information (such as hashtag barcodes) or measuring information (such as genotypes) prior to pooling. We introduce scSplit which utilises genetic differences inferred from scRNA-Seq data alone to demultiplex pooled s les. scSplit also extracts a minimal set of high confidence presence/absence genotypes in each cluster which can be used to map clusters to original s les. Using a range of simulated, merged in idual-s le as well as pooled multi-in idual scRNA-Seq datasets, we show that scSplit is highly accurate and concordant with demuxlet predictions. Furthermore, scSplit predictions are highly consistent with the known truth in cell-hashing dataset. We also show that multiplexed-scRNA-Seq can be used to reduce batch effects caused by technical biases. scSplit is ideally suited to s les for which external genome-wide genotype data cannot be obtained (for ex le non-model organisms), or for which it is impossible to obtain unmixed s les directly, such as mixtures of genetically distinct tumour cells, or mixed infections. scSplit is available at: on-xu/scSplit
Publisher: Springer Science and Business Media LLC
Date: 16-08-2023
DOI: 10.1038/S42003-023-05070-Z
Abstract: Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial s les from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis -mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.OPHTHA.2007.08.013
Abstract: To estimate heritability and locate quantitative trait loci influencing axial length. Classic twin study of monozygotic and dizygotic twins reared together. Eight hundred ninety-three in iduals from 460 families were recruited through the Twin Eye Study in Tasmania and the Brisbane Adolescent Twin Study (BATS) and had ocular axial length measured. Structural equation modeling on the entire s le was used to estimate genetic and environmental components of variation in axial length. Analysis of existing microsatellite marker genomewide linkage scan data was performed on 318 in iduals from 142 BATS families. Ocular axial length. The heritability estimate for axial length, adjusted for age and sex, in the full s le was 0.81. The highest multipoint logarithm of the odds (LOD) score observed was 3.40 (genomewide P = 0.0004), on chromosome 5q (at 98 centimorgans [cM]). Additional regions with suggestive multipoint LOD scores were also identified on chromosome 6 (LOD scores, 2.13 at 76 cM and 2.05 at 83 cM), chromosome 10 (LOD score, 2.03 at 131 cM), and chromosome 14 (LOD score, 2.84 at 97 cM). Axial length, a major endophenotype for refractive error, is highly heritable and is likely to be influenced by one or more genes on the long arm of chromosome 5.
Publisher: Wiley
Date: 18-03-2004
DOI: 10.1002/MRD.20049
Abstract: Sperm surface protein PH-20 expression was studied during spermatogenesis in pubertal and adult sheep, using molecular and histological methods. The effects of 24 hr of insulation raising scrotal temperatures to 39 degrees C on PH-20 expression in ejaculated sheep sperm were also determined. A 282 nt cDNA fragment of ovine PH-20 was identified in total RNA extracts of sheep testes, which exhibited 76% identity at the nucleotide level with the equivalent region of the human sequence. Ovine PH-20 mRNA and immunoreactivity were identified only in adult ram testis and not in peri-pubertal ram testis tubules lacking round spermatids, nor in adult sheep brain, pituitary, heart, spleen, lung, liver, kidney, epididymis, or ovary. Ovine PH-20 protein was distributed predominantly on the postacrosomal membrane and was also present on the anterior membrane of the sperm head in fresh, unheated sheep semen. Scrotal heating caused a significant, transient decrease in the percentage of PH-20 immunoreactive sperm, but did not change the pattern of PH-20 staining on the sperm head. The results strongly suggest that ovine PH-20 is postmeiotically expressed in haploid germ cells in sheep testis and is arrayed on the membrane of the mature ovine spermatozoon. Scrotal heating appears to have few effects on PH-20 expression and distribution on ejaculated sperm.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2018
DOI: 10.1038/S41467-018-04558-1
Abstract: Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis -expression or -DNA methylation (DNAm) quantitative trait loci ( cis -eQTLs or cis -mQTLs) between brain and blood ( r b ). Using publicly available data, we find that genetic effects at the top cis -eQTLs or mQTLs are highly correlated between independent brain and blood s les ( $$\\hat r_b = 0.70$$ r ^ b = 0.70 for cis -eQTLs and $$\\hat r_ b = 0.78$$ r ^ b = 0.78 for cis -mQTLs). Using meta-analyzed brain cis -eQTL/mQTL data ( n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger s le sizes ( n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis -eQTL/mQTL data with large s le sizes.
Publisher: Wiley
Date: 19-11-2012
DOI: 10.1002/IJC.26440
Abstract: Oncogenic PIK3CA mutations contribute to colorectal tumorigenesis by activating AKT signaling to decrease apoptosis and increase tumor invasion. A synergistic association of PIK3CA mutation with KRAS mutation has been suggested to increase AKT signaling and resistance to antiepidermal growth factor receptor inhibitor therapy for advanced colorectal cancer, although studies have been conflicting. We sought to clarify this by examining PIK3CA mutation frequency in relation to other key molecular features of defined pathways of tumorigenesis. PIK3CA mutation was assessed by high resolution melt analysis in 829 colorectal cancer s les and 426 colorectal polyps. Mutations were independently correlated with clinicopathological features including patient age, sex and tumor location as well as molecular features including microsatellite instability, KRAS and BRAF mutation, MGMT methylation and the CpG Island Methylator Phenotype (CIMP). Mutation of the helical (Exon 9) and catalytic (Exon 20) domain mutation hotspots were also examined independently. Overall, PIK3CA mutation was positively correlated with KRAS mutation (p < 0.001), MGMT methylation (p = 0.007) and CIMP (p < 0.001). Novel, exon-specific associations linked Exon 9 mutations to a subgroup of cancers characterized by KRAS mutation, MGMT methylation and CIMP-Low, whilst Exon 20 mutations were more closely linked to features of serrated pathway tumors including BRAF mutation, microsatellite instability and CIMP-High or Low. PIK3CA mutations were uncommonly, but exclusively, seen in tubulovillous adenomas (4/124, 3.2%) and 1/4 (25.0%) tubulovillous adenomas with a focus of cancer. These data provide insight into the molecular events driving traditional versus serrated pathway tumorigenesis.
Publisher: Springer Science and Business Media LLC
Date: 07-2000
DOI: 10.1038/77033
Abstract: Multiple ovulations are uncommon in humans, cattle and many breeds of sheep. Pituitary gonadotrophins and as yet unidentified ovarian factors precisely regulate follicular development so that, normally, only one follicle is selected to ovulate. The Inverdale (FecXI) sheep, however, carries a naturally occurring X-linked mutation that causes increased ovulation rate and twin and triplet births in heterozygotes (FecXI/FecX+ ref. 1), but primary ovarian failure in homozygotes (FecXI/FecXI ref. 2). Germ-cell development, formation of the follicle and the earliest stages of follicular growth are normal in FecXI/FecXI sheep, but follicular development beyond the primary stage is impaired. A second family unrelated to the Inverdale sheep also has the same X-linked phenotype (Hanna, FecXH). Crossing FecXI with FecXH animals produces FecXI/FecXH infertile females phenotypically indistinguishable from FecXI/FecXI females. We report here that the FecXI locus maps to an orthologous chromosomal region syntenic to human Xp11.2-11.4, which contains BMP15, encoding bone morphogenetic protein 15 (also known as growth differentiation factor 9B (GDF9B)). Whereas BMP15 is a member of the transforming growth factor beta (TGFbeta) superfamily and is specifically expressed in oocytes, its function is unknown. We show that independent germline point mutations exist in FecXI and FecXH carriers. These findings establish that BMP15 is essential for female fertility and that natural mutations in an ovary-derived factor can cause both increased ovulation rate and infertility phenotypes in a dosage-sensitive manner.
Publisher: Oxford University Press (OUP)
Date: 17-10-2020
DOI: 10.1093/HMG/DDAA222
Abstract: Germline genetic variants have been identified, which predispose in iduals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 in iduals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated in iduals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 in iduals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P & 5 × 10−8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2010
DOI: 10.1038/MP.2010.128
Publisher: Springer Science and Business Media LLC
Date: 28-09-2021
DOI: 10.1038/S41467-021-25583-7
Abstract: Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2013
DOI: 10.1038/NG.2756
Publisher: Wiley
Date: 08-2000
Publisher: Wiley
Date: 22-11-2010
DOI: 10.1002/GEPI.20541
Publisher: Oxford University Press (OUP)
Date: 03-2012
Publisher: Oxford University Press (OUP)
Date: 02-08-2008
DOI: 10.1093/HMG/DDN227
Publisher: Cambridge University Press (CUP)
Date: 03-12-2015
DOI: 10.1017/THG.2014.70
Abstract: Cytokines and vitamin D both have a role in modulating the immune system, and are also potentially useful biomarkers in mental illnesses such as major depressive disorder (MDD) and schizophrenia. Studying the variability of cytokines and vitamin D in a healthy population s le may add to understanding the association between these biomarkers and mental illness. To assess genetic and environmental contributions to variation in circulating levels of cytokines and vitamin D (25-hydroxy vitamin D: 25(OH)D3), we analyzed data from a healthy adolescent twin cohort (mean age 16.2 years standard deviation 0.25). Plasma cytokine measures were available for 400 in iduals (85 MZ, 115 DZ pairs), dried blood spot s le vitamin D measures were available for 378 in iduals (70 MZ, 118 DZ pairs). Heritability estimates were moderate but significant for the cytokines transforming growth factor-β1 (TGF-β1), 0.57 (95% CI 0.26–0.80) and tumor necrosis factor-receptor type 1 (TNFR1), 0.50 (95% CI 0.11–0.63) respectively. Measures of 25(OH)D3 were within normal range and heritability was estimated to be high (0.86, 95% CI 0.61–0.94). Assays of other cytokines did not generate meaningful results. These potential biomarkers may be useful in mental illness, with further research warranted in larger s le sizes. They may be particularly important in adolescents with mental illness where diagnostic uncertainty poses a significant clinical challenge.
Publisher: Oxford University Press (OUP)
Date: 19-08-2009
Publisher: Wiley
Date: 12-05-2014
DOI: 10.1111/PCMR.12253
Publisher: Cambridge University Press (CUP)
Date: 05-12-2014
DOI: 10.1017/THG.2014.74
Abstract: Breastfeeding has been an important survival trait during human history, though it has long been recognized that in iduals differ in their exact breastfeeding behavior. Here our aims were, first, to explore to what extent genetic and environmental influences contributed to the in idual differences in breastfeeding behavior second, to detect possible genetic variants related to breastfeeding and lastly, to test if the genetic variants associated with breastfeeding have been previously found to be related with breast size. Data were collected from a large community-based cohort of Australian twins, with 3,364 women participating in the twin modelling analyses and 1,521 of them included in the genome-wide association study (GWAS). Monozygotic (MZ) twin correlations ( r MZ = 0.52, 95% CI 0.46–0.57) were larger than dizygotic (DZ) twin correlations ( r DZ = 0.35, 95% CI 0.25–0.43) and the best-fitting model was the one composed by additive genetics and unique environmental factors, explaining 53% and 47% of the variance in breastfeeding behavior, respectively. No breastfeeding-related genetic variants reached genome-wide significance. The polygenic risk score analyses showed no significant results, suggesting breast size does not influence breastfeeding. This study confers a replication of a previous one exploring the sources of variance of breastfeeding and, to our knowledge, is the first one to conduct a GWAS on breastfeeding and look at the overlap with variants for breast size.
Publisher: Proceedings of the National Academy of Sciences
Date: 07-02-2013
Abstract: Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subs le. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.
Publisher: Springer Science and Business Media LLC
Date: 05-12-2012
Publisher: Cambridge University Press (CUP)
Date: 09-03-2016
DOI: 10.1017/THG.2016.11
Abstract: We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Oxford University Press (OUP)
Date: 18-04-2008
Publisher: Bentham Science Publishers Ltd.
Date: 25-09-2008
Publisher: Elsevier BV
Date: 11-1997
DOI: 10.1016/S0739-7240(98)00043-5
Abstract: The effects of natural variation in the number of copies of the growth hormone (GH) gene on growth parameters, plasma GH profiles, and the response to GHRH challenge were compared in Coopworth ram lambs from selection lines differing in body composition and GH levels. Different genotypes at the GH locus carried two, three, or four copies of the GH gene and GH secretion was studied under ad libitum feeding conditions and in the fasted state. There were no significant effects of GH genotype on any parameters of growth or body composition. Basal serum GH concentration, GH pulse frequency, and GH pulse litude differed significantly with selection line and fasting, but did not differ significantly between the GH genotypes. Significant differences of subtle nature were found between the GH genotypes in their responsiveness to GHRH. For the ad libitum-fed Lean selection line animals, the first GHRH challenge resulted in a higher mean maximum response for GH1/GH1 than GH2/GH2 (P < 0.05). Between the first and the second challenges there was a decrease in maximum response for the GH1/GH1 genotype and an increase for the GH2/GH2 genotype (P < 0.05 for GH genotype main effect). The differences between GH genotypes in response to GHRH challenge suggest that polymorphism in the number of GH gene copies in sheep may have physiological implications for the function of the GH axis, which may be manifested in growing lambs only under specific genotype-environment combinations.
Publisher: American Medical Association (AMA)
Date: 07-2012
Publisher: Elsevier BV
Date: 07-1994
Abstract: The Booroola (FecB) mutation in sheep is linked to markers from a region of syntenic homology to human chromosome HSA4q, but the chromosomal location in sheep has not been determined. Analysis of linkage in Booroola half-sib pedigrees and 17 full-sib families identified genetic linkage between platelet-derived growth factor receptor-alpha (PDGFRA) and alpha s1-casein (CSN1S1) at 12 cM (Zmax = 9.14) and between PDGFRA and the microsatellite markers BM143 and OarHH55 (Zmax = 6.28 and 3.83, respectively). The microsatellite markers OarAE101 and BM143 and genes from the linkage group (PDGFRA, SPP1, and EGF) were mapped in a partial sheep x hamster somatic cell hybrid panel. All markers identified bands specific to somatic cell hybrids containing the sheep chromosome t1 (rob6 ) or t1q (chromosome 6). In sheep the casein genes alpha s1 (CSN1S1), alpha s2 (CSN1S2), beta (CSN2), and kappa (CSN3) are tightly linked, and CSN2 has been mapped to sheep chromosome 6q23-q31. We conclude that the Booroola mutation is located within a conserved syntenic group that maps to sheep chromosome 6.
Publisher: Oxford University Press (OUP)
Date: 28-06-2007
Abstract: Tumour necrosis factor (TNF) is a pleiotropic cytokine with a wide range of immunoregulatory effects. Variation in the promoter region of TNF and the neighbouring lymphotoxin alpha (LTA) gene might be associated with endometriosis. We examined the association between endometriosis and common single-nucleotide polymorphisms (SNPs) or haplotypes in the TNF/LTA region in an Australian s le by analysing 26 SNPs in 958 endometriosis cases and 959 unrelated controls. We selected functional SNPs in the coding and the promoter region of the TNF gene and HapMap tagging SNPs and typed them on a Sequenom MassARRAY platform. A key SNP (rs1800630) in the promoter region typed in previous studies did not give reliable results. Therefore, we also examined a statistically identical (r(2) = 1) SNP (siSNP) (rs2844482), identified using the web based program ssSNPer. Genotype completion rate was 99.5% for SNPs spanning a region of 15.5 kb across the TNF/LTA locus. There was no evidence for association between endometriosis and TNF/LTA SNPs or SNP haplotypes in our case-control study. Our data suggest both TNF and LTA genes are not major susceptibility genes for endometriosis.
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: Springer Science and Business Media LLC
Date: 16-01-2008
Abstract: Most information in linkage analysis for quantitative traits comes from pairs of relatives that are phenotypically most discordant or concordant. Confounding this, within-family outliers from non-genetic causes may create false positives and negatives. We investigated the influence of within-family outliers empirically, using one of the largest genome-wide linkage scans for height. The subjects were drawn from Australian twin cohorts consisting of 8447 in iduals in 2861 families, providing a total of 5815 possible pairs of siblings in sibships. A variance component linkage analysis was performed, either including or excluding the within-family outliers. Using the entire dataset, the largest LOD scores were on chromosome 15q (LOD 2.3) and 11q (1.5). Excluding within-family outliers increased the LOD score for most regions, but the LOD score on chromosome 15 decreased from 2.3 to 1.2, suggesting that the outliers may create false negatives and false positives, although rare alleles of large effect may also be an explanation. Several regions suggestive of linkage to height were found after removing the outliers, including 1q23.1 (2.0), 3q22.1 (1.9) and 5q32 (2.3). We conclude that the investigation of the effect of within-family outliers, which is usually neglected, should be a standard quality control measure in linkage analysis for complex traits and may reduce the noise for the search of common variants of modest effect size as well as help identify rare variants of large effect and clinical significance. We suggest that the effect of within-family outliers deserves further investigation via theoretical and simulation studies.
Publisher: Wiley
Date: 21-05-2012
Publisher: Wiley
Date: 07-11-2012
DOI: 10.1111/ACER.12015
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2500
Publisher: Oxford University Press (OUP)
Date: 26-08-2005
Abstract: The progesterone receptor (PR) is a candidate gene for the development of endometriosis, a complex disease with strong hormonal features, common in women of reproductive age. We typed the 306 base pair Alu insertion (AluIns) polymorphism in intron G of PR in 101 in iduals, estimated linkage disequilibrium (LD) between five single-nucleotide polymorphisms (SNPs) across the PR locus in 980 Australian triads (endometriosis case and two parents) and used transmission disequilibrium testing (TDT) for association with endometriosis. The five SNPs showed strong pairwise LD, and the AluIns was highly correlated with proximal SNPs rs1042839 (delta2 = 0.877, D9 = 1.00, P < 0.0001) and rs500760 (delta2 = 0.438, D9 = 0.942, P < 0.0001). TDT showed weak evidence of allelic association between endometriosis and rs500760 (P = 0.027) but not in the expected direction. We identified a common susceptibility haplotype GGGCA across the five SNPs (P = 0.0167) in the whole s le, but likelihood ratio testing of haplotype transmission and non-transmission of the AluIns and flanking SNPs showed no significant pattern. Further, analysis of our results pooled with those from two previous studies suggested that neither the T2 allele of the AluIns nor the T1/T2 genotype was associated with endometriosis.
Publisher: Public Library of Science (PLoS)
Date: 13-05-2010
Publisher: Wiley
Date: 08-12-2009
Publisher: S. Karger AG
Date: 1994
DOI: 10.1159/000133705
Abstract: Restriction fragment length polymorphisms (RFLPs) demonstrating X-linked inheritance have been identified for proteolipid protein (PLP) and thyroxine-binding globulin (TBG) in sheep. Genetic linkage between ovine PLP and TBG was examined in a three-generation flock containing 122 in iduals. Significant linkage between the loci was observed with a combined lod score of 7.48 at a recombination fraction of 5 cM.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: Oxford University Press (OUP)
Date: 13-12-2015
DOI: 10.1093/JNCI/DJU408
Publisher: Springer Science and Business Media LLC
Date: 26-02-2014
DOI: 10.1038/NATURE13005
Publisher: Cambridge University Press (CUP)
Date: 12-01-2015
DOI: 10.1017/THG.2014.85
Abstract: Monozygotic (MZ) twins form an important system for the study of biological plasticity in humans. While MZ twins are generally considered to be genetically identical, a number of studies have emerged that have demonstrated copy-number differences within a twin pair, particularly in those discordant for disease. The rate of autosomal copy-number variation (CNV) discordance within MZ twin pairs was investigated using a population s le of 376 twin pairs genotyped on Illumina Human610-Quad arrays. After CNV calling using both QuantiSNP and PennCNV followed by manual annotation, only a single CNV difference was observed within the MZ twin pairs, being a 130 KB duplication of chromosome 5. Five other potential discordant CNV were called by the software, but excluded based on manual annotation of the regions. It is concluded that large CNV discordance is rare within MZ twin pairs, indicating that any CNV difference found within phenotypically discordant MZ twin pairs has a high probability of containing the causal gene(s) involved.
Publisher: Cambridge University Press (CUP)
Date: 04-09-2015
DOI: 10.1017/THG.2015.57
Abstract: A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m 2 in childhood and adolescence and up to 0.2 kg/m 2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
Publisher: Elsevier BV
Date: 06-1978
Publisher: Public Library of Science (PLoS)
Date: 09-06-2011
Publisher: American Medical Association (AMA)
Date: 08-2012
Publisher: Oxford University Press (OUP)
Date: 04-04-2013
DOI: 10.1093/AJE/KWS473
Publisher: Springer Science and Business Media LLC
Date: 09-12-2010
DOI: 10.1038/HDY.2009.175
Abstract: The Norfolk Island population in the South Pacific is primarily the product of recent admixture between a small number of British male and Polynesian female founders. We identified and genotyped 128 Ancestry Informative Markers (AIMs) spread across the autosomes, X/Y chromosomes and mitochondrial DNA genome, to explore and quantify the current levels of genetic admixture in the Norfolk Islanders. On the basis of autosomal AIMs, the population shows mean European and Polynesian ancestry proportions of 88 and 12%, respectively. However, there is a substantial variation between in iduals ranging from total European ancestry to near total Polynesian origin. There is a strong correlation between in idual genetic estimates of Polynesian ancestry and those derived from the extensive pedigree and genealogical records of Islanders. Also in line with historical accounts, there is a substantial asymmetry in the maternal and paternal origins of the Islanders with almost all Y-chromosomes of European origin whereas at least 25% of mtDNAs appear to have a Polynesian origin. Accurate knowledge of ancestry will be important in future attempts to use the Island population in admixture mapping approaches to find the genes that underlie differences in the risk to some diseases between Europeans and Polynesians.
Publisher: Oxford University Press (OUP)
Date: 23-02-2012
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1038/JID.2008.147
Abstract: Genetic studies of pigmentation have benefited from spectrophotometric measures of light-dark hair color. Here we use one of those measures, absorbance at 650 nm, to look for chromosomal regions that harbor genes affecting hair pigmentation. At 7p15.1, marker D7S1808 was suggestive of linkage to light-dark hair color (LOD approximately 2.99). Marker D1S235 at 1q42.3 was suggestive of linkage to hair color (light-dark or blonde-black continuum) (LOD approximately 2.14). However, the most consistent linkage peak was over the gene oculocutaneous albinism type II (OCA2) on chromosome 15. Linkage analysis of both spectrophotometrically quantified and ordered ratings of hair color had LOD scores about 1.2, significant because of the almost perfect concordance. A quantitative transmission disequilibrium test between light-dark hair color and 58 single nucleotide polymorphisms in OCA2 showed that the SNPs rs4778138 (also called rs11855019) and rs1375164 were associated with significantly darker hair color (P approximately 3 x 10(-4) and P approximately 0.03 after correction for multiple testing, respectively). These two SNPs explain 1.54 and 0.85% of variation in the A650t index, respectively.
Publisher: Springer Science and Business Media LLC
Date: 05-1996
Abstract: The genetic linkage map of sheep Chromosome (Chr) 6 has been extended to include 35 loci with the addition of 11 RFLP and 12 microsatellite loci. The sex-averaged linkage map now spans 154 cM from phosphodiesterase cyclic GMP beta polypeptide (PDE6B) to OarCP125, an anonymous sheep microsatellite. The male and female map lengths, at 180 cM and 132 cM respectively, did not differ significantly. The physical assignment of PDE6B to Chr 6q33-qter orientates the linkage map on sheep Chr 6 with PDE6B near the telomere and OarCP125 towards the centromere. The order and genetic distances between loci are similar for the sheep Chr 6 and cattle Chr 6 maps, except for the position of the casein genes. The sheep Chr 6 linkage map is also comparable to portions of human Chr 4, mouse Chrs 5 and 3, and pig Chr 8. The synteny between sheep Chr 6 and human Chr 4 has been extended from PDE6B (4p16.3) to epidermal growth factor (EGF, 4q25-q27). However, a region from platelet-derived growth factor receptor alpha polypeptide (PDGFRA) to bone morphogenetic protein 3 (BMP3), which spans 19 cM on sheep Chr 6, appears to be inverted with respect to the human and mouse loci. Other differences in the gene order between sheep, pig, and mouse suggest more complex rearrangements.
Publisher: Elsevier BV
Date: 11-2013
Publisher: Springer Science and Business Media LLC
Date: 03-01-2019
DOI: 10.1038/S41467-018-07867-7
Abstract: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 in iduals of erse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
Publisher: Oxford University Press (OUP)
Date: 10-11-2011
DOI: 10.1093/HMG/DDR523
Publisher: Springer Science and Business Media LLC
Date: 25-11-2020
DOI: 10.1038/S41467-020-19742-5
Abstract: Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10 −8 , odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10 −8 , OR = 1.7 rs143445068, MAF = 0.8%, P = 5.2 × 10 −9 , OR = 3.4 rs183453668, MAF = 0.5%, P = 2.8 × 10 −8 , OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
Publisher: Public Library of Science (PLoS)
Date: 18-04-2012
Publisher: Springer Science and Business Media LLC
Date: 14-04-2013
DOI: 10.1038/NG.2610
Publisher: Proceedings of the National Academy of Sciences
Date: 09-01-2012
Abstract: Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein that transports iron throughout the body, in the blood and brain. Here, we discovered that transferrin levels are related to detectable differences in the macro- and microstructure of the living brain. We collected brain MRI scans from 615 healthy young adult twins and siblings, of whom 574 were also scanned with diffusion tensor imaging at 4 Tesla. Fiber integrity was assessed by using the diffusion tensor imaging-based measure of fractional anisotropy. In bivariate genetic models based on monozygotic and dizygotic twins, we discovered that partially overlapping additive genetic factors influenced transferrin levels and brain microstructure. We also examined common variants in genes associated with transferrin levels, TF and HFE , and found that a commonly carried polymorphism (H63D at rs1799945) in the hemochromatotic HFE gene was associated with white matter fiber integrity. This gene has a well documented association with iron overload. Our statistical maps reveal previously unknown influences of the same gene on brain microstructure and transferrin levels. This discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment, and neurodegeneration.
Publisher: Wiley
Date: 29-01-2009
DOI: 10.1002/AJMG.B.30924
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.FERTNSTERT.2008.10.012
Abstract: To examine differences in body composition and smoking between mothers of spontaneous monozygotic and dizygotic twins, while taking into account maternal age, gravidity, and educational attainment. Retrospective cohort study. The Netherlands Twin Register. Mothers of twins (n = 19,357) registered with the Netherlands Twin Register. Data were selected from mothers of spontaneous monozygotic twins (MZ n = 5663) and mothers of spontaneous dizygotic twins (DZ n = 8515). None. The odds of having spontaneous DZ twins versus spontaneous MZ twins as a function of height, body mass index (BMI), and smoking before pregnancy, after accounting for age, gravidity, and educational attainment. Compared with spontaneous MZ twinning, spontaneous DZ twinning is significantly associated with increasing height (odds ratio, 1.6 95% confidence interval [CI], 1.5-1.8 for the tallest versus the shortest height quartile), an increased BMI (odds ratio, 1.3 95% CI, 1.1-1.4 for overweight vs. normal weight), and smoking before the twin pregnancy (odds ratio, 1.4 95% CI, 1.3-1.5 for smoker vs. nonsmoker). Maternal age and gravidity, but not educational attainment, had to be included in the model. Spontaneous dizygotic twinning is associated with body composition and smoking.
Publisher: CSIRO Publishing
Date: 2020
DOI: 10.1071/RD20281
Abstract: Poor replication of published research results is the subject of debate. A common problem is the failure to adequately account for multiple testing issues. In this regard, the evolution of mapping studies to identify genetic risk factors for common diseases has been instructive. Large genome-wide association studies (GWAS) reliably detect the genetic factors with small effects that contribute to risk for many common diseases. GWAS superseded candidate gene studies from the previous decade and looking back, almost no genetic risk factors reported from earlier candidate gene studies replicate in the GWAS results. Candidate gene studies often used small s les and failed to appreciate and adequately account for the multiple testing issues. The failure to replicate results from most candidate gene studies highlights the importance of study power and appropriate statistical analysis to prevent publication of false-positive results.
Publisher: American Medical Association (AMA)
Date: 03-2007
DOI: 10.1001/ARCHPSYC.64.3.318
Abstract: Reduction in adult neurogenesis has been proposed as a mechanism for onset of depression. Semaphorins and their coreceptors, plexins, have been implicated in nervous system development and in adult neurogenesis. A recent genomewide association study of schizophrenia identified a variant of the gene encoding plexin A2 (PLXNA2) to be most consistently associated across study s les. Common genetic liabilities have been reported between psychiatric and psychological measures, but few ex les exist of common genetic variants. To perform a genetic association study between 6 single nucleotide polymorphisms from the PLXNA2 gene (rs3736963, rs2767565, rs752016, rs1327175, rs2478813, and rs716461) and anxiety, depression, neuroticism, and psychological distress. Extreme discordant and concordant siblings. Australia. Study participants were selected with respect to extreme neuroticism scores from a population cohort of 18 742 twin in iduals and their siblings. The participants and their parents (if blood or buccal s les were available) were genotyped, for a total of 2854 genotyped in iduals from 990 families. Of these, 624 in iduals with a diagnosis of anxiety or depression from 443 families were used in the association analysis. All the participants completed the Composite International Diagnostic Interview, the 23-item Neuroticism scale of the revised Eysenck Personality Questionnaire, and the 10-item Kessler Psychological Distress Scale. Diagnoses of DSM-IV depression and anxiety were determined from the Composite International Diagnostic Interview. There was evidence of an allelic association between rs2478813 (and other single nucleotide polymorphisms correlated with it) and anxiety, depression, neuroticism, and psychological distress the association with anxiety is significant after Bonferroni correction for multiple testing (empirical P<.001). The mouse ortholog of PLXNA2 is located in a highly significant linkage region previously reported for anxiety in mice. PLXNA2 is a candidate for causal variation in anxiety and in other psychiatric disorders through its comorbidity with anxiety.
Publisher: The Endocrine Society
Date: 11-2006
DOI: 10.1210/JC.2006-0970
Abstract: Genes from the ovarian bone morphogenetic signaling pathway (GDF9 and BMP15) are critical for normal human fertility. We previously identified a deletion mutation in GDF9 in sisters with spontaneous dizygotic (DZ) twins, but the prevalence of rare GDF9 variants in twinning families is unknown. The objective was to evaluate the frequency of rare variants in GDF9 in families with a history of DZ twinning. We recruited 3450 in iduals from 915 DZ twinning families (1693 mothers of twins) and 1512 controls of Caucasian origin. One mother of DZ twins was selected from 279 of the 915 families, and a DNA s le was screened for rare variants in GDF9 using denaturant HPLC. Variants were confirmed by DNA sequencing and genotyped in the entire s le by matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry. We found two novel insertion/deletions (c.392-393insT, c.1268-1269delAA) and four missense alterations in the GDF9 sequence in mothers of twins. Two of the missense variants (c.307C > T, p.Pro103Ser and c.362C > T, p.Thr121Leu) were located in the pro-region of GDF9 and two (c.1121C > T, p.Pro374Leu and c.1360C > T, p.Arg454Cys) in the mature protein region. For each variant, the frequencies were higher in cases compared with controls. The proportion of mothers of DZ twins carrying any variant (4.12%) was significantly higher (P < 0.0001) than the proportion of carriers in controls (2.29%). We describe new variants in the GDF9 gene that are significantly more common in mothers of DZ twins than controls, suggesting that rare GDF9 variants contribute to the likelihood of DZ twinning.
Publisher: Oxford University Press (OUP)
Date: 30-07-2010
DOI: 10.1093/HMG/DDQ324
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
DOI: 10.1161/HYPERTENSIONAHA.109.132902
Abstract: Research into the genetic effects and specific genes associated with retinal vascular caliber, a risk marker of cardiovascular diseases, may provide new insights into the genetic contribution of early microvascular disease. A combined 374 monozygotic and 536 dizygotic twin pairs and 322 siblings from the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study underwent complete ophthalmic examinations, including retinal photography, and bilateral retinal vascular caliber was measured. Structural equation modeling was used to estimate the heritability. Genome-wide linkage analysis was conducted on 836 in iduals from 381 Brisbane Adolescent Twin Study families, with adjustments for age, sex, and other covariates. The heritabilities for the retinal arteriolar caliber were 59.4% (95% CI: 53.2% to 64.7%) and 56.5% (95% CI: 50.1% to 61.9%) in the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study, respectively, and for venular caliber they were 61.7% (95% CI: 55.6% to 67.0%) and 64.2% (95% CI: 58.7% to 68.8%), respectively, after adjusting for age, sex, and body mass index. Two multipoint peaks detected on chromosomes 3p12.3 and 8p23.1 for retinal arteriolar caliber had suggestive linkage, with the highest multipoint peak logarithm of odds score of 2.24 on chromosome 8p23.1 (genome-wide P =7.0×10 −4 ). Two suggestive logarithm of odds scores for venular caliber were identified on chromosomes 2p14 and 9q21.13. The largest multipoint logarithm of odds score was 2.69 on chromosome 2p14 (genome-wide P =2.0×10 −4 ). In this large twin population, genetic factors appear to play a significant role in the variation of retinal vascular caliber. Several putative loci were identified for the retinal vascular caliber.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2008
DOI: 10.1038/NG.269
Publisher: Springer Science and Business Media LLC
Date: 08-1993
DOI: 10.1038/NG0893-410
Abstract: The autosomal Booroola fecundity gene (FecB) mutation in sheep increases ovulation rate and litter size, with associated effects on ovarian physiology and hormone profiles. Analysis of segregation in twelve families (379 female progeny) identified linkage between the mutation, two microsatellite markers (OarAE101 and OarHH55, Zmax > 9.0) and epidermal growth factor (EGF) from human chromosome 4q25 (Zmax > 3.0). The marker OarAE101 was linked to secreted phosphoprotein 1 (SPP1, which maps to chromosome 4q21-23 in man) in the test pedigrees and independent families (Zmax > 9.7). The identification of linkage between the FecB mutation and markers from human chromosome 4q is an important step towards further understanding the control of ovulation rates in mammals.
Publisher: Springer Science and Business Media LLC
Date: 30-03-2014
DOI: 10.1038/NG.2947
Publisher: Oxford University Press (OUP)
Date: 07-2008
DOI: 10.1373/CLINCHEM.2007.101733
Abstract: Background: Carbohydrate-deficient transferrin (CDT) is a marker of alcohol intake that is used for detecting or monitoring alcohol-use disorders. The introduction of a new direct immunoassay for CDT justifies reevaluation of test performance and reexamination of factors affecting test diagnostic sensitivity and specificity. Methods: In iduals enrolled in twin/family studies of alcohol use and dependence provided blood s les and information on recent alcohol use. Serum CDT concentration was measured in 2 088 people with the N Latex CDT (Dade Behring) method, and CDT percentage (CDT%) was calculated as the proportion of the total transferrin concentration measured with Roche reagents. Results: Diagnostic sensitivity was low, both for comparisons of men who reported an alcohol intake of & drinks/week vs those who consumed ≤28 drinks/week (28% sensitivity) and for women who consumed & drinks/week vs those who consumed ≤14 drinks/week (18% sensitivity), at cutoff values that yielded a 95% specificity. Body mass index, variables associated with metabolic syndrome, and smoking had notable effects on the probability of an abnormal CDT result with excessive alcohol use. Diagnostic sensitivity was greater in men of normal weight (43%) than in obese men (10%) and greater in male smokers (38%) than in male nonsmokers (21%). In women, diagnostic sensitivities were ≤20%, even for those of normal weight and for smokers. Conclusions: CDT is a poor marker of excessive alcohol intake in both women and men who are overweight or obese. It is also less useful in nonsmokers than in smokers. The diagnostic performance of the direct immunoassay and the effects of obesity and smoking are similar to those reported with previous anion-exchange immunoassay methods.
Publisher: Wiley
Date: 14-11-2008
DOI: 10.1002/AJMG.A.32585
Publisher: Wiley
Date: 05-04-2009
DOI: 10.1002/AJMG.B.30817
Publisher: Oxford University Press (OUP)
Date: 04-2015
DOI: 10.1095/BIOLREPROD.114.126458
Abstract: Endometriosis is a common estrogen-dependent gynecological disease influenced by multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified eight genomic regions with strong evidence for association with endometriosis risk and excellent replication in multiple studies. The results represent a significant breakthrough toward understanding endometriosis. However, the significance can be realized only when the associated DNA sequence variation is linked to the altered regulation and/or function of specific genes and pathways modifying endometriosis risk. This review sets out the multiple steps required to interpret the genetic association results, identify the specific genes likely to be responsible for the altered risk within each region, and obtain the necessary genomic evidence connecting the genetic results to the target genes. Strategies include fine mapping, functional annotation, genomics, and target gene identification through gene expression, epigenetics, and cell-based studies to define direct interactions between causal single nucleotide polymorphisms (SNPs) and target genes. To help decode GWAS "hits" affecting endometriosis from multiple regions, there is an urgent need for well-powered genome-wide studies of the regulation of gene expression and epigenetic mechanisms in the endometrium and other reproductive tissues. The system genetics and genomic studies needed to follow-up GWAS signals will also provide insights into gene regulation influencing other reproductive functions. These studies require multidisciplinary research combining genetics, genomics, functional biology, and clinical research to determine the biological pathways responsible and translate the new knowledge into better outcomes for patients.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2014
DOI: 10.1038/TP.2013.114
Abstract: Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 in iduals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N -methyl-D-aspartate receptor complex P =0.002. Replication was sought in two additional cohorts ( N =670 and 2062). A meta-analytic P -value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.
Publisher: MDPI AG
Date: 06-12-2021
DOI: 10.3390/JPM11121314
Abstract: Endometrial organoids (EMO) are an important tool for gynecological research but have been limited by generation from (1) invasively acquired tissues and thus advanced disease states and (2) from women who are not taking hormones, thus excluding 50% of the female reproductive-aged population. We sought to overcome these limitations by generating organoids from (1) menstrual fluid (MF MFO) using a method that enables the concurrent isolation of menstrual fluid supernatant, stromal cells, and leukocytes and (2) from biopsies and hysterectomy s les from women taking hormonal medication (EMO-H). MF was collected in a menstrual cup for 4–6 h on day 2 of menstruation. Biopsies and hysterectomies were obtained during laparoscopic surgery. Organoids were generated from all s le types, with MFO and EMO-H showing similar cell proliferation rates, proportion and localization of the endometrial basalis epithelial marker, Stage Specific Embryonic Antigen-1 (SSEA-1), and gene expression profiles. Organoids from different disease states showed the moderate clustering of epithelial secretory and androgen receptor signaling genes. Thus, MFO and EMO-H are novel organoids that share similar features to EMO but with the advantage of (1) MFO being obtained non-invasively and (2) EMO-H being obtained from 50% of the women who are not currently being studied through standard methods. Thus, MFO and EMO-H are likely to prove to be invaluable tools for gynecological research, enabling the population-wide assessment of endometrial health and personalized medicine.
Publisher: Oxford University Press (OUP)
Date: 13-04-2006
DOI: 10.1093/NAR/GKL136
Publisher: Cambridge University Press (CUP)
Date: 10-2008
Abstract: Human height is a highly heritable trait, with genetic factors explaining up to 90% of phenotypic variation. Vitamin D levels are known to influence several physiological processes, including skeletal growth. The vitamin D receptor (VDR) gene has been reported as contributing to variation in height. A meta-analysis of 13607 adult in iduals found a small but significant association with the rs1544410 (BsmI) polymorphism. In contrast, the meta-analysis found no effect in a s le of 550 children. Two recent studies reported variants with large effect on height elsewhere in VDR (rs10735810 [FokI] and rs7139166 [-1521] polymorphisms). We genotyped large Caucasian s les from Australia ( N = 3906) and the Netherlands ( N = 1689) for polymorphisms in VDR. The Australian s les were twin families with height measures from 3 time points throughout adolescence. The Dutch s les were adult twins. We use the available family data to perform both within and between family tests of association. We found no significant associations for any of the genotyped variants after multiple testing correction. The (non-significant) effect of rs1544410 in the Australian adolescent cohort was in the same direction and of similar magnitude (additive effect 0.3cm) to the effect observed in the published adult meta-analysis. An effect of this size explains ~0.1% of the phenotypic variance in height — this implies that many, probably hundreds, of such variants are responsible for the observed genetic variation. Our results did not support any role for two other regions (rs10735810, rs7139166) of VDR in explaining variation in height.
Publisher: Elsevier BV
Date: 08-2005
Publisher: Public Library of Science (PLoS)
Date: 20-06-2014
Publisher: Mary Ann Liebert Inc
Date: 12-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2008
Publisher: Springer Science and Business Media LLC
Date: 1996
Abstract: The purpose of this study was to investigate the variables that significantly associated with the quality of life in people with heart failure, and particularly, to identify the association between self-management behaviour and the quality of life. This retrospective study used data from heart failure outpatient clinics at two large tertiary medical centres in Seoul and Suwon, South Korea. We enrolled 119 participants who completed echocardiography and stress tests and responded to questionnaires on self-management behaviour and quality of life. We collected more data on sociodemographic and clinical characteristics and anthropometric and serum blood test results through electronic medical record review. We analysed data using multiple linear regression and the classification and regression tree (CART) method to explore the associated factors with the quality of life in participants with heart failure. Participants' mean age was 74.61 years, and women represented 52.1% of the s le. It showed that cardiac systolic function (β = 0.26, p = .013) and self-management behaviour (β = 0.20, p = .048) were two major associated factors with the quality of life in participants with heart failure in the multiple linear regression analysis. Also, cardiac systolic function and self-management behaviour were shown to be the primary determinants for the quality of life in those with heart failure in the CART analysis. Therefore, self-management behaviour of the participants with heart failure was a significant modifiable factor that can improve their quality of life. Healthcare providers should be aware of the importance of self-management in people with heart failure and help promote their quality of life by enhancing their self-management behaviour as own efforts to properly maintain and monitor the health status and prevent further worsening of heart failure.
Publisher: Bioscientifica
Date: 2000
Abstract: Genetic maps provide a critical link between genes and phenotypes and are essential tools in the search for the genetic basis of variation in reproductive traits. Genes coding for hormones, growth factors, receptors, binding proteins, transcription factors and enzymes that influence the development and function of the reproductive axis have been assigned to genetic maps of ruminants and locations can be found in the respective genome databases. In addition, comparative information on gene structure and map location will help define the functions of essential genes. Gene locations from other species can be used because of extensive comparative links among mammalian gene maps. Large-scale projects to sequence genes and the ability to map these genes in parallel in radiation hybrid panels of different species will greatly improve the maps and our ability to translate between them. Cloning the genes responsible for genetic differences in fertility and fecundity in ruminants is likely to provide valuable clues to understanding ovarian function and germ cell development.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2202
DOI: 10.1038/NG.2711
Publisher: Wiley
Date: 11-05-2012
Publisher: Springer Science and Business Media LLC
Date: 10-11-2010
DOI: 10.1038/MP.2009.120
Abstract: The status of DYX1C1 (C15q21.3) as a susceptibility gene for dyslexia is unclear. We report the association of this gene with reading and spelling ability in a s le of adolescent twins and their siblings. Family-based association analyses were carried out on 13 single-nucleotide polymorphisms (SNPs) in DYX1C1, typed in 790 families with up to 5 offspring and tested on 6 validated measures of lexical processing (irregular word) and grapheme-phoneme decoding (pseudo-word) reading- and spelling-based measures of dyslexia, as well as a short-term memory measure. Significant association was observed at the misssense mutation rs17819126 for all reading measures and for spelling of lexical processing words, and at rs3743204 for both irregular and nonword reading. Verbal short-term memory was associated with rs685935. Support for association was not found at rs3743205 and rs61761345 as previously reported by Taipale et al., but these SNPs had very low (0.002 for rs3743205) minor allele frequencies in this s le. These results suggest that DYX1C1 influences reading and spelling ability with additional effects on short-term information storage or rehearsal. Missense mutation rs17819126 is a potential functional basis for the association of DYX1C1 with dyslexia.
Publisher: Oxford University Press (OUP)
Date: 12-01-2007
DOI: 10.1093/HMG/DDL487
Abstract: Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent s les were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2014
DOI: 10.1038/MP.2012.184
Publisher: Oxford University Press (OUP)
Date: 11-2003
Abstract: Folate metabolism is critical to embryonic development, influencing neural tube defects (NTD) and recurrent early pregnancy loss. Polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) have been associated with dizygotic (DZ) twinning through pregnancy loss. The C677T and A1298C polymorphisms in MTHFR were genotyped in 258 Australasian families (1016 in iduals) and 118 Dutch families (462 in iduals) of mothers of DZ twins and a population s le of 462 adolescent twin families (1861 in iduals). Haplotypes were constructed from the alleles, and transmission of the MTHFR haplotypes to mothers of DZ twins and from parents to twins in the adolescent twin families analysed. The C677T and A1298C were common in all three populations (frequencies > 0.29). There was strong linkage disequilibrium (D' = 1) between the variants, showing that specific combinations of alleles (haplotypes) were transmitted together. Three haplotypes accounted for nearly all the variation. There was no evidence of any association between MTHFR genotype and twinning in mothers of twins, or of the loss of specific MTHFR genotypes during twin pregnancies. It is concluded that variation in twinning frequency is not associated with MTHFR genotype.
Publisher: Cambridge University Press (CUP)
Date: 20-06-2014
DOI: 10.1017/THG.2014.34
Abstract: Low weight at birth has previously been shown to be associated with a number of adult diseases such as type 2 diabetes, cardiovascular disease, high blood pressure, and obesity later in life. Genome-wide association studies (GWAS) have been published for singleton-born in iduals, but the role of genetic variation in birth weight (BW) in twins has not yet been fully investigated. A GWAS was performed in 4,593 female study participants with BW data available from the TwinsUK cohort. A genome-wide significant signal was found in chromosome 9, close to the NTRK2 gene (OMIM: 600456). QIMR, an Australian twin cohort ( n = 3,003), and UK-based singleton-birth in iduals from the Hertfordshire cohort ( n = 2,997) were used as replication for the top two single nucleotide polymorphism (SNPs) underpinning this signal, rs12340987 and rs7849941. The top SNP, rs12340987, was found to be in the same direction in the Australian twins and in the singleton-born females (fixed effects meta-analysis beta = -0.13, SE = 0.02, and p = 1.48 × 10 −8 ) but not in the singleton-born males tested. These findings provide an important insight into the genetic component of BW in twins who are normally excluded due to their lower BW when compared with singleton births, as well as the difference in BW between twins. The NTRK2 gene identified in this study has previously been associated with obesity.
Publisher: Elsevier BV
Date: 03-2011
Publisher: Springer Science and Business Media LLC
Date: 11-1996
Publisher: Oxford University Press (OUP)
Date: 16-09-2022
Abstract: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [non-MRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. MRUC–control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10−9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10−19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p & 9.0 × 10−6]. No SNPs reached significance in the non-MRUC–control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10−8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of in iduals with severe disease.
Publisher: Public Library of Science (PLoS)
Date: 10-2015
Publisher: Springer Science and Business Media LLC
Date: 25-10-2007
Abstract: High numbers of melanocytic naevi (moles), and mutations in the p16 gene (CDKN2A), are two strong risk factors for cutaneous malignant melanoma. We have previously reported linkage of mole count to the CDKN2A locus. Here, we report genome-wide scans for mole counts (differentiated into flat, raised and atypical subtypes) with a total of 796 microsatellite markers for 424 families with 1024 twins and siblings, plus genotypes for 690 parents. Inclusion of 221 pairs of MZ twins enabled separation of shared environmental and polygenic influences, so placing an upper limit to estimates of QTL variance. Maximum likelihood multipoint variance component methods were used to assess linkage of naevus count. Sex, age, body surface area, skin colour, hair colour, sunburn and facial freckles were included as covariates. Peak linkage of flat mole count was to regions on chromosomes 2, 9, 8 and 17 with lod scores 2.95, 2.95, 2.50 and 2.15, respectively. The support for linkage to the CDKN2A gene region (9p21) increased to 3.42 when additional fine mapping markers were added. For raised mole count, there was suggestive evidence of linkage in our s le to chromosome 16 (lod=1.87), and for atypical mole count on chromosomes 1, 6 and X with lod scores of 2.20, 2.00 and 2.00, respectively. The multivariate linkage peaks generally match those from in idual trait analyses, with the exception of a new peak on chromosome 4 (point-wise empirical P-value=0.001). We replicate our earlier finding of linkage to CDKN2A and discovering linkage to several novel regions that may also influence risk of the development of malignant melanoma.
Publisher: Wiley
Date: 27-03-2013
DOI: 10.1111/PCMR.12069
Publisher: Cambridge University Press (CUP)
Date: 19-03-2015
DOI: 10.1017/THG.2015.12
Abstract: Mutations in Cyclin-Dependent Kinase Inhibitor 2A ( CDKN2A) and Cyclin-Dependent Kinase 4 ( CDK4 ) contribute to susceptibility in approximately 40% of high-density cutaneous melanoma (CMM) families and about 2% of unselected CMM cases. BRCA-1 associated protein-1 ( BAP1) has been more recently shown to predispose to CMM and uveal melanoma (UMM) in some families however, its contribution to CMM development in the general population is unreported. We sought to determine the contribution of these genes to CMM susceptibility in a population-based s le of cases from Australia. We genotyped 1,109 probands from Queensland families and found that approximately 1.31% harbored mutations in CDKN2A , including some with novel missense mutations (p.R22W, p.G35R and p.I49F). BAP1 missense variants occurred in 0.63% of cases but no CDK4 variants were observed in the s le. This is the first estimate of the contribution of BAP1 and CDK4 to a population-based s le of CMM and supports the previously reported estimate of CDKN2A germline mutation prevalence.
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1053/J.GASTRO.2006.08.038
Abstract: Sporadic colorectal cancers with a high degree of microsatellite instability are a clinically distinct subgroup with a high incidence of BRAF mutation and are widely considered to develop from serrated polyps. Previous studies of serrated polyps have been highly selected and largely retrospective. This prospective study examined the prevalence of sessile serrated adenomas and determined the incidence of BRAF and K-ras mutations in different types of polyps. An unselected consecutive series of 190 patients underwent magnifying chromoendoscopy. Polyp location, size, and histologic classification were recorded. All polyps were screened for BRAF V600E and K-ras codon 12 and 13 mutations. Polyps were detected in 72% of patients. Most (60%) were adenomas (tubular adenomas, tubulovillous adenomas), followed by hyperplastic polyps (29%), sessile serrated adenomas (SSAs 9%), traditional serrated adenomas (0.7%), and mixed polyps (1.7%). Adenomas were more prevalent in the proximal colon (73%), as were SSAs (75%), which tended to be large (64% >5 mm). The presence of at least one SSA was associated with increased polyp burden (5.0 vs 2.5 P < .0001) and female sex (P < .05). BRAF mutation was rare in adenomas (1/248 [0.4%]) but common in SSAs (78%), traditional serrated adenomas (66%), mixed polyps (57%), and microvesicular hyperplastic polyps (70%). K-ras mutations were significantly associated with goblet cell hyperplastic polyps and tubulovillous adenomas (P < .001). The prevalence of SSAs is approximately 9% in patients undergoing colonoscopy. They are associated with BRAF mutation, proximal location, female sex, and presence of multiple polyps. These findings emphasize the importance of identifying and removing these lesions for endoscopic prevention of colorectal cancer.
Publisher: Elsevier BV
Date: 10-2015
Publisher: American Medical Association (AMA)
Date: 03-2013
Publisher: Springer Science and Business Media LLC
Date: 18-05-2008
DOI: 10.1038/NG.163
Publisher: Springer Science and Business Media LLC
Date: 18-01-2009
DOI: 10.1038/NG.286
Abstract: Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of approximately 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 x 10(-294)). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2010
DOI: 10.1038/MP.2010.109
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: Public Library of Science (PLoS)
Date: 10-04-2015
Publisher: Springer Science and Business Media LLC
Date: 20-12-2006
DOI: 10.1007/S10519-005-9004-0
Abstract: Many twin studies have identified sex differences in the influence of genetic and environmental factors on smoking behaviors. We explore the evidence for sex differences for smoking initiation and cigarette consumption in a s le of Australian twin families, and extend these models to incorporate sex differences in linkage analyses for these traits. We further examine the impact of including or excluding non-smokers in genetic analyses of tobacco consumption. Accounting for sex differences improved linkage results in some instances. We identified one region suggestive of linkage on chromosome 11p12. This locus, as well as another region identified on chromosome 6p12, replicates regions identified in previous studies.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.ANNEPIDEM.2021.10.005
Abstract: Endometriosis is a chronic inflammatory disease affecting the reproductive, gastrointestinal, and urinary systems. We examined changes in labor force participation amongst women with endometriosis following diagnosis. We analyzed data from 4494 women born in 1973-78 from the Australian Longitudinal Study on Women's Health. We used multinomial logistic regression models with generalized estimating equations to examine changes in labor force participation amongst 468 women with surgically confirmed endometriosis, and 375 women with clinically suspected endometriosis, relative to a comparison group of 4151 women without endometriosis. At diagnosis, women with surgically confirmed endometriosis were somewhat more likely to be working part-time (OR 1.26, 95% CI 0.94-1.68) or unemployed (OR 1.46, 95% CI 0.96-2.23) than before diagnosis. After diagnosis, women with surgically confirmed endometriosis remained somewhat more likely to be working part-time (OR 1.26, 95% CI 0.88-1.80) but were significantly more likely to be unemployed (OR 1.85, 95% CI 1.16-2.96) than before diagnosis. Labor force participation for women with clinically suspected endometriosis did not differ from women without endometriosis at diagnosis and did not change over time. Women with surgically confirmed endometriosis transitioned out the labor force following diagnosis. Supportive workplace practices may help women remain in the labor force.
Publisher: American Medical Association (AMA)
Date: 02-06-2008
DOI: 10.1001/ARCHPSYC.65.6.713
Abstract: Despite accumulating evidence that there is a genetic basis for cannabis use disorders (ie, abuse and dependence), few studies have identified genomic regions that may harbor biological risk and protective factors. To conduct autosomal linkage analyses that identify genomic regions that may harbor genes conferring a vulnerability to cannabis use disorders. In 289 Australian families who participated in the Nicotine Addiction Genetics Project, 423 autosomal markers were genotyped. Families were ascertained for heavy cigarette smoking. Linkage was conducted for DSM-IV cannabis dependence and for a novel factor score representing problems with cannabis use, including occurrence of 3 of 4 abuse criteria (excluding legal problems) and 6 DSM-IV dependence criteria. A maximum logarithm of odds (LOD) of 3.36 was noted for the cannabis problems factor score on chromosome arm 1p. An LOD of 2.2 was noted on chromosome 4 in the region of the gamma-aminobutyric acid type A gene cluster, including GABRA2, which has been implicated in drug use disorders. For DSM-IV cannabis dependence, a modest LOD score on chromosome 6 (1.42) near cannabinoid receptor 1 (CNR1) was identified. In addition, support for an elevation on chromosome 3, identified in prior independent studies, was noted for the factor score and cannabis dependence (LOD, 1.4). Genes such as ELTD1 on chromosome 1, in addition to genes on chromosomes 4 (eg, GABRA2) and 6 (eg, CNR1), may be associated with the genetic risk for cannabis use disorders. We introduce a novel quantitative phenotype, a cannabis problems factor score composed of DSM-IV abuse and dependence criteria, that may be useful for future linkage and association studies.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2009
DOI: 10.1038/IJO.2008.223
Abstract: To further investigate a common variant (rs9939609) in the fat mass- and obesity-associated gene (FTO), which recent genome-wide association studies have shown to be associated with body mass index (BMI) and obesity. We examined the effect of this FTO variant on BMI in 3353 Australian adult male and female twins. The minor A allele of rs9939609 was associated with an increased BMI (P=0.0007). Each additional copy of the A allele was associated with a mean BMI increase of approximately 1.04 kg/m(2) (approximately 3.71 kg). Using variance components decomposition, we estimate that this single-nucleotide polymorphism accounts for approximately 3% of the genetic variance in BMI in our s le (approximately 2% of the total variance). By comparing intrapair variances of monozygotic twins of different genotypes we were able to perform a direct test of gene by environment (G x E) interaction in both sexes and gene by parity (G x P) interaction in women, but no evidence was found for either. In addition to supporting earlier findings that the rs9939609 variant in the FTO gene is associated with an increased BMI, our results indicate that the associated genetic effect does not interact with environment or parity.
Publisher: Cold Spring Harbor Laboratory
Date: 19-12-2012
Abstract: The degree to which the level of genetic variation for gene expression is shared across multiple tissues has important implications for research investigating the role of expression on the etiology of complex human traits and diseases. In the last few years, several studies have been published reporting the extent of overlap in expression quantitative trait loci (eQTL) identified in multiple tissues or cell types. Although these studies provide important information on the regulatory control of genes across tissues, their limited power means that they can typically only explain a small proportion of genetic variation for gene expression. Here, using expression data from monozygotic twins (MZ), we investigate the genetic control of gene expression in lymphoblastoid cell lines (LCL) and whole blood (WB). We estimate the genetic correlation that represents the combined effects of all causal loci across the whole genome and is a measure of the level of common genetic control of gene expression between the two RNA sources. Our results show that, when averaged across the genome, mean levels of genetic correlation for gene expression in LCL and WB s les are close to zero. We support our results with evidence from gene expression in an independent s le of LCL, T-cells, and fibroblasts. In addition, we provide evidence that housekeeping genes, which maintain basic cellular functions, are more likely to have high genetic correlations between the RNA sources than non-housekeeping genes, implying a relationship between the transcript function and the degree to which a gene has tissue-specific genetic regulatory control.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2019
DOI: 10.1038/S41467-019-10598-Y
Abstract: Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a s le of more than 450,000 in iduals from the UK Biobank and 1600 gene expression traits from a s le of 2000 in iduals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h 2 SNP = 0.63%) compared to females (mean h 2 SNP = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight ex les of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for.
Publisher: Oxford University Press (OUP)
Date: 11-2013
DOI: 10.1534/GENETICS.113.153221
Abstract: Principal components analysis has been employed in gene expression studies to correct for population substructure and batch and environmental effects. This method typically involves the removal of variation contained in as many as 50 principal components (PCs), which can constitute a large proportion of total variation present in the data. Each PC, however, can detect many sources of variation, including gene expression networks and genetic variation influencing transcript levels. We demonstrate that PCs generated from gene expression data can simultaneously contain both genetic and nongenetic factors. From heritability estimates we show that all PCs contain a considerable portion of genetic variation while nongenetic artifacts such as batch effects were associated to varying degrees with the first 60 PCs. These PCs demonstrate an enrichment of biological pathways, including core immune function and metabolic pathways. The use of PC correction in two independent data sets resulted in a reduction in the number of cis- and trans-expression QTL detected. Comparisons of PC and linear model correction revealed that PC correction was not as efficient at removing known batch effects and had a higher penalty on genetic variation. Therefore, this study highlights the danger of eliminating biologically relevant data when employing PC correction in gene expression data.
Publisher: Wiley
Date: 06-02-2009
Publisher: MDPI AG
Date: 29-02-2020
Abstract: Observational epidemiological studies indicate that endometriosis and migraine co-occur within in iduals more than expected by chance. However, the aetiology and biological mechanisms underlying their comorbidity remain unknown. Here we examined the relationship between endometriosis and migraine using genome-wide association study (GWAS) data. Single nucleotide polymorphism (SNP) effect concordance analysis found a significant concordance of SNP risk effects across endometriosis and migraine GWAS. Linkage disequilibrium score regression analysis found a positive and highly significant genetic correlation (rG = 0.38, P = 2.30 × 10−25) between endometriosis and migraine. A meta-analysis of endometriosis and migraine GWAS data did not reveal novel genome-wide significant SNPs, and Mendelian randomisation analysis found no evidence for a causal relationship between the two traits. However, gene-based analyses identified two novel loci for migraine. Also, we found significant enrichment of genes nominally associated (Pgene 0.05) with both traits (Pbinomial-test = 9.83 × 10−6). Combining gene-based p-values across endometriosis and migraine, three genes, two (TRIM32 and SLC35G6) of which are at novel loci, were genome-wide significant. Genes having Pgene 0.1 for both endometriosis and migraine (Pbinomial-test = 1.85 ×10−°3) were significantly enriched for biological pathways, including interleukin-1 receptor binding, focal adhesion-PI3K-Akt-mTOR-signaling, MAPK and TNF-α signalling. Our findings further confirm the comorbidity of endometriosis and migraine and indicate a non-causal relationship between the two traits, with shared genetically-controlled biological mechanisms underlying the co-occurrence of the two disorders.
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1086/510136
Publisher: Informa UK Limited
Date: 04-2017
DOI: 10.2147/HP.S133231
Publisher: Wiley
Date: 03-08-2012
DOI: 10.1002/IJC.26175
Abstract: The majority of "serrated pathway" colorectal cancers have mutation of the BRAF oncogene and display the CpG island methylator phenotype (CIMP). Half these cancers have microsatellite instability (MSI) and an excellent prognosis. In the absence of MSI (microsatellite stable, MSS), BRAF mutation has been associated with a particularly poor prognosis. "Traditional pathway" cancers are BRAF wild type. Mutation of p53 is common and this correlates with advanced stage. We therefore hypothesized that p53 mutation would be common in MSS/BRAF mutant colorectal cancer. One thousand and eighty-one colorectal cancers were screened for BRAF mutation to identify two BRAF mutant study groups (MSI: n = 77 MSS: n = 69) and a BRAF wild type control group (n = 101). These were screened for p53 mutation by high resolution melt analysis and classified for CIMP and MGMT methylation by quantitative methylation specific PCR. Molecular data were compared to patient age, gender, tumor location and stage. p53 was mutated significantly more frequently in MSS/BRAF mutant (28/69, 40.6%) compared to MSI/BRAF mutant cancers (13/77, 16.9%), but this mutation rate did not differ from MSS/BRAF wild type cancers (47/101, 46.5%)(p < 0.0001). CIMP was less common in MSS/BRAF mutant (26/47, 55.3%) compared to MSI/BRAF mutant cancers (41/54, 75.9%), but was more common than in MSS/BRAF wild type cancers (3/85, 3.5%) (p < 0.0001). MSS/BRAF mutant cancers were more commonly proximal (38/54, 70.3%), but were similar to MSS/BRAF wild type cancers in terms of patient age, gender distribution and stage at presentation. MSS/BRAF mutant cancers share molecular and clinical features of both the serrated and traditional pathways of colorectal tumorigenesis.
Publisher: Cambridge University Press (CUP)
Date: 06-03-2015
DOI: 10.1017/THG.2015.3
Abstract: Shorter telomere length (TL) has found to be associated with lower birth weight and with lower cognitive ability and psychiatric disorders. However, the direction of causation of these associations and the extent to which they are genetically or environmentally mediated are unclear. Within-pair comparisons of monozygotic (MZ) and dizygotic (DZ) twins can throw light on these questions. We investigated correlations of within pair differences in telomere length, IQ, and anxiety/depression in an initial s le from Brisbane (242 MZ pairs, 245 DZ same sex (DZSS) pairs) and in replication s les from Amsterdam (514 MZ pairs, 233 DZSS pairs) and Melbourne (19 pairs selected for extreme high or low birth weight difference). Intra-pair differences of birth weight and telomere length were significantly correlated in MZ twins, but not in DZSS twins. Greater intra-pair differences of telomere length were observed in the 10% of MZ twins with the greatest difference in birth weight compared to the bottom 90% in both s les and also in the Melbourne s le. Intra-pair differences of telomere length and IQ, but not of TL and anxiety/depression, were correlated in MZ twins, and to a smaller extent in DZSS twins. Our findings suggest that the same prenatal effects that reduce birth weight also influence telomere length in MZ twins. The association between telomere length and IQ is partly driven by the same prenatal effects that decrease birth weight.
Publisher: Wiley
Date: 29-03-2014
DOI: 10.1002/AJMG.B.32230
Publisher: Springer Science and Business Media LLC
Date: 08-2001
DOI: 10.1038/91074
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1038/JID.2009.258
Publisher: S. Karger AG
Date: 1999
DOI: 10.1159/000015264
Abstract: The low density of genetic markers on livestock maps limits progress in positional cloning projects. We demonstrate a strategy of combining comparative mapping with AFLP fingerprinting to develop physical maps in a defined region of the sheep genome. Sequence tagged sites for alcohol dehydrogenase 2 (ADH2) and microsomal triglyceride transfer protein (MTP) were developed and used to screen a sheep yeast artificial chromosome (YAC) library. Nine YACs were identified containing the microsatellite marker BM1329 and either ADH2 or MTP. Additional markers in the region were not available, and AFLP analysis was developed to identify sheep-specific bands within the YACs to determine their degree of overlap. Fourteen bands common to more than one YAC were analysed and provided the markers necessary to develop a YAC contig containing the three STS markers. One YAC (yac260B5) containing all three markers (ADH2, MTP, and BM1329) was mapped to sheep chromosome 6q1.6→q1.8 by FISH analysis.
Publisher: Wiley
Date: 16-12-2010
DOI: 10.1002/AJMG.B.31149
Publisher: Springer Science and Business Media LLC
Date: 12-10-2008
DOI: 10.1038/NG.228
Abstract: We carried out a genome-wide association study in 296 in iduals with male-pattern baldness (androgenetic alopecia) and 347 controls. We then investigated the 30 best SNPs in an independent replication s le and found highly significant association for five SNPs on chromosome 20p11 (rs2180439 combined P = 2.7 x 10(-15)). No interaction was detected with the X-chromosomal androgen receptor locus, suggesting that the 20p11 locus has a role in a yet-to-be-identified androgen-independent pathway.
Publisher: Public Library of Science (PLoS)
Date: 31-10-2013
Publisher: Springer Science and Business Media LLC
Date: 23-07-2014
DOI: 10.1038/NATURE13545
Publisher: Elsevier BV
Date: 07-2010
Publisher: Environmental Health Perspectives
Date: 06-2010
DOI: 10.1289/EHP.0901541
Publisher: Springer Science and Business Media LLC
Date: 09-2023
Publisher: American Diabetes Association
Date: 23-02-2015
DOI: 10.2337/DB14-0988
Abstract: Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese in iduals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 in iduals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P & 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the & -year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the & -year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
Publisher: Oxford University Press (OUP)
Date: 11-04-2014
DOI: 10.1093/HMG/DDU174
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.CCA.2006.05.033
Abstract: Plasma triglyceride concentration is known to be a significant risk factor for cardiovascular disease (CVD). Previous studies have found that the level of triglycerides is strongly influenced by genetic factors. To identify quantitative trait loci influencing triglycerides, we conducted a genome-wide linkage scan on data from 485 Australian adult dizygotic twin pairs. Prior to linkage analysis, triglyceride values were adjusted for the effects of covariates including age, sex, time since last meal, time of blood collection (CT) and time to plasma separation. The heritability estimate for ln(triglyceride) adjusted for all above fixed effects was 0.49. The highest multipoint LOD score observed was 2.94 (genome-wide p=0.049) on chromosome 7 (at 65 cM). This 7p region contains several candidate genes. Two other regions with suggestive multipoint LOD scores were also identified on chromosome 4 (LOD score=2.26 at 62 cM) and chromosome X (LOD score=2.01 at 81 cM). The linkage peaks found represent newly identified regions for more detailed study, in particular the significant linkage observed on chromosome 7p13.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2006
DOI: 10.1007/S10519-005-9003-1
Abstract: A genome-wide linkage scan of 795 microsatellite markers (761 autosomal, 34 X chromosome) was performed on Multidimensional Aptitude Battery subtests and verbal, performance and full scale scores, the WAIS-R Digit Symbol subtest, and two word-recognition tests (Schonell Graded Word Reading Test, Cambridge Contextual Reading Test) highly predictive of IQ. The s le included 361 families comprising 2-5 siblings who ranged in age from 15.7 to 22.2 years genotype, but not phenotype, data were available for 81% of parents. A variance components analysis which controlled for age and sex effects showed significant linkage for the Cambridge reading test and performance IQ to the same region on chromosome 2, with respective LOD scores of 4.15 and 3.68. Suggestive linkage (LOD score>2.2) for various measures was further supported on chromosomes 6, 7, 11, 14, 21 and 22. Where location of linkage peaks converged for IQ subtests within the same scale, the overall scale score provided increased evidence for linkage to that region over any in idual subtest. Association studies of candidate genes, particularly those involved in neural transmission and development, will be directed to genes located under the linkage peaks identified in this study.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2018
DOI: 10.1038/S41467-018-03371-0
Abstract: The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i.e., pleiotropy). We identify pleiotropic associations between 7858 DNAm sites and 2733 genes. These DNAm sites are enriched in enhancers and promoters, and % of them are mapped to distal genes. Further pleiotropic association analyses, which link both the methylome and transcriptome to 12 complex traits, identify 149 DNAm sites and 66 genes, indicating a plausible mechanism whereby the effect of a genetic variant on phenotype is mediated by genetic regulation of transcription through DNAm.
Publisher: Springer Science and Business Media LLC
Date: 09-2009
DOI: 10.1038/IJO.2009.168
Publisher: MDPI AG
Date: 28-06-2023
Abstract: Identifying tissue-specific molecular signatures of active regulatory elements is critical to understanding gene regulatory mechanisms. In this study, transcription start sites (TSS) and enhancers were identified using Cap analysis of gene expression (CAGE) across endometrial stromal cell (ESC) s les obtained from women with (n = 4) and without endometriosis (n = 4). ESC TSSs and enhancers were compared to those reported in other tissue and cell types in FANTOM5 and were integrated with RNA-seq and ATAC-seq data from the same s les for regulatory activity and network analyses. CAGE tag count differences between women with and without endometriosis were statistically tested and tags within close proximity to genetic variants associated with endometriosis risk were identified. Over 90% of tag clusters mapping to promoters were observed in cells and tissues in FANTOM5. However, some potential cell-type-specific promoters and enhancers were also observed. Regions of open chromatin identified using ATAC-seq provided further evidence of the active transcriptional regions identified by CAGE. Despite the small s le number, there was evidence of differences associated with endometriosis at 210 consensus clusters, including IGFBP5, CALD1 and OXTR. ESC TSSs were also located within loci associated with endometriosis risk from genome-wide association studies. This study provides novel evidence of transcriptional differences in endometrial stromal cells associated with endometriosis and provides a valuable cell-type specific resource of active TSSs and enhancers in endometrial stromal cells.
Publisher: Public Library of Science (PLoS)
Date: 03-05-2012
Publisher: Springer Science and Business Media LLC
Date: 05-06-2019
DOI: 10.1038/S41593-019-0402-7
Abstract: Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.
Publisher: Elsevier BV
Date: 05-1982
DOI: 10.1016/0093-691X(82)90181-9
Abstract: Effects of restricted suckling frequency and bromocryptine treatment on return of ovarian cycles after calving were studied on 151 Angus and Friesian Angus crossbred cows. A control group consisted of cows and calves grazed together. In two groups, calves were allowed to suckle for one hour only each morning (1 x S) or one hour each morning and afternoon (2 x S). A further group of cows, grazed with their calves, were treated with 10 mg bromocryptine per day from days 2-11 post-partum (BCT). Interval from calving to resumption of ovarian cycles, assessed from oestrous records and weekly progesterone s les, did not differ between control and 2 x S cows. Interval from calving to a recorded progesterone s le greater than 1.7 ng/ml associated with oestrus in 1 x S cows was 13 days shorter than for control cows (63 vs 76 days, SED = 1.4, p < 0.05) although, the difference in interval to first oestrus of 11 days was not significantly different in these groups (64 vs. 75 days, SED = 4.5). Time from calving to resumption of ovarian cycles did not differ between BCT and control cows. Collectively these data indicate that suckling frequency per se is not a major factor influencing resumption of ovarian cycles after calving. Instead they suggest the association of the cow and its calf may influence the long post-partum anoestrous intervals in these animals.
Publisher: Wiley
Date: 17-12-2009
Publisher: Springer Science and Business Media LLC
Date: 12-1997
Publisher: Wiley
Date: 2010
DOI: 10.1002/AJMG.B.31044
Publisher: Springer Science and Business Media LLC
Date: 06-1995
DOI: 10.1007/BF00355648
Publisher: Springer Science and Business Media LLC
Date: 18-11-2016
Publisher: Oxford University Press (OUP)
Date: 27-07-2020
DOI: 10.1093/HMG/DDAA156
Abstract: Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of in idually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2013
Publisher: Elsevier BV
Date: 07-2015
Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1038/NATURE14618
Publisher: Public Library of Science (PLoS)
Date: 24-03-2006
Publisher: Springer Science and Business Media LLC
Date: 18-10-2011
DOI: 10.1038/TP.2011.45
Publisher: Cambridge University Press (CUP)
Date: 03-06-2013
DOI: 10.1017/THG.2013.30
Abstract: Imprinting control regions (ICRs) play a fundamental role in establishing and maintaining the non-random monoallelic expression of certain genes, via common regulatory elements such as non-coding RNAs and differentially methylated regions (DMRs) of DNA. We recently surveyed DNA methylation levels within four ICRs ( H19 -ICR, IGF2 -DMR, KvDMR, and NESPAS -ICR) in whole-blood genomic DNA from 128 monozygotic (MZ) and 128 dizygotic (DZ) human twin pairs. Our analyses revealed high in idual variation and intra-domain covariation in methylation levels across CpGs and emphasized the interaction between epigenetic variation and the underlying genetic sequence in a parent-of-origin fashion. Here, we extend our analysis to conduct two genome-wide screenings of single nucleotide polymorphisms (SNPs) underlying either intra-domain covariation or parent-of-origin-dependent association with methylation status at in idual CpG sites located within ICRs. Although genome-wide significance was not surpassed due to s le size limitations, the most significantly associated SNPs found through multiple-trait genome-wide association (MQFAM) included the previously described rs10732516, which is located in the vicinity of the H19 -ICR. Similarly, we identified an association between rs965808 and methylation status within the NESPAS -ICR. This SNP is positioned within an intronic region of the overlapping genes GNAS and GNAS-AS1 , which are imprinted genes regulated by the NESPAS -ICR. Sixteen other SNPs located in regions apart from the analyzed regions displayed suggestive association with intra-domain methylation. Additionally, we identified 13 SNPs displaying parent-of-origin association with in idual methylation sites through family-based association testing. In this exploratory study, we show the value and feasibility of using alternative GWAS approaches in the study of the interaction between epigenetic state and genetic sequence within imprinting regulatory domains. Despite the relatively small s le size, we identified a number of SNPs displaying suggestive association either in a domain-wide or in a parent-of-origin fashion. Nevertheless, these associations will require future experimental validation or replication in larger and independent s les.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2011
DOI: 10.1038/TP.2011.42
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1086/444510
Publisher: American Association for Cancer Research (AACR)
Date: 12-2013
DOI: 10.1158/1078-0432.CCR-13-0550
Abstract: Purpose: Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas. Experimental Design: Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10−7. Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58]. Results: Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P & 10−7 level with OR & 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241 r2 = 0.8–1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11 OR, 2.09 95% confidence interval (CI), 1.50–2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia N = 9,211). Conclusions: Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance. Clin Cancer Res 19(23) 6430–7. ©2013 AACR.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-06-2013
Abstract: Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 s les, Rietveld et al. (p. 1467 , published online 30 May see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.
Publisher: Wiley
Date: 28-03-2014
DOI: 10.1002/GCC.22164
Abstract: Formalin fixation and embedding of clinical tissue s les in paraffin is a common method for archiving biological material. These s les are often well annotated and provide an invaluable resource for research. However, this process of fixation and storage of tissue leads to DNA damage and fragmentation. The use of DNA from formalin fixed, paraffin-embedded (FFPE) tissue to interrogate methylation levels on a genome-wide scale can pose challenges. We compared fresh and matched FFPE tissue DNA s les using the Illumina Infinium HD Human Methylation 450K BeadChip platform with a companion application for repair and "restoration" of DNA from FFPE tissue. Our results showed good correlation between fresh and FFPE s le data. FFPE DNA captured 99% of the CpG sites on the array on average. Significant cancer subgroups based on the CpG island methylator phenotype (CIMP) were clearly distinguished for both fresh and FFPE s le sets with cluster and scaling analysis. The DNA methylation status for the five standard CIMP panel genes which was evaluated for all s les by the MethyLight assay was correctly assigned in both fresh and FFPE s les by the array data. We conclude that the "restoration" method followed by assay on the Infinium HD Human Methylation 450K microarray can produce good quality data for DNA from FFPE s les.
Publisher: Springer Science and Business Media LLC
Date: 04-2009
Publisher: Springer Science and Business Media LLC
Date: 08-2010
DOI: 10.1038/NATURE09270
Publisher: Wiley
Date: 11-07-2013
Publisher: Oxford University Press (OUP)
Date: 27-03-2014
Publisher: Springer Science and Business Media LLC
Date: 06-12-2006
DOI: 10.1007/S10519-005-9002-2
Abstract: Working memory is an essential component of wide-ranging cognitive functions. It is a complex genetic trait probably influenced by numerous genes that in idually have only a small influence. These genes may have an lified influence on phenotypes closer to the gene action. In this study, event-related potential (ERP) phenotypes recorded during a working-memory task were collected from 656 adolescents from 299 families for whom genotypes were available. Univariate linkage analyses using the MERLIN variance-components method were conducted on slow wave phenotypes recorded at multiple sites while participants were required to remember the location of a target. Suggestive linkage (LOD > 2.2) was found on chromosomes 4, 5, 6, 10, 17, and 20. After correcting for multiple testing, suggestive linkage remained on chromosome 10. Empirical thresholds were computed for the most promising phenotypes. Those on chromosome 10 remained suggestive. A number of genes reported to regulate neural differentiation and function (i.e. NRP1, ANK3, and CHAT) were found under these linkage peaks and may influence the levels of neural activity occurring in in iduals participating in a spatial working-memory task.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2004
Publisher: Public Library of Science (PLoS)
Date: 20-03-2014
Publisher: Elsevier BV
Date: 11-2014
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
DOI: 10.1038/S41467-018-08078-W
Abstract: The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
Publisher: Elsevier BV
Date: 03-2013
Publisher: Springer Science and Business Media LLC
Date: 12-2012
DOI: 10.1038/NATURE11677
Publisher: Wiley
Date: 06-2008
DOI: 10.1111/J.1360-0443.2008.02236.X
Abstract: The gamma-aminobutyric acid receptor A (GABRA) gene clusters on chromosomes 4 and 5 have been examined previously for their association with alcohol and drug dependence phenotypes. Compelling evidence suggests that GABRA2 is associated with alcohol and drug dependence. However, no study has investigated whether genes in the GABA(A) gene clusters are associated with nicotine dependence, an important phenotype with a high correlation to persistent smoking, the single most preventable cause of mortality world-wide. Using data on 1050 nicotine-dependent cases and 879 non-dependent smoking controls, we used logistic regression to examine the association between single nucleotide polymorphisms (SNPs) in 13 genes in the GABA(A) receptor system as well as GABBR2 (a GABA(B) gene). We found evidence for association between four SNPs in GABRA4, two SNPs in GABRA2 and one SNP in GABRE with nicotine dependence. These included a synonymous polymorphism in GABRA2 (rs279858), lying in a highly conserved region, which has been shown previously to be associated with alcohol and drug dependence. A non-synonymous polymorphism (rs16859834/rs2229940) in GABRA4, also highly conserved, was associated at P-value of 0.03. Significant haplotypes associated with nicotine dependence were found for GABRA2. No evidence for epistatic interactions were noted. Our study did not find evidence for an association between GABBR2 gene and nicotine dependence. Given the potential role of compounds that enhance GABAergic neurotransmission in smoking cessation research, these findings have enormous potential for informing the wider field of addiction research.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2015
DOI: 10.1038/NCOMMS9570
Abstract: Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 in iduals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age’ of an in idual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2008
DOI: 10.1111/J.1572-0241.2008.02023.X
Abstract: Crohn's disease (CD) and ulcerative colitis (UC) are the two most common forms of inflammatory bowel disease (IBD), representing a significant health-care burden. A variant in the autophagy gene ATG16L1 (T300A) has been newly identified as a CD susceptibility locus by genome-wide association. Our aim was to assess the contribution of T300A in determining disease susceptibility and phenotype in two independent Australian IBD cohorts and explore the relationship between T300A and known CD risk factors (NOD2[nucleotide-binding oligomerization domain containing 2] status and smoking). In total, 669 CD and 543 UC cases, and 1,244 controls (study 1), 154 CD cases and 420 controls (study 2), and 702 unaffected parents from both groups were genotyped. We conducted case-control and family association analyses, and investigated relationships between T300A and disease subgroups and between NOD2 status and cigarette smoking (CD only). The strong association between CD and T300A was confirmed (P < 0.001), with a two-fold increase in disease risk associated with the GG genotype (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.49-2.58), while ileal CD risk was almost three-fold (OR 2.73, CI 1.87-4.0). ATG16L1 and NOD2 were found to contribute independently to CD risk. A greater than seven-fold increased CD risk was observed for current smokers with a GG genotype (vs nonsmoking AA genotype P < 0.001, OR 7.65, CI 4.21-13.91). A significant inverse association was found between T300A and UC (P= 0.002). This was strongest for patients with extensive, severe disease. We confirm the strong association between T300A and CD, specifically ileal subphenotype, and also report the first strong association of this variant with UC.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2012
DOI: 10.1038/TP.2012.37
Publisher: Springer Science and Business Media LLC
Date: 24-09-2011
Publisher: American Academy of Pediatrics (AAP)
Date: 02-2012
Abstract: Previous studies have suggested associations between certain genetic variants and susceptibility to cerebral palsy (CP). This study was designed to assess established and novel maternal and child genetic and epidemiologic risk factors for CP along with their interactions. DNA from 587 case and 1154 control mother-child pairs was analyzed. A panel of 35 candidate single nucleotide polymorphisms (SNPs) were examined and included SNPs in genes associated with (1) thrombophilia, (2) inflammation, and (3) risk factors for CP (eg, preterm birth). Comparisons were specified a priori and made by using a χ2 test. There were 40 fetal and 28 maternal associations with CP when analyzed by CP subtype, gestational age, genotypes of apolipoprotein E, and haplotypes of mannose-binding-lectin. After Bonferroni correction for multiple testing, no fetal or maternal candidate SNP was associated with CP or its subtypes. Only fetal carriage of prothrombin gene mutation remained marginally associated with hemiplegia in term infants born to mothers with a reported infection during pregnancy. Odds ratio directions of fetal SNP associations were compared with previously reported studies and confirmed no trend toward association. Except for the prothrombin gene mutation, in idual maternal and fetal SNPs in our candidate panel were not found to be associated with CP outcome. Past reported SNP associations with CP were not confirmed, possibly reflecting type I error from small numbers and multiple testing in the original reports.
Publisher: Oxford University Press (OUP)
Date: 07-2012
DOI: 10.5665/SLEEP.1962
Publisher: Elsevier BV
Date: 11-2012
Publisher: Cambridge University Press (CUP)
Date: 06-2011
Abstract: A set of 10 SNPs associated with reading ability in 7-year-olds was reported based on initial pooled analyses of 100K SNP chip data, with follow-up testing stages using pooling and in idual testing. Here we examine this association in an adolescent population s le of Australian twins and siblings ( N = 1177) aged 12 to 25 years. One (rs1842129) of the 10 SNPs approached significance ( P = .05) but no support was found for the remaining 9 SNPs or the SNP set itself. Results indicate that these SNPs are not associated with reading ability in an Australian population. The results are interpreted as supporting use of much larger SNP sets in common disorders where effects are small.
Publisher: Elsevier BV
Date: 10-2010
Publisher: Public Library of Science (PLoS)
Date: 28-09-2007
Publisher: Springer Science and Business Media LLC
Date: 27-08-2201
Publisher: Oxford University Press (OUP)
Date: 04-2001
DOI: 10.1095/BIOLREPROD64.4.1225
Abstract: The Booroola fecundity gene (FecB) increases ovulation rate and litter size in sheep and is inherited as a single autosomal locus. The effect of FecB is additive for ovulation rate (increasing by about 1.6 corpora lutea per cycle for each copy) and has been mapped to sheep chromosome 6q23-31, which is syntenic to human chromosome 4q21-25. Bone morphogenetic protein IB (BMP-IB) receptor (also known as ALK-6), which binds members of the transforming growth factor-beta (TGF-beta) superfamily, is located in the region containing the FecB locus. Booroola sheep have a mutation (Q249R) in the highly conserved intracellular kinase signaling domain of the BMP-IB receptor. The mutation segregated with the FecB phenotype in the Booroola backcross and half-sib flocks of sheep with no recombinants. The mutation was not found in in iduals from a number of sheep breeds not derived from the Booroola strain. BMPR-IB was expressed in the ovary and in situ hybridization revealed its specific location to the oocyte and the granulosa cell. Expression of mRNA encoding the BMP type II receptor was widespread throughout the ovary. The mutation in BMPR-IB found in Booroola sheep is the second reported defect in a gene from the TGF-beta pathway affecting fertility in sheep following the recent discovery of mutations in the growth factor, GDF9b/BMP15.
Publisher: Elsevier BV
Date: 11-2009
Publisher: Elsevier BV
Date: 08-2011
Publisher: Springer Science and Business Media LLC
Date: 05-2013
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1086/432647
Publisher: Elsevier BV
Date: 09-2009
Publisher: Springer Science and Business Media LLC
Date: 06-03-2020
DOI: 10.1038/S41467-020-15065-7
Abstract: An improved understanding of etiological mechanisms in Parkinson’s disease (PD) is urgently needed because the number of affected in iduals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.
Publisher: Elsevier BV
Date: 02-2012
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.BIOPSYCH.2007.09.002
Abstract: The P3(00) event-related potential is an index of processing capacity (P3 litude) and stimulus evaluation (P3 latency) as well as a phenotypic marker of various forms of psychopathology where P3 abnormalities have been reported. A genome-wide linkage scan of 400-761 autosomal markers, at an average spacing of 5-10 centimorgans (cM), was completed in 647 twins/siblings (306 families mostly comprising dizygotic twins), mean age 16.3, range 15.4-20.1 years, for whom P3 litude and latency data were available. Significant linkage for P3 litude was observed on chromosome 7q for the central recording site (logarithm-of-odds [LOD] = 3.88, p = .00002) and in the same region for both frontal (LOD = 2.19, p = .0015) and parietal (LOD = 1.67, p = .0053) sites, with multivariate analysis also identifying linkage in this region (LOD = 2.14, p = .0017). Suggestive linkage was also identified on 6p (LOD(max) = 2.49) and 12q (LOD(max) = 2.24), with other promising regions identified on 9q (LOD(max) = 2.14) and 10p (LOD(max) = 2.18). Less striking were the results for P3 latency LOD > 1.5 were found on chromosomes 1q, 9q, 10q, 12q, and 19p. This is a first step in the identification of genes for normal variation in the P3. Loci identified here for P3 litude suggest the possible importance of neurodevelopmental genes in addition to those influencing neurotransmitters, fitting with the evidence that P3 litude is sensitive to erse types of brain abnormalities.
Publisher: Elsevier BV
Date: 11-2009
Publisher: Wiley
Date: 31-05-2013
DOI: 10.1002/AJMG.B.32168
Publisher: Springer Science and Business Media LLC
Date: 17-04-2012
DOI: 10.1038/TP.2012.27
Publisher: Springer Science and Business Media LLC
Date: 11-10-2009
DOI: 10.1038/NG.456
Publisher: Wiley
Date: 20-04-2012
Publisher: Springer Science and Business Media LLC
Date: 25-04-2010
DOI: 10.1038/NG.573
Publisher: Oxford University Press (OUP)
Date: 06-10-2007
DOI: 10.1093/HMG/DDM295
Abstract: Seven alcohol-metabolizing enzymes are encoded by the human alcohol dehydrogenase (ADH) gene cluster on chromosome 4q22-23. One of these genes, ADH7, is uniquely expressed in the stomach mucosa and can influence metabolism of alcohol before its absorption into the blood. However, the contribution of ADH7 to the overall genetic variation in alcohol oxidation in vivo is unknown. Data on in vivo alcohol metabolism were obtained for 206 Australian twin pairs of Caucasian ancestry, following ingestion of a standard dose (0.75 g kg(-1) body weight) of alcohol. Twenty-five single nucleotide polymorphisms that cover the ADH7 encoding region were genotyped. The patterns of linkage disequilibrium among these SNPs identified a recombinational hotspot within intron 7 of the ADH7 gene. A model for the absorption and elimination of alcohol from the body led to the identification of haplotypes associated with inter-in idual variation in the early stages of alcohol metabolism. These are within a 35 kb DNA tract contained in the region 5' of intron 7 in the ADH7 gene. The region accounts for 18% of the linkage for alcohol concentration associated with the ADH region, or approximately 11% of the genetic variance.
Publisher: Wiley
Date: 04-1999
Publisher: Elsevier BV
Date: 10-2004
Publisher: Cambridge University Press (CUP)
Date: 06-2012
DOI: 10.1017/THG.2012.15
Abstract: The development of late-onset Alzheimer's disease (LOAD) is under strong genetic control and there is great interest in the genetic variants that confer increased risk. The Alzheimer's disease risk gene, growth factor receptor bound protein 2-associated protein ( GAB2 ), has been shown to provide a 1.27–1.51 increased odds of developing LOAD for rs7101429 major allele carriers, in case-control analysis. GAB2 is expressed across the brain throughout life, and its role in LOAD pathology is well understood. Recent studies have begun to examine the effect of genetic variation in the GAB2 gene on differences in the brain. However, the effect of GAB2 on the young adult brain has yet to be considered. Here we found a significant association between the GAB2 gene and morphological brain differences in 755 young adult twins (469 females) ( M = 23.1, SD = 3.1 years), using a gene-based test with principal components regression (PCReg). Detectable differences in brain morphology are therefore associated with variation in the GAB2 gene, even in young adults, long before the typical age of onset of Alzheimer's disease.
Publisher: Public Library of Science (PLoS)
Date: 13-09-2012
Publisher: Humana Press
Date: 2011
DOI: 10.1007/978-1-61779-176-5_3
Abstract: Association mapping seeks to identify marker alleles present at significantly different frequencies in cases carrying a particular disease or trait compared with controls. Genome-wide association studies are increasingly replacing candidate gene-based association studies for complex diseases, where a number of loci are likely to contribute to disease risk and the effect size of each particular risk allele is typically modest or low. Good study design is essential to the success of an association study, and factors such as the heritability of the disease under investigation, the choice of controls, statistical power, multiple testing and whether the association can be replicated need to be considered before beginning. Likewise, thorough quality control of the genotype data needs to be undertaken prior to running any association analyses. Finally, it should be kept in mind that a significant genetic association is not proof positive that a particular genetic locus causes a disease, but rather an important first step in discovering the genetic variants underlying a complex disease.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2006
DOI: 10.1007/S10519-005-9013-Z
Abstract: This study used genome-wide linkage analysis to detect Quantitative Trait Loci (QTLs) implicated in variation in general academic achievement as measured by the Queensland Core Skills Test (QCST) (Queensland Studies Authority, 2004). Data from 210 families were analysed. While no empirically derived significant or suggestive peaks for general academic achievement were indicated a peak on chromosome 2 was observed in a region where Posthuma et al. (2005) reported significant linkage for Performance IQ (PIQ) and suggestive linkage for Full Scale IQ (FSIQ), and Luciano et al. (this issue) observed significant linkage for PIQ and word reading. A peak on chromosome 18 was also observed approximately 20 cM removed from a region recently implicated in reading achievement. In addition, on chromosomes 2 and 18 peaks for a number of specific academic skills, two of which were suggestive, coincided with the general academic achievement peaks. The findings suggest that variation in general academic achievement is influenced by genes on chromosome 2 which have broad influence on a variety of cognitive abilities.
Publisher: Springer Science and Business Media LLC
Date: 30-01-2015
Publisher: Springer Science and Business Media LLC
Date: 03-06-2011
Publisher: Elsevier BV
Date: 06-2011
Publisher: Springer Science and Business Media LLC
Date: 15-06-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2009
Publisher: Springer Science and Business Media LLC
Date: 31-08-2014
DOI: 10.1038/NG.3079
Publisher: SAGE Publications
Date: 14-10-2013
Abstract: Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system which responds to therapies targeting circulating immune cells. Our aim was to test if the T-cell activation gene expression pattern (TCAGE) we had previously described from whole blood was replicated in an independent cohort. We used RNA-seq to interrogate the whole blood transcriptomes of 72 in iduals (40 healthy controls, 32 untreated MS). A cohort of 862 control in iduals from the Brisbane Systems Genetics Study (BSGS) was used to assess heritability and seasonal expression. The effect of interferon beta (IFNB) therapy on expression was evaluated. The MS/TCAGE association was replicated and rationalized to a single marker, ribosomal protein S6 (RPS6). Expression of RPS6 was higher in MS than controls ( p .0004), and lower in winter than summer ( p .6E-06). The seasonal pattern correlated with monthly UV light index ( R=0.82, p .002), and was also identified in the BSGS cohort ( p .0016). Variation in expression of RPS6 was not strongly heritable. RPS6 expression was reduced by IFNB therapy. These data support investigation of RPS6 as a potential therapeutic target and candidate biomarker for measuring clinical response to IFNB and other MS therapies, and of MS disease heterogeneity.
Publisher: Elsevier BV
Date: 07-2010
Publisher: Cambridge University Press (CUP)
Date: 06-2008
Abstract: Based on results from a survey study in a s le of Australian parents of twins, Raj and Morley (2007) reported that questions concerning the mode of conception of twins may be offensive to parents. We looked at the willingness to reply to questions about mode of conception of twin pregnancies in a large survey study that was completed by 20,150 mothers of twins from the Netherlands Twin Registry. Data collection took place in 2005/2006. The amount of missing data was examined and by using data from earlier survey studies, responders and nonresponders were compared with respect to their answers to questions on assisted reproduction techniques. In addition, we assessed the reliability of the question on mode of conception by comparing the survey data with hospital records in a subs le of 80 mothers of twins. We found no indication that mothers of twins were not prepared to reply to questions on mode of conception. Only a small number of mothers did not fill in the question on mode of conception (0.8%). Also, the use of artificial fertility techniques did not differ between mothers who returned and mothers who did not return the 2005/2006 survey. The comparison of the survey data with the hospital records showed that mothers can accurately report on the mode of conception of their twins.
Publisher: Oxford University Press (OUP)
Date: 07-11-2009
DOI: 10.1093/HMG/DDN372
Publisher: Wiley
Date: 02-1999
Publisher: Public Library of Science (PLoS)
Date: 29-05-2015
Publisher: Elsevier BV
Date: 03-2001
No related grants have been discovered for Grant Montgomery.