ORCID Profile
0000-0001-7227-632X
Current Organisations
University of Queensland
,
QIMR Berghofer Medical Research Institute
,
Tianjin University
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Publisher: Public Library of Science (PLoS)
Date: 06-05-2010
Publisher: Springer Science and Business Media LLC
Date: 12-08-2004
Publisher: Wiley
Date: 09-2008
DOI: 10.1002/GEPI.20324
Abstract: The probabilities that two in iduals share 0, 1, or 2 alleles identical by descent (IBD) at a given genotyped marker locus are quantities of fundamental importance for disease gene and quantitative trait mapping and in family-based tests of association. Until recently, genotyped markers were sufficiently sparse that founder haplotypes could be modelled as having been drawn from a population in linkage equilibrium for the purpose of estimating IBD probabilities. However, with the advent of high-throughput single nucleotide polymorphism genotyping assays, this is no longer a reasonable assumption. Indeed, the imminent arrival of in idual sequencing will enable high-density single nucleotide polymorphism genotyping on a scale for which current algorithms are not equipped. In this paper, we present a simple new model in which founder haplotypes are modelled as a Markov chain. Another important innovation is that genotyping errors are explicitly incorporated into the model. We compare results obtained using the new model to those obtained using the popular genetic linkage analysis package Merlin, with and without using the cluster model of linkage disequilibrium that is incorporated into that program. We find that the new model results in accuracy approaching that of Merlin with haplotype blocks, but achieves this with orders of magnitude faster run times. Moreover, the new algorithm scales linearly with number of markers, irrespective of density, whereas Merlin scales supralinearly. We also confirm a previous finding that ignoring linkage disequilibrium in founder haplotypes can cause errors in the calculation of IBD probabilities.
Publisher: Wiley
Date: 06-2003
DOI: 10.1111/J.1749-6632.2003.TB03199.X
Abstract: We have examined MC1R variant allele frequencies in the general population of South East Queensland and in a collection of adolescent dizygotic and monozygotic twins and family members to define statistical associations with hair and skin color, freckling, and mole count. Results of these studies are consistent with a linear recessive allelic model with multiplicative penetrance in the inheritance of red hair. Four alleles, D84E, R151C, R160W, and D294H, are strongly associated with red hair and fair skin with multinomial regression analysis showing odds ratios of 63, 118, 50, and 94, respectively. An additional three low-penetrance alleles V60L, V92M, and R163Q have odds ratios 6, 5, and 2 relative to the wild-type allele. To address the cellular effects of MC1R variant alleles in signal transduction, we expressed these receptors in permanently transfected HEK293 cells. Measurement of receptor activity via induction of a cAMP-responsive luciferase reporter gene found that the R151C and R160W receptors were active in the presence of NDP-MSH ligand, but at much reduced levels compared with that seen with the wild-type receptor. The ability to stimulate phosphorylation of the cAMP response element binding protein (CREB) transcription factor was also apparent in all stimulated MC1R variant allele-expressing HEK293 cell extracts as assessed by immunoblotting. In contrast, human melanoma cell lines showed wide variation in the their ability to undergo cAMP-mediated CREB phosphorylation. Culture of human melanocytes of known MC1R genotype may provide the best experimental approach to examine the functional consequences for each MC1R variant allele. With this objective, we have established more than 300 melanocyte cell strains of defined MC1R genotype.
Publisher: Springer Science and Business Media LLC
Date: 08-12-2011
Publisher: Elsevier BV
Date: 02-2002
DOI: 10.1086/338658
Publisher: Oxford University Press (OUP)
Date: 05-11-2008
DOI: 10.1093/JNCI/DJN345
Abstract: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction lification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood s les obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2 P = .02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8 P = .005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] of breast or ovarian cancer = 0.37, 95% CI = 0.14 to 0.95 P = .04). Among BRCA2 mutation carriers, skewed X inactivation also occurred more frequently in unaffected carriers than in those diagnosed with breast or ovarian cancer (OR = 5.2, 95% CI = 0.5 to 28.9 P = .08) and was associated with delayed age at onset (HR = 0.59, 95% CI = 0.37 to 0.94 P = .03). Skewed X inactivation occurs at an increased frequency in BRCA1 (and possibly BRCA2) mutation carriers compared with control subjects and is associated with a statistically significant increase in age at diagnosis of breast and ovarian cancer.
Publisher: Oxford University Press (OUP)
Date: 30-06-2014
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: S. Karger AG
Date: 2014
DOI: 10.1159/000358217
Abstract: Acquired melanocytic naevi (AMN) are a well-known risk factor for the development of melanoma. Whereas previous studies have reviewed AMN distributions on in idual body sites, the clinical distribution of AMN on the adult trunk has not been thoroughly investigated. We studied 40 participants with 1,282 naevi mm, of which 781 were located on the trunk. Remarkably, 70% of these truncal naevi were located on the back and we produced a continuous mathematical description of decreasing naevus frequency moving dorsolaterally from the back midline. Furthermore we found that for both sexes the mean naevus size was larger on the front as well as on the lower trunk. This distinct pattern, whilst probably being unwritten knowledge (in the dermatology domain), has not been discussed before.
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: Oxford University Press (OUP)
Date: 28-09-2023
DOI: 10.1093/BJD/LJAD365
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: Wiley
Date: 19-12-1997
DOI: 10.1002/(SICI)1096-8628(19971219)73:3<337::AID-AJMG21>3.0.CO;2-J
Abstract: Extensive epidemiological and genetic studies of the cause of oral clefts have demonstrated strong familial aggregation but have failed to yield definitive evidence of any single genetic mechanism. We used the transmission/disequilibrium test (TDT) to investigate the relationship between oral clefts and markers associated with five candidate genes by utilizing 160 parent-offspring trios. Conditional logistic regression models extended the TDT to include covariates as effect modifiers, thus permitting tests for gene-environment interactions. For four of these candidates [transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGFB3), retinoic acid receptor (RARA), and the proto-oncogene BCL3], we detected modestly elevated odds ratios for the transmission of one marker allele to cleft probands when all the trios were analyzed together. These odds ratios increased when information on type of cleft, race, family history, or maternal smoking were incorporated as effect modifiers. We detected significant interaction between maternal smoking and the transmission of alleles for markers near TGFA and TGFB3 excess transmission of allele 3 at BCL3 was most significant among cleft lip probands and the odds ratios for transmission of alleles at D19S178 and THRA1 were significant when ethnic group was included in the model. We suggest that utilizing an analytical strategy that allows for stratification of data and incorporating environmental effects into a single analysis may be more effective for detecting genes of small effect.
Publisher: Wiley
Date: 17-11-2011
DOI: 10.1111/J.1398-9995.2010.02504.X
Abstract: To examine the relationship between asthma, type 2 diabetes and increased body mass index (BMI) in adult twins. We performed record linkage between questionnaire-defined asthma and BMI, and hospital discharge diagnoses of type 2 diabetes in 34,782 Danish twins, 20-71 years of age. The risk of asthma was increased in subjects with type 2 diabetes relative to nondiabetic subjects both in men (13.5%vs 7.5%), P = 0.001 and in women (16.6%vs 9.6%), P = 0.001. The result remained significant after adjustment for age, BMI, smoking, symptoms of chronic bronchitis, marital status and zygosity, men: OR = 1.70 (1.07-2.70), P = 0.026 women: OR = 1.88 (1.24-2.85), P = 0.003. In this analysis, BMI remained a highly significant predictor for asthma independently of diabetes status in women, P < 0.000 but not in men, P = 0.336. Significant positive genetic correlations were found between asthma and type 2 diabetes, 0.20 (0.01-0.40), P = 0.047 between asthma and BMI in women, 0.15 (0.07-0.22), P < 0.000 and between BMI and type 2 diabetes, 0.40 (0.29-0.43), P < 0.000. Asthma, type 2 diabetes and increased BMI are strongly associated in adults, particularly in women. These results suggest a common aetiology for asthma and metabolic syndrome.
Publisher: Oxford University Press (OUP)
Date: 31-07-2007
DOI: 10.1093/HMG/DDM268
Publisher: Oxford University Press (OUP)
Date: 08-04-2010
Publisher: Elsevier BV
Date: 08-1992
Publisher: Wiley
Date: 03-1991
DOI: 10.1111/J.1365-2222.1991.TB00835.X
Abstract: We have examined the relationship between month of birth and episodes of wheezing, productive cough, eczema and hayfever, and also standardized maximum mid-expiratory flow (FEF25-75) in a representative s le of 4549 Australian primary schoolchildren (mean age 10.1 years). Children experiencing frequent wheezing (one or more episodes per month) were more likely to be born in spring and summer (odds ratio = 1.6, 95% confidence interval = 1.1-2.4), but this was not seen for less severe disease. No effect of season or birth month was seen for the other illnesses examined or for lung function.
Publisher: Oxford University Press (OUP)
Date: 08-07-2008
Publisher: Wiley
Date: 26-01-2011
DOI: 10.1111/J.1365-3164.2010.00939.X
Abstract: Human and canine atopic dermatitis (AD) share an association with IgE specific to environmental allergens, but few studies have evaluated serum allergen-specific IgE in nonatopic dogs. This study compared serum allergen-specific IgE levels in 30 atopic and 18 nonatopic West Highland white terriers. Atopic dermatitis was confirmed using standard criteria. Nonatopic dogs were over 5 years of age and had no clinical signs or history of AD. Serum allergen-specific IgE levels were measured with Allercept(®) IgE ELISAs using a 48-allergen Australian panel. Positive reactions were defined as ≥150 ELISA absorbance units. Intradermal tests were performed in 16 atopic dogs, either at the time of or at various times prior to serum collection. In atopic dogs, the most common positive ELISA and intradermal test results were to Dermatophagoides farinae (11 of 30 dogs), but there were no statistically significant correlations between results from the two methods for any allergen. In nonatopic dogs, multiple high-positive ELISA reactions were reported to 45 of 48 allergens, most commonly D. farinae and Tyrophagus putrescentiae (17 of 18 dogs each). Positive ELISA results in nonatopic dogs were statistically significantly higher than those in atopic dogs for 44 of 48 allergens, including two allergens (D. farinae and Dermatophagoides pteronyssinus) commonly regarded as significant in canine AD. In conclusion, positive allergen-specific IgE ELISAs were not specific for canine AD, and high allergen-specific IgE levels were seen in nonatopic dogs. The clinical significance of this and whether it characterizes a protective phenotype is unclear.
Publisher: Cambridge University Press (CUP)
Date: 02-2008
DOI: 10.1375/TWIN.11.1.28
Abstract: Twin studies of diabetes mellitus can help elucidate genetic and environmental factors in etiology and can provide valuable biological s les for testing functional hypotheses, for ex le using expression and methylation studies of discordant pairs. We searched the volunteer Australian Twin Registry (19,387 pairs) for twins with diabetes using disease checklists from nine different surveys conducted from 1980–2000. After follow-up questionnaires to the twins and their doctors to confirm diagnoses, we eventually identified 46 pairs where one or both had type 1 diabetes (T1D), 113 pairs with type 2 diabetes (T2D), 41 female pairs with gestational diabetes (GD), 5 pairs with impaired glucose tolerance (IGT) and one pair with MODY. Heritabilities of T1D, T2D and GD were all high, but our s les did not have the power to detect effects of shared environment unless they were very large. Weight differences between affected and unaffected cotwins from monozygotic (MZ) discordant pairs were large for T2D and GD, but much larger again for discordant dizygotic (DZ) pairs. The bivariate genetic analysis (under the multifactorial threshold model) estimated the genetic correlation between body mass index (BMI) and T2D to be 0.46, and the environmental correlation at only 0.06.
Publisher: Elsevier BV
Date: 07-2004
Publisher: Springer Science and Business Media LLC
Date: 12-05-2015
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1086/510885
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1086/432960
Publisher: Springer Science and Business Media LLC
Date: 13-11-2012
Publisher: American Thoracic Society
Date: 15-06-2009
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: BMJ
Date: 03-2005
Publisher: Wiley
Date: 12-05-2014
DOI: 10.1111/PCMR.12253
Publisher: Springer Science and Business Media LLC
Date: 05-07-2009
DOI: 10.1038/NG.410
Publisher: Wiley
Date: 11-2004
DOI: 10.1111/J.1365-2222.2004.02094.X
Abstract: Cyclooxygenase (COX)-2 is a key inducible enzyme that regulates the production of anti-inflammatory prostaglandin E(2). A single-nucleotide polymorphism, -765G>C, located within a stimulatory protein-1 binding site in the COX-2 promoter region, has been shown to have significantly lower promoter activity in vitro compared with the wild-type and was associated with decreased plasma levels of C-reactive protein after coronary artery bypass surgery. We hypothesized that this polymorphism, which may result in decreased COX-2 transcription, could be associated with more severe asthma, and/or aspirin-intolerant asthma (AIA). To determine the association between the -765G>C COX-2 polymorphism and asthma, disease severity and AIA in a large, well-phenotyped Australian population. PCR and restriction fragment length polymorphism analysis was used to characterize the polymorphism in an Australian Caucasian population of patients with mild (n=322), moderate (n=254) or severe (n=88) asthma and in non-asthmatic control subjects (n=512), as well as in patients with AIA (n=58). Genotype and allele association analyses were performed using chi(2) tests. The polymorphic -765C allele was present in approximately 30% of asthmatic patients and non-asthmatic controls. There was no association between the -765G>C polymorphism and asthma (P=0.920), disease severity (P=0.840), atopy (P=0.655) or AIA (P=0.841) in this population. Although the -765G>C polymorphism may have lower promoter activity and result in decreased COX-2 expression, it is not associated with asthma, disease severity, AIA or atopy in this Australian population.
Publisher: Wiley
Date: 1993
Abstract: We performed multivariate genetic analyses of cardiovascular risk factors from two sets of data on US and Australian female twins. Similar models for body mass index (BMI), serum low density (LDL) and high density (HDL) lipoproteins, including age as a covariate, were fitted successfully to both groups. These suggested that BMI, or genes responsible for a significant proportion of the variance of BMI, explained correlations between lipid subfractions, as well as those between blood pressure and lipid subfractions, especially HDL.
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: Springer Science and Business Media LLC
Date: 03-2004
Publisher: Elsevier BV
Date: 12-2011
Publisher: Cambridge University Press (CUP)
Date: 12-2004
Publisher: Cambridge University Press (CUP)
Date: 10-2019
DOI: 10.1017/THG.2019.82
Abstract: A high prevalence of asthma has been documented among the inhabitants of Tristan da Cunha, an isolated island in the South Atlantic. The population derives from just 28 founders. We performed lung function testing, including methacholine inhalation challenge, allergen skin prick testing, and collected DNA from essentially all of the current island population (269 in iduals), and genotyped a panel of 43 single-nucleotide polymorphisms (SNPs) reported as associated with asthma and atopy. We carried out a mixed-model association analysis using the known pedigree. There were 96 in iduals diagnosed as asthmatic (36%), and heritability estimates were similar to those from nonisolated population s les (multifactorial threshold model, h 2 = 48%). The first component from a genetic principal components analysis using the entire SNP panel was nonlinearly associated with asthma, with the maximum risk to those intermediate to reference (Human Genome Diversity Project) European and African s les means. The single most strongly associated SNP was rs2786098 ( p = 5.5 × 10 −5 ), known to regulate the gene DENND1B . This explained approximately one-third of the trait heritability, with an allelic odds ratio for the A allele of 2.6. Among A/A carriers, 10 out of 12 in iduals were asthmatic. The rs2786098*A variant was initially reported to decrease the risk of childhood (atopic) asthma in European but slightly increase the risk in African-descended populations, and does significantly alter Th2 cell function. Despite an absence of overall association with this variant in recent asthma genome wide association studies meta-analyses, an effect may exist on the particular genetic background of the Tristan da Cunha population.
Publisher: Elsevier BV
Date: 05-2022
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: Elsevier BV
Date: 05-1993
Publisher: Wiley
Date: 14-07-2009
DOI: 10.1111/J.1365-2052.2009.01863.X
Abstract: Bull terrier polycystic kidney disease (BTPKD) is a Mendelian disorder with many features reminiscent of human autosomal dominant polycystic disease, the latter disease being due to mutations at PKD1 and PKD2 loci. We investigated the role of the canine pkd1 orthologue in BTPKD via linkage analysis of a large kindred in which the disorder is segregating. Twelve microsatellite markers around the canine pkd1 locus (CFA6) were lified from the genomic DNA of 20 affected and 16 unaffected bull terriers. An additional 28 affected dogs were genotyped at five key microsatellites. A highly significant multi-point LOD score that peaked over the canine pkd1 locus was observed (LOD = 6.59, best two-point LOD score LOD = 6.02), implicating this as the BTPKD locus.
Publisher: MDPI AG
Date: 27-02-2021
Abstract: Visceral hemangiosarcoma (HSA) is one of the more frequent cancers in dogs and has a high metastatic rate and poor prognosis, as clinical signs only become apparent in advanced stages of tumor development. In order to improve early and differential diagnostic capabilities and hence, prognosis for dogs with HSA, two types of biomarker are needed: a point-of-care diagnostic biomarker and a prognostic biomarker—preferentially based on s les obtained with minimally invasive methods. In this study, we applied a lectin magnetic bead array-coupled tandem mass spectrometry (LeMBA-MS/MS) workflow through discovery and validation phases to discover serum glycoprotein biomarker candidates for canine HSA. By this approach, we found that Datura stramonium (DSA), wheat germ agglutinin (WGA), Sambucus nigra (SNA), and Pisum sativum (PSA) lectins captured the highest number of validated candidate glycoproteins. Secondly, we independently validated serum LeMBA-MS/MS results by demonstrating the in situ relationship of lectin-binding with tumor cells. Using lectin-histochemistry and immunohistochemistry (IHC) for key proteins on tissues with HSA and semi-quantitation of the signals, we demonstrate that a combination of DSA histochemistry and IHC for complement C7 greatly increases the prospect of a more specific diagnosis of canine HSA.
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: Elsevier BV
Date: 09-2009
DOI: 10.1038/JID.2009.48
Publisher: Springer Science and Business Media LLC
Date: 24-05-2006
Abstract: Univariate linkage analysis is used routinely to localise genes for human complex traits. Often, many traits are analysed but the significance of linkage for each trait is not corrected for multiple trait testing, which increases the experiment-wise type-I error rate. In addition, univariate analyses do not realise the full power provided by multivariate data sets. Multivariate linkage is the ideal solution but it is computationally intensive, so genome-wide analysis and evaluation of empirical significance are often prohibitive. We describe two simple methods that efficiently alleviate these caveats by combining P-values from multiple univariate linkage analyses. The first method estimates empirical pointwise and genome-wide significance between one trait and one marker when multiple traits have been tested. It is as robust as an appropriate Bonferroni adjustment, with the advantage that no assumptions are required about the number of independent tests performed. The second method estimates the significance of linkage between multiple traits and one marker and, therefore, it can be used to localise regions that harbour pleiotropic quantitative trait loci (QTL). We show that this method has greater power than in idual univariate analyses to detect a pleiotropic QTL across different situations. In addition, when traits are moderately correlated and the QTL influences all traits, it can outperform formal multivariate VC analysis. This approach is computationally feasible for any number of traits and was not affected by the residual correlation between traits. We illustrate the utility of our approach with a genome scan of three asthma traits measured in families with a twin proband.
Publisher: Springer Science and Business Media LLC
Date: 07-1995
DOI: 10.1038/NG0795-260A
Publisher: Public Library of Science (PLoS)
Date: 27-07-2011
Publisher: Wiley
Date: 04-09-2009
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: Public Library of Science (PLoS)
Date: 08-01-2016
Publisher: Wiley
Date: 12-01-2006
DOI: 10.1111/J.1398-9995.2006.01004.X
Abstract: The liability to asthma is influenced both by genetic and environmental factors. The objective of this study was to identify risk factors for asthma in young adult twin pairs during an 8-year period. From the birth cohorts 1953-1982 of the Danish Twin Registry, 6,090 twin pairs who were initially unaffected with respect to asthma at a nationwide questionnaire-based study in 1994 participated in a similar follow-up study in 2002. Subjects were regarded incident asthma cases when responding affirmatively to the question 'Do you have, or have you ever had asthma'? in 2002. Pairs in which only one twin developed asthma -- discordant pairs -- were identified and conditional logistic regression was applied to detect effects of risk factors. A total of 126 monozygotic (MZ) and 273 dizygotic (DZ) discordant twin pairs were identified. In MZ twins hay fever (OR = 3.16, 95% CI: 1.29-7.73, P = 0.007) and exercise (OR for inactivity = 0.35, 95% CI: 0.13-0.91, P = 0.023) were significantly associated with asthma, whereas in DZ twins, hay fever (OR = 2.44, 95% CI: 1.44-4.13, P = 0.001), eczema (OR = 1.96, 95% CI: 1.02-3.78, P = 0.040), female sex (OR between males and females = 0.54, 95% CI: 0.36-0.80, P = 0.002), and increasing levels of body mass index (BMI OR per unit = 1.11, 95% CI: 1.02-1.20, P = 0.009) were significant predictors of asthma. Hay fever, eczema, female sex, exercise and increasing levels of BMI were risk factors for asthma in young adults. The different risk profile observed in MZ twins compared with DZ twins may reflect an underlying genetic vulnerability shared between those risk factors and asthma.
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: Springer Science and Business Media LLC
Date: 03-08-2015
DOI: 10.1038/NG.3373
Publisher: Elsevier BV
Date: 03-1995
Publisher: Oxford University Press (OUP)
Date: 17-09-2011
DOI: 10.1093/HMG/DDR415
Publisher: Wiley
Date: 22-03-2004
DOI: 10.1002/AJMG.B.30014
Abstract: Until recently, cortical Lewy body disease (CLB) was considered essentially the same as dementia with Lewy bodies (DLB). It is now known patients with Parkinson's disease (PD) with a later-onset dementia (PD-dementia) have the same pattern and extent of cortical Lewy body pathology. Inheritance patterns of CLB have not been evaluated previously. To identify genetic influence on CLB, all cases with this pathology need to be considered. We selected 180 cases meeting clinical and/or pathological criteria for DLB or PD (+/-dementia) from two patient groups: a PD and PD-dementia brain donor program, and a case-control study of Alzheimer's disease (AD). Cases meeting NINCDS-ADRDA criteria for probable AD were excluded and non-demented PD cases used as a comparison group. A detailed family history was taken analyzing onset and progression of dementia and PD phenotypes and a family tree constructed. The frequency of a positive family history of dementia and/or PD and risk of developing CLB in relatives was calculated. Fifty-five percent of dementia and 52% of PD cohorts did not have relatives with clinical disease. There was no increased frequency of familial disease in the CLB cohort compared with PD. However, in half the CLB families, rather than a dominant dementia, the clinical presentation varied (dementia and/or PD). Unlike PD, there was an increased risk of dementia if CLB was present in a parent ( approximately 20% risk) compared with another family member ( approximately 5% risk), suggesting CLB is more likely than PD to occur in a pattern consistent with autosomal dominant inheritance.
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: Oxford University Press (OUP)
Date: 17-07-2019
DOI: 10.1111/BJD.17833
Abstract: A high total body naevus count is the highest risk factor for melanoma the phenotype of red hair colour, freckling and pale skin that burns easily, produced by MC1R R alleles, also predisposes to melanoma. To determine whether the known melanoma risk factors of high naevus count and red hair or MC1R R alleles act synergistically to increase melanoma risk. The Brisbane Naevus Morphology Study involved 1267 participants from volunteers presenting at a melanoma unit, dermatology outpatient clinic, private dermatology clinics, the Brisbane Longitudinal Twin Study and the QSkin Study. We examined pigmentation characteristics, total body naevus ≥ 5 mm count, and MC1R, ASIP and CDKN2A genotype in participants with and without a personal history of melanoma, living in Queensland, Australia, which is an area of high ultraviolet radiation. Cases were older than controls (median 57 vs. 33 years). Compared with in iduals with dark brown hair and zero to four naevi, in iduals with red hair and ≥ 20 naevi had a melanoma odds ratio of 10·0 (95% confidence interval 4·2-24·3). In iduals with MC1R R/R genotype and ≥ 20 naevi (≥ 5 mm diameter) had a melanoma odds ratio of 25·1 (95% confidence interval 8·4-82·7) compared with wild-type (WT)/WT in iduals with zero to four naevi. The highest risk group is Australian men with the MC1R R/R genotype and ≥ 20 moles, who have an absolute risk of melanoma to age 75 years of 23·3%, compared with 0·8% for men with the WT/WT genotype and zero to four naevi. Patients who live in areas of high ultraviolet radiation, and have many large naevi and the red hair colour phenotype, particularly those with the MC1R R/R genotype, have a high risk of melanoma above the threshold recommended for screening in other cancers. Therefore, they should undergo intensive physician-led surveillance. What's already known about this topic? A high number of acquired melanocytic naevi, the red hair phenotype and MC1R R alleles all independently increase melanoma risk. Women with atypical naevi have an increasing melanoma risk gradient from darker hair to lighter hair. Women with many naevi have an increasing melanoma risk gradient from those with no elements of the red hair phenotype, to those with freckles but not red hair, to those with red hair. What does this study add? In Queensland, Australia, people with ≥ 20 naevi (≥ 5 mm diameter) and MC1R R/R genotype have a 25-fold increased melanoma risk, relative to people with zero to four naevi and the MC1R WT/WT genotype. In Queensland, in iduals with ≥ 20 naevi and the MC1R R/R genotype have an absolute melanoma risk to age 75 years of 23·3% for men and 19·3% for women. This effect is independent of CDKN2A genotype. Further research is required to determine the effect of areas of lower ultraviolet radiation, as this study took place in the Queensland, Australia, which is an area of high ultraviolet radiation. MC1R R/r genotype is associated with increased total body naevus count but this is not the case for R/R. What is the translational message? Patients with many large naevi and the red hair colour phenotype, particularly those with an MC1R R/R genotype, have an unusually high risk of melanoma. In a high ultraviolet environment, this risk exceeds the threshold recommended for screening in other cancers, and such in iduals should undergo intensive, regular, physician-led surveillance. Patients with many large naevi but with non-red colour hair may benefit further from clinical MC1R genotyping.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2011
DOI: 10.1038/NATURE10630
Publisher: Wiley
Date: 06-1995
Abstract: To quantify the magnitude and distribution of osteoporosis in rheumatoid arthritis (RA). Bone mineral density (BMD) was measured by dual x-ray absorptiometry, in a monozygotic co-twin control study. BMD was reduced at most skeletal sites in the twin with RA compared with the co-twin (lumbar spine 4.6%, femoral neck 9.7%, total body 5.7%). Differences in lean soft tissue (5.6% for total body) correlated with differences in BMD between twins at multiple sites. Osteoporosis in RA is generalized and may be related to loss of mobility or muscle mass associated with the disease.
Publisher: Wiley
Date: 02-12-2014
DOI: 10.1111/JSAP.12156
Abstract: To determine the heritability of extra-hepatic portosystemic shunts and elevated post-prandial serum bile acid concentrations in Maltese dogs. Maltese dogs were recruited and investigated by a variable combination of procedures including dynamic bile acid testing, rectal ammonia tolerance testing, ultrasonography, portal venography, surgical inspection or necropsy. In addition, nine test matings were carried out between affected and affected dogs, and affected and unaffected dogs. In 135 variably related Maltese, shunt status could be confirmed in 113, including 19 with an extra-hepatic portosystemic shunt (17 confirmed at surgery, 2 at necropsy). Rectal ammonia tolerance testing results and post-prandial serum bile acid concentrations were retrievable for 50 and 88 dogs, respectively. Pedigree information was available for these 135 and an additional 164 related dogs. Two consecutive test matings were carried out between two affected animals (whose shunts had been attenuated), with 2 of 8 (25%) of offspring having an extra-hepatic portosystemic shunt. Six test matings were carried out between an affected and an unaffected animal, with 2 of 22 (9%) offspring affected. Heritability of extra-hepatic portosystemic shunt was 0·61 calculated using variance components analysis [95% confidence interval (CI) 0·14 to 1·0, P=0·001]. The best fitting model from segregation analysis was a common, partially penetrant, recessive model (allele frequency 0·34, penetrance 0·99, CI 0·09 to 1·0). The heritability of elevated post-prandial serum bile acid (and thus likely portal vein hypoplasia) was 0·81 (CI 0·43 to 1·0, P=0·2) after logarithmic transformation of post-prandial serum bile acid concentrations. There is strong support for extra-hepatic portosystemic shunts and elevated post-prandial serum bile acid concentrations both being inherited conditions in Maltese.
Publisher: Wiley
Date: 03-1998
DOI: 10.1046/J.1365-2222.1998.00223.X
Abstract: Both genetic and environmental factors are thought to contribute to specific IgE responses, however, the relative contribution of each in the responses to in idual ryegrass pollen allergens is largely unknown even though some responses to allergens have been linked to certain HLA complexes. Using a large group of monozygotic and dizygotic twins, this study was designed to investigate the IgE binding profiles of in idual ryegrass pollen (Lolium perenne) components to assess the relative contribution of genetic and environmental factors in determining IgE responses to specific allergens. Ryegrass pollen proteins were separated by electrophoresis and immunoblotted with sera from 191 pairs of twins where at least one sibling had a SPT > 2 mm to perennial ryegrass. Concordance levels for in idual ryegrass pollen components were compared between monozygotic and dizygotic twins in a subset group where both twins had SPT > 3 mm to perennial ryegrass. Immunoblotting revealed 23 in idual IgE-binding components from ryegrass pollen. Although there was a significantly greater proportion of monozygotic twins with SPT wheals greater than 3 mm when compared with the dizygotic twins, the mean case-wise concordance for the immunoblot components was similar for both groups of twins. The mean case-wise concordance when at least four pairs of sera were involved was 44% for the MZ twins (n=11 components) and 45% for the DZ twins (n=12 components). We found no significant differences in concordance levels for any of the 23 in idual components including allergens previously associated with HLA. Evidence for genetic control of allergen-specific IgE responses in a large population s le of twins to in idual ryegrass allergens is limited, indicating that the IgE responses to specific ryegrass pollen allergens are determined largely by environmental factors.
Publisher: Cambridge University Press (CUP)
Date: 04-2001
Abstract: Twins taking part in two unrelated studies were sent a questionnaire together with a self-addressed envelope that either carried one or multiple (up to 5) st s to the same value. The unprompted proportion of questionnaires returned (before commencement of telephone reminder calls) was increased from 62% to 71% in one study, and from 43% to 52% in the other study (test for common odds ratio in studies, p = 0.04).
Publisher: Springer Science and Business Media LLC
Date: 21-11-2016
Publisher: BMJ
Date: 08-2005
Publisher: Public Library of Science (PLoS)
Date: 23-09-2020
Publisher: Elsevier BV
Date: 07-2019
Publisher: Elsevier BV
Date: 10-1996
Abstract: To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum IgE concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to this region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) controlling asthma and the associated "high total IgE" trait.
Publisher: Public Library of Science (PLoS)
Date: 10-10-2012
Publisher: Wiley
Date: 1997
DOI: 10.1002/(SICI)1098-2272(1997)14:6<815::AID-GEPI42>3.0.CO;2-Q
Publisher: SAGE Publications
Date: 05-1997
Publisher: Wiley
Date: 12-2011
DOI: 10.1111/J.1398-9995.2010.02517.X
Abstract: To study the association between type 1 diabetes and atopic diseases in a twin population. We performed record linkage between questionnaire-defined atopic dermatitis, asthma and hay fever, and hospital discharge diagnoses of type 1 diabetes in 54,530 Danish twins, 3-71 years of age. The age- and sex-adjusted risk of atopic dermatitis was decreased in subjects with type 1 diabetes compared with nondiabetic subjects, (2.1%vs 9.9%), odds ratio (OR)= 0.23 (0.07-0.71), P = 0.011, whereas asthma and hay fever were not significantly associated with type 1 diabetes. Within twin pairs discordant for type 1 diabetes, the diabetic twin had a lower risk of atopic dermatitis relative to the nondiabetic co-twin. Genetic factors for atopic dermatitis and type 1 diabetes were negatively correlated (r = -0.30), P = 0.0009. These findings substantiate the Th1 vs Th2 cell dichotomy for type 1 diabetes and atopic dermatitis, and indicate an inverse association between genetic factors for these disorders.
Publisher: BMJ
Date: 03-1992
DOI: 10.1136/ARD.51.3.375
Abstract: Although a genetic predisposition to gout has been recognised for centuries, its mechanism has never been defined. This study was designed to determine whether this factor might be the renal clearance of urate, which is an important determinant of the concentration of urate in serum. In this study the renal clearance of urate was examined in 37 pairs of normouricaemic twins to determine whether this resemblance was genetically mediated. Monozygotic twins had more similar values of urate clearance and fractional excretion of urate than dizygotic twins. The heritability of the renal clearance of urate was estimated as about 60% (95% confidence limits 40 to 100%), whereas the heritability of the fractional excretion of urate was 87% (confidence limits 45 to 100%). This study supports the hypothesis that genetic factors exert an important control on the renal clearance of urate, which determines some of the familiarity of hyperuricaemia and gout.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.IJROBP.2009.07.1690
Abstract: The melanocortin-1 receptor (MC1R) regulates melanin biogenesis. Deoxyribonucleic acid sequence variants in the form of single nucleotide polymorphisms (SNPs) of MC1R affect melanin expression and are linked to skin phenotype. We aimed to determine whether SNPs of MC1R were associated with unexpectedly severe ionizing radiation reactions. The MC1R genotype of a cohort of Australians with unexpectedly severe acute and/or late reactions (Common Terminology Criteria Version 3 (CTCv3) Grade 3 or 4) to radiotherapy (RT) for cancer (n = 30) was analyzed. The findings were compared with control data from our previous study of MC1R representative of the general Australian population (n = 1,787). The difference in frequency of alleles encoding a "red hair color" phenotype in the cohort of patients with unexpectedly severe acute radiation reactions (n = 12) was significantly increased compared with the control population (p = 0.003). Acute radiosensitivity was especially associated with the R160W variant allele (odds ratio, 3.64 [95% confidence interval, 1.3-10.27]). The corresponding comparison of MC1R controls with unexpectedly severe late radiation reactions (n = 18) was not significant. It was also found that R160W as a part of the genotype in the patients with unexpectedly severe acute RT side effects as compared with the control group was also significant (p = 0.043). In this small cohort of cancer patients, deoxyribonucleic acid sequence variants of the MC1R gene, especially the R160W variant, have been associated with unexpectedly severe acute reactions to RT. This result needs to be verified in a larger cohort of patients.
Publisher: Elsevier BV
Date: 12-2005
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: Springer Science and Business Media LLC
Date: 08-05-2018
DOI: 10.1038/S41467-018-04086-Y
Abstract: The skin’s tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.
Publisher: Springer Science and Business Media LLC
Date: 03-1998
DOI: 10.1007/S10787-998-0009-1
Abstract: To compare methodological aspects of the impact of different classification procedures used in three phases of a twin study examining genetic factors in the aetiopathogenesis of rheumatoid arthritis (RA). We have previously reported the results of a study of the aetiopathogenesis of RA based on the Australian Twin Registry (ATR). In the original 258 pairs self-reporting a diagnosis of RA in twin, co-twin or both, a very high false positive self-reporting rate for RA was noted (Phase 1). Subsequent diagnostic information obtained by a disease-specific questionnaire, followed by telephone interviews with subjects and review of information obtained by mail and telephone interview from the patient's general practitioner or musculoskeletal specialist, identified 23 'true' RA pairs (Phase 2). Pairwise concordance percentages for RA based on those 20 discordant and 3 concordant pairs were as follows: monozygotic (MZ) 21% (95% confidence interval (CI)=6-44%), dizygotic (DZ) 0% (95% CI=0-25%) (probandwise concordance MZ 35% (8.9-67.3), DZ 0% (0-50.3)). Given the potential effects of misclassification on data interpretation, we have further pursued the accuracy of diagnosis by a systematic clinical, serological and radiographical evaluation of the 23 RA pairs (Phase 3). In only one instance did more intense diagnostic investigation of the 23 pairs result in recategorization. The probandwise concordance percentages were recalculated: MZ=37.5%, DZ=0%. Our original contention that genetic factors play some part in the aetiopathogenesis of RA, but do not account entirely for its determination, has been substantiated at a higher level of confidence and at almost identical levels of concordance.
Publisher: Cambridge University Press (CUP)
Date: 04-2009
Abstract: Appendicitis usually afflicts the young, but there is a large tail in the distribution of onset age. The genetics of this disease are still not well understood. A heritability analysis and genome wide linkage analysis of a large twin dataset was undertaken. Treating age of onset of appendicitis as a censored survival trait revealed a heritability of 0.21, and found evidence of linkage to Chromosome 1p37.3.
Publisher: Wiley
Date: 15-05-2000
DOI: 10.1002/(SICI)1097-0258(20000515)19:9<1217::AID-SIM421>3.0.CO;2-Q
Abstract: Multi-wave self-report data on age at menopause in 2182 female twin pairs (1355 monozygotic and 827 dizygotic pairs), were analysed to estimate the genetic, common and unique environmental contribution to variation in age at menopause. Two complementary approaches for analysing correlated time-to-onset twin data are considered: the generalized estimating equations (GEE) method in which one can estimate zygosity-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modelled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs s ling using the freeware package BUGS.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.JID.2017.04.026
Abstract: Loss of fine skin patterning is a sign of both aging and photoaging. Studies investigating the genetic contribution to skin patterning offer an opportunity to better understand a trait that influences both physical appearance and risk of keratinocyte skin cancer. We undertook a meta-analysis of genome-wide association studies of a measure of skin pattern (microtopography score) damage in 1,671 twin pairs and 1,745 singletons (N = 5,087) drawn from three independent cohorts. We identified that rs185146 near SLC45A2 is associated with a skin aging trait at genome-wide significance (P = 4.1 × 10
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: Wiley
Date: 20-03-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2008
Publisher: Cambridge University Press (CUP)
Date: 10-2002
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-04-1997
DOI: 10.1126/SCIENCE.276.5309.17B
Abstract: Lamotrigine is commonly prescribed for the treatment of neurological conditions and is increasingly being prescribed for psychiatric conditions as well. Although largely well tolerated, it is known to have a number of potential side effects, and in March 2021, the FDA issued its most recent warning for the medication due to its increased risk of cardiac arrhythmias. In this report, we describe a case in which an adolescent patient was found to be bradycardic after starting lamotrigine for antidepressant augmentation, with a gradual return to normal heart rate as the medication was subsequently tapered and discontinued. Further research is needed to more accurately estimate the risk of cardiac side effects and to establish appropriate monitoring guidelines for cardiac arrhythmias in those taking lamotrigine.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2008
DOI: 10.1007/S10549-007-9627-3
Abstract: Association studies aimed at identifying breast cancer susceptibility variants in the progesterone receptor (PGR) gene have been previously reported in the literature with conflicting results, ranging from a protective effect conferred by the PROGINS allele in German Caucasian women, to an increased risk for the leucine variant of the Val660Leu (rs1042838) polymorphism in East Anglian cases. We report the results of genotype and haplotype analyses of five PGR polymorphisms, +44C/T (rs518162), +331G/A (rs10895068), V660L (rs1042838), H770H (rs1042839) and Q886Q (rs500760), conducted on 1,847 Australian breast cancer cases (including 276 cases from a cohort of multiple-case breast cancer families) and 833 controls. Genotype and haplotype analyses of the five polymorphisms showed no evidence of an association with breast cancer (p>0.3). We also conducted a meta-analysis of the V660 L (rs1042838) polymorphism on our and six other published studies including 10,205 cases and 11,320 controls. Compared to the VV homozygotes, VL heterozygotes and LL homozygotes were associated with a non-significant increased risk for breast cancer [Odds ratio (OR)VL, 1.06 95% confidence intervals (95% CI), 0.97-1.15, ORLL, 1.05 95% CI, 0.75-1.49]. Analysis of a per-leucine allele risk under a codominant model, however, suggested a significant leucine-allele dose effect, ORper-L, 1.07 95% CI, 1.02-1.13, p=0.01. We conclude that the leucine allele of the V660L SNP may be associated with a small increase in breast cancer risk, while the other four PGR SNPs, +44C/T (rs518162), +331G/A (rs10895068), H770H (rs1042839) and Q886Q (rs500760), do not substantially increase breast cancer risk.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.JID.2021.08.449
Abstract: Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be combined while accounting for s le overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci, 19 of them were not previously reported in the input cutaneous melanoma GWAS meta-analysis. Of these loci, 55 were replicated (P < 0.05/74, Bonferroni-corrected P-value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the, to our knowledge, previously unreported cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2005
DOI: 10.1007/S00439-005-0066-0
Abstract: EPAS1 is a gene involved in complex oxygen sensing. It is expressed in microvascular endothelial cells, lung epithelial cells, cardiac myocytes and the brain. An association study was undertaken comparing elite endurance athletes classified into two groups according to a power-time model of performance intensity: power-time-maximum (PT-MAX N=242, event duration 50 s to 10 min) and power-time-steady state (PT-SS N=151, event duration ~2-10 h), with normal controls (N=444) using 12 SNPs across EPAS1. Ordinal regression analysis of allele frequencies revealed significant differences at SNPs 2 and 3 (P=0.01). Haplotype analysis revealed the presence of haplotypes involving SNPs 2-5 that significantly differentiated (P<0.05) the groups based on an ordinal ranking using the power-time classification. These same haplotypes differentiated the PT-MAX group in which a significant decrease in a haplotype (F: G-C-C-G OR=0.57, P=0.02, 95% CI 0.36-0.92) and increase in a second haplotype (G: A-T-G-G OR=1.75, P=0.03, 95% CI 1.05-2.91) was observed compared to controls. The PT-SS group was differentiated from the PT-MAX group by a third haplotype (H: A-T-G-A OR=0.46, P=0.04, 95% CI 0.22-0.96). Since EPAS1 has a role as a sensor capable of integrating cardiovascular function, energetic demand, muscle activity and oxygen availability into physiological adaptation, we propose that DNA variants in EPAS1 influence the relative contribution of aerobic and anaerobic metabolism and hence the maximum sustainable metabolic power for a given event duration.
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: BMJ
Date: 09-2018
DOI: 10.1136/BMJOPEN-2018-025857
Abstract: Having many melanocytic naevi or ‘moles’ on the skin is the strongest predictor of melanoma thus, much can be learnt from investigating naevi in the general population. We aim to improve the understanding of the epidemiology and biology of naevi by conducting a 3-year prospective study of melanocytic naevi in adults. This is a population-based cohort study of melanocytic naevi in 200 adults aged 20–69 years recruited via the Australian electoral roll. At baseline, participants will complete a questionnaire on their sun behaviour and health and undergo a clinical examination. Three-dimensional (3D) total-body photography will be used to record the images of skin lesions. Pigmented naevi will be analysed in terms of number, diameter, colour and border irregularity using automated analysis software (excluding scalp, beneath underwear and soles of feet). All naevi ≥5 mm will be recorded using the integrated dermoscopy photographic system. A saliva s le will be obtained at baseline for genomic DNA analysis of pigmentation, naevus and melanoma-associated genes using the Illumina HumanCoreExome platform. The sun behaviour and health follow-up questionnaire, clinical examination and 3D total-body photography will be repeated every 6 months for 3 years. The first 50 participants will also undergo manual counts of naevi ≥2 mm and ≥5 mm at baseline, 6-month and 12-month follow-ups. Microbiopsy and excision of naevi of research interest is planned to commence at the 18-month time point among those who agree to donate s les for detailed histopathological and molecular assessment. This study was approved by the Metro South Health Human Research Ethics Committee in April 2016 (approval number: HREC/16/QPAH/125). The findings will be disseminated through peer-reviewed and non-peer-reviewed publications and presentations at conferences.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2004
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.YGYNO.2005.03.007
Abstract: The object of this study was to test the hypothesis that BRAF is a low-risk susceptibility gene for low malignant potential (LMP) ovarian cancer. A recent study of the relationship between BRAF polymorphisms and malignant melanoma identified strong linkage disequilibrium across the BRAF gene with one of the three most common haplotypes (haplotype C) having a population attributable risk of approximately 1.6%. We therefore hypothesized that the same BRAF haplotype may confer an increased risk of serous ovarian tumors of low malignant potential. We genotyped 383 cases of LMP ovarian cancer, including 234 of serous histology, and 987 controls for seven SNPs, representative of the most common BRAF gene haplotypes, using MALDI-TOF mass spectrometry. Haplotype information was obtained for 369 LMP ovarian cancer cases and 983 healthy controls. None of the haplotypes were found to be associated with risk of LMP ovarian cancer (OR for haplotype C 0.81, 95% CI = 0.54-1.22), or with the risk of serous LMP ovarian cancer (OR for haplotype C 0.90, 95% CI = 0.56-1.45). We found no evidence to suggest that BRAF is a low-risk LMP ovarian cancer susceptibility gene.
Publisher: Wiley
Date: 17-10-1997
DOI: 10.1002/(SICI)1096-8628(19971017)72:2<245::AID-AJMG24>3.0.CO;2-M
Abstract: We present a genome assembly from an in idual female
Publisher: Springer Science and Business Media LLC
Date: 18-05-2008
DOI: 10.1038/NG.163
Publisher: Wiley
Date: 17-07-2007
Publisher: Hindawi Limited
Date: 08-2008
DOI: 10.1002/HUMU.20788
Abstract: The Melanocortin-1 Receptor (MC1R) is a G-protein coupled receptor, which is responsible for production of the darker eumelanin pigment and the tanning response. The MC1R gene has many polymorphisms, some of which have been linked to variation in pigmentation phenotypes within human populations. In particular, the p.D84E, p.R151C, p.R160W and p.D294 H alleles have been strongly associated with red hair, fair skin and increased skin cancer risk. These red hair colour (RHC) variants are relatively well described and are thought to result in altered receptor function, while still retaining varying levels of signaling ability in vitro. The mouse Mc1r null phenotype is yellow fur colour, the p.R151C, p.R160W and p.D294 H alleles were able to partially rescue this phenotype, leading to the question of what the true null phenotype of MC1R would be in humans. Due to the rarity of MC1R null alleles in human populations, they have only been found in the heterozygous state until now. We report here the first case of a homozygous MC1R null in idual, phenotypic analysis indicates that red hair and fair skin is found in the absence of MC1R function.
Publisher: The Society for the Study of Evolution
Date: 2001
Publisher: Wiley
Date: 1991
Abstract: This brief note examines the precision of segregation parameter estimates from both twin-nuclear family and conventional nuclear family designs. The program MENDEL was used to derive expected frequencies of different family patterns of affectation (with fixed sibship size) under various single gene models, and then to estimate the standard errors (and information) associated with gene frequency and penetrance values at given s le sizes. As might be expected, a 2- to 5-fold increase in relative efficiency was found for the same family size if families included an MZ twin pair among their offspring. The methods used allow convenient calculation of expected informativeness of a given study design.
Publisher: Springer Science and Business Media LLC
Date: 07-1994
DOI: 10.1007/BF01067535
Publisher: Elsevier BV
Date: 04-2000
DOI: 10.1086/302862
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: Public Library of Science (PLoS)
Date: 17-10-2017
Publisher: Wiley
Date: 18-09-2006
Publisher: Cambridge University Press (CUP)
Date: 08-2003
Publisher: Wiley
Date: 2001
DOI: 10.1359/JBMR.2001.16.1.33
Abstract: Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis remains largely unknown. Susceptibility loci for Paget's disease of bone have been mapped to chromosome 6p21.3 (PDB1) and 18q21.1-q22 (PDB2) in different pedigrees. We have identified a large pedigree of over 250 in iduals with 49 informative in iduals affected with Paget's disease of bone 31 of whom are available for genotypic analysis. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Linkage analysis has been performed with markers at PDB1 these data show significant exclusion of linkage with log10 of the odds ratio (LOD) scores < -2 in this region. Linkage analysis of microsatellite markers from the PDB2 region has excluded linkage with this region, with a 30 cM exclusion region (LOD score < -2.0) centered on D18S42. These data confirm the genetic heterogeneity of Paget's disease of bone. Our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Paget's disease of bone lies elsewhere in the genome in the affected members of this pedigree and will be identified using a microsatellite genomewide scan followed by positional cloning.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2010
Publisher: Elsevier BV
Date: 02-2008
Publisher: Elsevier BV
Date: 05-2004
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1086/510136
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1086/497997
Publisher: American Thoracic Society
Date: 03-1998
DOI: 10.1164/AJRCCM.157.3.9702070
Abstract: In complex diseases of genetic etiology such as asthma and atopy, it is difficult to differentiate causes of disease from consequences, and quantitate the importance of such causative factors. We examined possible risk factors for the development of wheezing and bronchial hyperresponsiveness in a cotwin-control study nested within a larger community-based twin-family study. In 62 monozygotic (MZ) twin pairs discordant for a history of wheezing, skin prick test to house dust extract was the most important discriminator, followed by sensitization to cat and cockroach allergens. In contrast, 62 dizygotic (DZ) discordant twin pairs differed additionally in sensitization to grass pollens and fungi. Markers such as serum haptoglobin, serum magnesium, and alpha-1-antitrypsin levels did not differ significantly between discordant twins. This MZ/DZ difference suggests that pollen allergy in asthmatics is more an epiphenomenon due to a genetic correlation between asthma and the allergic diathesis, whereas indoor allergens are likely to be direct environmental causes of asthma.
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: Elsevier BV
Date: 09-1998
DOI: 10.1016/S0091-6749(98)70132-0
Abstract: Dermatophagoides pteronyssinus (Der p) is one of the most frequently implicated allergens in atopic diseases. Although HLA could play an important role in the development of the IgE response to the Der p allergens, genetic regulation by non-HLA genes influences certain HLA-associated IgE responses to complex allergens. To clarify genetic control for the expression of Der p-specific IgE responsiveness, we conducted a genome-wide search for genes influencing Der p-specific IgE antibody levels by using 45 Caucasian and 53 African American families ascertained as part of the Collaborative Study on the Genetics of Asthma (CSGA). Specific IgE antibody levels to the Der p crude allergen and to the purified allergens Der p 1 and Der p 2 were measured. Multipoint, nonparametric linkage analysis of 370 polymorphic markers was performed with the GENEHUNTER program. The best evidence of genes controlling specific IgE response to Der p was obtained in 2 novel regions: chromosomes 2q21-q23 (P = .0033 for Caucasian subjects) and 8p23-p21 (P = .0011 for African American subjects). Three regions previously proposed as candidate regions for atopy, total IgE, or asthma also showed evidence for linkage to Der p-specific IgE responsiveness: 6p21 (P = .0064) and 13q32-q34 (P = 0.0064) in Caucasian subjects and 5q23-q33 (P = 0.0071) in African American subjects. No single locus generated overwhelming evidence for linkage in terms of established criteria and guidelines for a genome-wide screening, which supports previous assertions of a heterogeneous etiology for Der p-specific IgE responsiveness. Two novel regions, 2q21-q23 and 8p23-p21, that were identified in this study merit additional study.
Publisher: Cambridge University Press (CUP)
Date: 04-2011
Abstract: There is evidence that tamoxifen treatment of BRCA1 and BRCA2 carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence that BRCA1 and BRCA2 mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC with BRCA1 or BRCA2 mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater in BRCA1 -positive families (35/218 (16%) p = .03) and non-significantly greater in BRCA2 -positive families (23/189 (12%) p = .6), compared to high-risk breast cancer families without a BRCA1/2 mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses from BRCA1/2 families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed in iduals from 57 BRCA1/2 pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater for BRCA1 carriers (hazard ratio = 1.25, 95%CI = 0.65–2.41), and BRCA2 carriers (HR = 1.12, 95%CI = 0.51–2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68, 95%CI = 3.12–15.15 p = 1.7 x 10 -6 ) in BRCA1/2 families, with no evidence for interaction between tamoxifen therapy and BRCA1/2 genotype. Our family-based study supports a 7-fold increase in EC risk with tamoxifen exposure for female family members from BRCA1/2 families. Early onset EC in carriers without tamoxifen use suggests that further study is required to assess association of modest EC risk with BRCA1/2 mutation status alone.
Publisher: Springer Science and Business Media LLC
Date: 10-06-2009
DOI: 10.1007/S10549-008-0083-5
Abstract: The p27(kip1) protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. S les were genotyped for five single nucleotide polymorphisms, including coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216 rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI = 0.53-0.99 P = 0.04 for BRCA1, HR 1.47 (95% CI = 0.99-2.18 P = 0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers.
Publisher: Springer Science and Business Media LLC
Date: 24-08-2015
DOI: 10.1007/S10519-014-9670-X
Abstract: The heritability of attention-deficit/hyperactivity disorder (ADHD) is higher for children than adults. This may be due to increasing importance of environment in symptom variation, measurement inaccuracy when two raters report behavior of a twin-pair, a contrast effect resulting from parental comparison of siblings and/or dimensionality of measures. We examine rater contrast and sex effects in ADHD subtypes using a dimensional scale and compare the aetiology of self, versus maternal-report. Data were collected using the Strengths and Weaknesses of ADHD and Normal Behaviour Scale (SWAN): maternal-report for 3,223 twins and siblings (mean age 21.2, SD = 6.3) and self-report for 1,617 twins and siblings (mean age 25.5, SD = 3.2). Contrast effects and magnitude of genetic and environmental contributions to variance of ADHD phenotypes (inattention, hyperactivity-impulsivity, combined behaviours) were examined using structural equation modeling. Contrast effects were evident for maternal-report hyperactivity-impulsivity (b = -0.04) and self-report inattention (-0.09) and combined ADHD (-0.08). Dominant genetic effects were shared by raters for inattention, hyperactivity-impulsivity and combined ADHD. Broad-sense heritability was equal across sex for maternal-report inattention, hyperactivity-impulsivity and combined ADHD (0.72, 0.83, 0.80). Heritability for corresponding subtypes in self-reported data were best represented by sex (0.46, 0.30, 0.39 for males 0.69, 0.41, 0.65 for females). Heritability difference between maternal and self-report ADHD was due to greater variance of male specific environment in self-report data. Self-reported ADHD differed across sex by magnitude of specific environment and genetic effects.
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: Wiley
Date: 03-2005
DOI: 10.1111/J.1365-2222.2005.02188.X
Abstract: The cysteinyl-leukotrienes (cys-LTs) are important pro-inflammatory mediators in asthma, and have been shown to have a role in specific disease subtypes, including asthma severity. Few studies have investigated the role of polymorphisms in the ALOX5AP gene, encoding 5-lipoxygenase activating protein (FLAP), and asthma. We hypothesized that polymorphisms in this gene are associated with asthma and in particular, with asthma severity, in an Australian population. To screen the coding region of the ALOX5AP gene for polymorphisms and to determine the association between previously described polymorphisms and asthma and asthma severity in an Australian population. We used PCR-SSCP and PCR-RFLP analysis to examine a previously described promoter polyA variable repeat polymorphism and two intronic polymorphisms (IVS2+12C>A, IVS2+105T>C), and to screen all five exons of the gene for new polymorphisms, in a large Australian population of randomly selected, non-asthmatic controls (n=457), mild asthmatics (n=274), moderate asthmatics (n=231) and severe asthmatics (n=79). We confirmed the presence of two polymorphisms in intron 2 and found no association between these polymorphisms and asthma or asthma severity, nor between a promoter polymorphism in the ALOX5AP gene and asthma or asthma severity. Gene fragment analysis of the promoter polymorphism revealed novel, conserved repeat numbers in our population, and no new polymorphisms were found in the coding region of the gene. These findings in a large, well characterized asthma population, reveal that, while FLAP is an important enzyme in cys-LTs biosynthesis, polymorphisms in the ALOX5AP gene are not likely to be functionally associated with the asthma phenotype.
Publisher: Cambridge University Press (CUP)
Date: 25-03-2013
DOI: 10.1017/THG.2013.12
Abstract: Genome-wide association studies (GWAS) of attention-deficit/hyperactivity disorder (ADHD) offer the benefit of a hypothesis-free approach to measuring the quantitative effect of genetic variants on affection status. Generally the findings of GWAS relying on ADHD status have been non-significant, but the one study using quantitative measures of symptoms found SLC9A9 and SLC6A1 were associated with inattention and hyperactivity–impulsivity. Accordingly, we performed a GWAS using quantitative measures of each ADHD subtype measured with the Strengths and Weaknesses of ADHD and Normal Behaviour (SWAN) scale in two community-based s les. This scale captures the full range of attention and kinetic behavior from high levels of attention and appropriate activity to the inattention and hyperactivity–impulsivity associated with ADHD within two community-based s les. Our discovery s le comprised 1,851 participants (mean age = 22.8 years [4.8] 50.6% female), while our replication s le comprised 155 participants (mean age = 26.3 years [3.1] 68.4% females). Age, sex, age × sex, and age 2 were included as covariates and the results from each s le were combined using meta-analysis, then analyzed with a gene-based test to estimate the combined effect of markers within genes. We compare our results with markers that have previously been found to have a strong association with ADHD symptoms. Neither the GWAS nor subsequent meta-analyses yielded genome-wide significant results the strongest effect was observed at rs2110267 (4.62 × 10 −7 ) for symptoms of hyperactivity–impulsivity. The strongest effect in the gene-based test was for GPR139 on symptoms of inattention (6.40 × 10 −5 ). Replication of this study with larger s les will add to our understanding of the genetic etiology of ADHD.
Publisher: Cold Spring Harbor Laboratory
Date: 09-03-2007
DOI: 10.1101/GR.6023607
Abstract: Effective population size ( N e ) determines the amount of genetic variation, genetic drift, and linkage disequilibrium (LD) in populations. Here, we present the first genome-wide estimates of human effective population size from LD data. Chromosome-specific effective population size was estimated for all autosomes and the X chromosome from estimated LD between SNP pairs kb apart. We account for variation in recombination rate by using coalescent-based estimates of fine-scale recombination rate from one s le and correlating these with LD in an independent s le. Phase I of the HapMap project produced between 18 and 22 million SNP pairs in s les from four populations: Yoruba from Ibadan (YRI), Nigeria Japanese from Tokyo (JPT) Han Chinese from Beijing (HCB) and residents from Utah with ancestry from northern and western Europe (CEU). For CEU, JPT, and HCB, the estimate of effective population size, adjusted for SNP ascertainment bias, was ∼3100, whereas the estimate for the YRI was ∼7500, consistent with the out-of-Africa theory of ancestral human population expansion and concurrent bottlenecks. We show that the decay in LD over distance between SNPs is consistent with recent population growth. The estimates of N e are lower than previously published estimates based on heterozygosity, possibly because they represent one or more bottlenecks in human population size that occurred ∼10,000 to 200,000 years ago.
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.HUMPATH.2009.08.010
Abstract: Ductal adenocarcinoma of the prostate is an aggressive malignancy, often presenting at an advanced stage. In mixed ductal and acinar adenocarcinomas, the relationship between the proportion of the ductal component of the tumor and the pathologic stage and whether or not aggressive behavior is simply a function of grade remains undetermined. From 268 consecutive radical prostatectomies undertaken as a curative procedure for clinical localized prostate cancer, we identified 34 cases (12.7%) with ductal adenocarcinoma of the prostate comprising 5% to 100% of the total tumor volume. For cases with a ductal adenocarcinoma of the prostate component, the mean age at diagnosis of 60 years (range 49-69 years), mean serum prostate-specific antigen of 8.4 ng/mL (range, 0.8-21 ng/mL) and positive surgical margin rate of 17.6% did not differ significantly from that of the pure adenocarcinoma group. All 34 patients with ductal adenocarcinoma of the prostate had peripheral zone involvement while 16 (46%) also had transition zone involvement. Twenty-five (73%) cases with ductal adenocarcinoma of the prostate had extraprostatic extension (pT3), which compared to 32.9% with acinar adenocarcinoma. The presence of ductal adenocarcinoma of the prostate (P 7 (P = .04) significantly predicted pT3 staging category, and the presence of ductal adenocarcinoma of the prostate remained a significant predictor for pT3, after adjusting for tumor volume and Gleason score >7. The proportion of ductal adenocarcinoma of the prostate did not significantly modify the strength of the observed association with pathological stage. In view of the significant association with extraprostatic extension we would recommend that in both core biopsies and radical prostatectomy specimens any proportion of ductal adenocarcinoma of the prostate should be reported.
Publisher: Cambridge University Press (CUP)
Date: 04-2008
Abstract: Cutaneous malignant melanoma (CMM) is a major health issue in Queensland, Australia, which has the world's highest incidence. Recent molecular and epidemiologic studies suggest that CMM arises through multiple etiological pathways involving gene–environment interactions. Understanding the potential mechanisms leading to CMM requires larger studies than those previously conducted. This article describes the design and baseline characteristics of Q-MEGA, the Queensland Study of Melanoma: Environmental and Genetic Associations, which followed up 4 population-based s les of CMM patients in Queensland, including children, adolescents, men aged over 50, and a large s le of adult cases and their families, including twins. Q-MEGA aims to investigate the roles of genetic and environmental factors, and their interaction, in the etiology of melanoma. Three thousand, four hundred and seventy-one participants took part in the follow-up study and were administered a computer-assisted telephone interview in 2002–2005. Updated data on environmental and phenotypic risk factors, and 2777 blood s les were collected from interviewed participants as well as a subset of relatives. This study provides a large and well-described population-based s le of CMM cases with follow-up data. Characteristics of the cases and repeatability of sun exposure and phenotype measures between the baseline and the follow-up surveys, from 6 to 17 years later, are also described.
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: 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: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2005
DOI: 10.1097/01.HJH.0000174299.66369.26
Abstract: Familial hyperaldosteronism type II (FH-II) is characterized by the familial occurrence of primary aldosteronism unlike FH-I, it is not glucocorticoid-remediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. Linkage to a 5-Mbp region of chromosome 7p22 was previously reported in an Australian family with eight affected members. Mutations in the exons or intron-exon boundaries of PRKAR1B (7p22, closely related to PRKAR1A, which is mutated in Carney complex) have been excluded in this family. To refine the region of linkage, and to seek evidence of linkage in a South American family and in three other Australian families with FH-II, using seven closely spaced markers at 7p22. To establish phenotypes (affected, uncertain or unaffected), blood pressure, plasma aldosterone and plasma renin (activity or concentration) were measured and the aldosterone: renin ratio (ARR) calculated. In iduals with consistently increased ARR underwent fludrocortisone suppression testing. The genotypes of the five pedigrees were analysed using seven closely spaced microsatellite markers at 7p22, and two-point and multipoint logarithm of odds (LOD) scores were calculated to assess linkage with FH-II. The combined multipoint LOD score for three families (the original Australian, the South American and a new Australian family) showing linkage at 7p22 was highly significant at 4.61 (theta = 0) for markers D7S462 and D7S517. A newly found recombination event in the first Australian family narrowed the area of linkage by 1.8 Mbp, permitting exclusion of approximately half the candidate genes in the originally reported locus. It was not possible to demonstrate linkage at the 7p22 region in the remaining two Australian families. This study provides further evidence for linkage of FH-II to 7p22, refines the locus, and supports the notion that FH-II may be genetically heterogeneous.
Publisher: Wiley
Date: 12-01-2006
DOI: 10.1111/J.1398-9995.2005.00954.X
Abstract: Intermediate phenotypes are often measured as a proxy for asthma. It is largely unclear to what extent the same set of environmental or genetic factors regulate these traits. Estimate the environmental and genetic correlations between self-reported and clinical asthma traits. A total of 3,073 subjects from 802 families were ascertained through a twin proband. Traits measured included self-reported asthma, airway histamine responsiveness (AHR), skin prick response to common allergens including house dust mite (Dermatophagoides pteronyssinus [D. pter]), baseline lung function, total serum immunoglobulin E (IgE) and eosinophilia. Bivariate and multivariate analyses of eight traits were performed with adjustment for ascertainment and significant covariates. Overall 2,716 participants completed an asthma questionnaire and 2,087 were clinically tested, including 1,289 self-reported asthmatics (92% previously diagnosed by a doctor). Asthma, AHR, markers of allergic sensitization and eosinophilia had significant environmental correlations with each other (range: 0.23-0.89). Baseline forced expiratory volume in 1 s (FEV(1)) showed low environmental correlations with most traits. Fewer genetic correlations were significantly different from zero. Phenotypes with greatest genetic similarity were asthma and atopy (0.46), IgE and eosinophilia (0.44), AHR and D. pter (0.43) and AHR and airway obstruction (-0.43). Traits with greatest genetic dissimilarity were FEV(1) and atopy (0.05), airway obstruction and IgE (0.07) and FEV(1) and D. pter (0.11). These results suggest that the same set of environmental factors regulates the variation of many asthma traits. In addition, although most traits are regulated to great extent by specific genetic factors, there is still some degree of genetic overlap that could be exploited by multivariate linkage approaches.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-03-2021
Abstract: A GWAS including 192,986 European and 1636 Asian participants identifies 50 novel discrete associations with eye color.
Publisher: Springer Science and Business Media LLC
Date: 09-1994
DOI: 10.1007/BF01076182
Abstract: Obesity is a prevalent childhood condition and the degree of adiposity appears likely to be an important covariate in the pharmacokinetics (PKs) of many drugs. We undertook these studies to facilitate the evaluation and, where appropriate, quantification of the covariate effect of body fat percentage (BF%) on PK parameters in children. We examined two large databases to determine the values and variabilities of BF% in children with healthy body weights and in those with obesity, comparing the accuracy and precision of BF% estimation by both clinical methods and demographically derived techniques. Additionally, we conducted simulation studies to evaluate the utility of the several methods for application in clinical trials. BF% was correlated with body mass index (BMI), but was highly variable among both children with healthy body weights and those with obesity. Bio-impedance and several demographically derived techniques produced mean estimates of BF% that differed from dual x-ray absorptiometry by < 1% (accuracy) and a SD of 5% or less (precision). Simulation studies confirmed that when the differences in precision among the several methods were small compared with unexplained between-subject variability of a PK parameter, the techniques were of similar value in assessing the contribution of BF%, if any, as a covariate for that PK parameter. The combination of sex and obesity stage explained 68% of the variance of BF% with BMI. The estimation of BF% from sex and obesity stage can routinely be applied to PK clinical trials to evaluate the contribution of BF% as a potential covariate.
Publisher: BMJ
Date: 05-1992
DOI: 10.1136/ARD.51.5.588
Abstract: The 1980 cohort of the Australian Twin Registry contains 3808 pairs of twins, 258 of whom self reported a diagnosis of rheumatoid arthritis (RA) in one or both subjects. Seventy two pairs were lost to follow up by 1990. The remaining 186 pairs received a self administered questionnaire, followed, if necessary, by telephone interviews to them, their general practitioners, and their specialists. Twenty discordant and three concordant pairs of twins were verified as having RA. The prevalence of RA in this s le was 0.40%. There was an 89% false positive rate for the self reported diagnosis of RA. Pairwise concordance percentages for RA were as follows: monozygotic 21% (95% confidence interval (CI) = 6 to 44), dizygotic 0% (95% CI = 0 to 25). It was concluded that: (a) there is a high false positive rate in self reporting RA (b) the prevalence of RA in Australia may be less than the 0.8-1.0% often quoted and (c) genetic factors play some part in the aetiopathogenesis of RA but do not account entirely for its determination.
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.1186/BCR971
Publisher: Oxford University Press (OUP)
Date: 08-2005
DOI: 10.1093/AJE/KWI184
Abstract: A number of studies have investigated two common polymorphisms in the beta(2)-adrenoceptor gene, Arg/Gly16 and Gln/Glu27, in relation to asthma susceptibility. The authors performed a meta-analysis of each polymorphism, as well as haplotype analysis, for adult and pediatric populations separately, using published data, supplemented by additional data requested from the original authors. In idual analysis detected no effect of Arg/Gly16 in adults but did suggest a recessive protective effect of Gly16 for children, with an odds ratio of 0.71 (95% confidence interval (CI): 0.53, 0.96) compared with the other genotypes. Results for Gln/Glu27 in adults seem to indicate that heterozygotes are at decreased risk of asthma than either homozygote (odds ratio = 0.73, 95% CI: 0.62, 0.87), although the studies are heterogeneous in children, the Glu/Glu genotype has a decreased risk of asthma (odds ratio = 0.60, 95% CI: 0.35, 0.99) compared with the other genotypes. Despite the proximity of these two polymorphic sites, the linkage disequilibrium coefficient of 0.41 was not high (p < 0.001). Haplotype analysis suggests that there may be an interaction between the two sites, with a lower risk of asthma associated with the Glu27 allele (compared with Gln27), and that this risk is modified by the allele at position 16.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2007
Publisher: Springer Science and Business Media LLC
Date: 03-05-2014
Publisher: Wiley
Date: 23-03-2017
DOI: 10.1111/EXD.13114
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: American Diabetes Association
Date: 11-1998
DOI: 10.2337/DIABETES.47.11.1793
Abstract: NIDDM has a substantial genetic component, but the nature of the genetic susceptibility is largely unknown. Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of NIDDM characterized by an early age of onset and autosomal dominant inheritance, and linkage studies have identified genes that are mutated in different MODY pedigrees on chromosome 20 (MODY1 locus, hepatocyte nuclear factor-4alpha [HNF-4alpha] gene), chromosome 7 (MODY2 locus, glucokinase gene), and chromosome 12 (MODY3 locus, HNF-1alpha gene). We studied an extended pedigree in which multiple members are affected by late-onset NIDDM associated with insulin resistance and performed linkage analysis with four microsatellite markers in the MODY3 region of chromosome 12q. We found significant evidence for linkage between NIDDM and the MODY3 locus (logarithm of odds score 3.65 at theta = 0.008 telomeric to marker D12S321), but sequencing of the 10 exons and promoter of HNF-1alpha did not identify any causative mutation in this gene. Our results indicate that the region of chromosome 12q close to MODY3 harbors a novel susceptibility gene or genes for NIDDM.
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1007/S10519-005-9015-X
Abstract: Here I describe an Internet accessible database containing interpolated genetic map positions for 12917 marker loci. These are estimated via locally weighted linear regression (loess) from the Build 35.1 physical map position and the linkage map of Kong, X., and coworkers (2004) Am. J. Hum. Genet. 75:1143-1148. For the pseudoautosomal region, I have interpolated a male map based on the sperm typing data of Lien, S., and coworkers (2000) Am. J. Hum. Genet. 66:557-566.
Publisher: The Endocrine Society
Date: 09-2000
DOI: 10.1210/JC.85.9.3391
Publisher: Wiley
Date: 26-07-2014
DOI: 10.1002/IID3.27
Publisher: Cambridge University Press (CUP)
Date: 04-2003
Publisher: SAGE Publications
Date: 28-07-2013
Abstract: Objective: The findings of genetic, imaging and neuropsychological studies of attention-deficit hyperactivity disorder (ADHD) are mixed. To understand why this might be the case we use both dimensional and categorical symptom measurement to provide alternate and detailed perspectives of symptom expression. Method: Interviewers collected ADHD, conduct problems (CP) and sociodemographic data from 3793 twins and their siblings aged 22 to 49 ( M = 32.6). We estimate linear weighting of symptoms across ADHD and CP items. Latent class analyses and regression describe associations between measured variables, environmental risk factors and subsequent disadvantage. Additionally, the clinical relevance of each class was estimated. Results: Five classes were found for women and men few symptoms, hyperactive-impulsive, CP, inattentive, combined symptoms with CP. Women within the inattentive class reported more symptoms and reduced emotional health when compared to men and to women within other latent classes. Women and men with combined ADHD symptoms reported comorbid conduct problems but those with either inattention or hyperactivity-impulsivity only did not. Conclusion: The dual perspective of dimensional and categorical measurement of ADHD provides important detail about symptom variation across sex and with environmental covariates.
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.ANNEPIDEM.2008.04.004
Abstract: Appendicitis is an inflammation of the appendix, the etiology of which is still poorly understood. Previous studies have shown an increased risk for cigarette smokers but no accounts for the timing of exposure to smoking relative to appendectomy were made. Based on questionnaire data, both cohort and co-twin case-control analyses were conducted to assess the effect of active cigarette smoking on appendectomy in 3808 Australian twin pairs. Smoking status was defined as a time-dependent covariate to account for differences in timing of smoking initiation and onset of appendicitis. The questionnaire had a 65% pairwise response rate. After controlling for sex, age, and year of birth, appendectomy risk in current smokers was statistically significantly increased by 65% relative to never-smokers. This was largely unchanged by the duration or intensity of smoking and was not affected by socioeconomic status or father's occupation. The effect was stronger in females. Among former smokers, increased time since quitting significantly reduced the odds ratio of appendectomy by 15% for every year since quitting. After adjustment for age and other confounders, there was an increase in risk of appendectomy among current smokers relative to never-smokers, particularly in females. This study adds to the body of knowledge on the effects of tobacco smoking on the gastrointestinal tract.
Publisher: Elsevier BV
Date: 06-1998
DOI: 10.1086/301867
Publisher: Wiley
Date: 09-2001
Publisher: Medical Journals Sweden AB
Date: 2015
Abstract: The aim of this study was to determine the age at onset of psoriasis in a population-based twin s le. Questionnaire-data in 10,725 twin pairs, 20-71 years of age, from the Danish Twin Registry, was collected, and analysed using survival regression analysis. Median age at onset was 25 and 28 years among women and men, respectively. The correlation between the ages was 0.84 (bootstrap standard error?=?0.044) in monozygotic twin pairs and 0.60 (0.051) in dizygotic twin pairs, permutation p?=?0.001. Age at onset of psoriasis in the index twin did not predict risk of psoriasis in the co-twin, hazard ratio (per year of later onset =?1.01 (0.99-1.03), p?=?0.434. In conclusion, these data support that the age at onset of psoriasis is, in part, an inherited property. Our results do not support that early-onset psoriasis is more genetically determined.
Publisher: Wiley
Date: 10-1999
Publisher: Elsevier BV
Date: 09-1998
DOI: 10.1016/S0091-6749(98)70133-2
Abstract: Recently, we have obtained evidence for linkage between Der p 1-specific IgE antibodies and markers on chromosome 6p21 (HLA-D region) in a genome-wide screening in Caucasian families recruited as a part of the Collaborative Study on the Genetics of Asthma (CSGA). Specific IgE antibodies toward different Dermatophagoides pteronyssinus (Der p) polypeptides were detected by immunoblotting analysis, and the transmission/disequilibrium test (TDT) was performed between specific IgE responsiveness toward each different Der p polypeptide and markers on chromosome 6p21 to better clarify the genetic contribution of HLA-D genes. We studied 299 in iduals in 45 Caucasian families participating in the CSGA. Serum s les from 137 in iduals that showed elevated specific IgE antibodies toward the Der p crude allergen (> -0.5 log IU/mL) by ACCESS immunoassay were subjected to immunoblotting analysis. TDT was conducted between the presence of specific IgE antibodies toward each of 12 different Der p polypeptides and 4 polymorphic markers on chromosome 6p21. The 196-bp allele of D6S1281 and the 104-bp allele of DQCAR showed significant excess transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 55 kd, 45 kd, or 37 kd). In contrast, the 200-bp allele of D6S1281 and the 204-bp allele of D6S291 showed significantly decreased transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 90 kd, 52 kd, or 45 kd). Deviation from the expected 50% transmission in heterozygous parents was statistically significant after correcting for multiple comparisons. This study supported our previous findings that genes on chromosome 6p21 (HLA-D region) may influence the expression of Der p-specific IgE responsiveness in this Caucasian population. Our results, however, reveal the complexity of genetic regulations of Der p-specific IgE responsiveness by HLA-D genes, suggesting the strong influence of non-HLA loci and perhaps environmental factors for the development of Der p-specific IgE responsiveness.
Publisher: BMJ
Date: 06-07-2007
Publisher: Cambridge University Press (CUP)
Date: 04-2019
DOI: 10.1017/THG.2019.13
Abstract: Type 2 diabetes (T2D) is a chronic disease that disproportionately affects Indigenous Australians. We have previously reported the localization of a novel T2D locus by linkage analysis to chromosome 2q24 in a large admixed Indigenous Australian pedigree (Busfield et al. (2002). American Journal of Human Genetics , 70, 349–357). Here we describe fine mapping of this region in this pedigree, with the identification of SNPs showing strong association with T2D: rs3845724 (diabetes p = 7 × 10 −4 ), rs4668106 (diabetes p = 9 × 10 −4 ) and rs529002 (plasma glucose p = 3 × 10 −4 ). These associations were successfully replicated in an independent collection of Indigenous Australian T2D cases and controls. These SNPs all lie within the gene encoding ceramide synthase 6 ( CERS6 ) and thus may regulate ceramide synthesis.
Publisher: PeerJ
Date: 20-12-2017
DOI: 10.7717/PEERJ.4168
Abstract: Early detection and treatment are the most important elements in reducing the incidence of melanoma deaths. Acquired melanocytic naevi (AMN) are well-known precursors of melanoma but most of our knowledge on the clinico-dermoscopic phenotypes of AMN is based on studies in European-background populations, particularly American and Australian populations. There has been little research in Chinese Han populations on clinico-dermoscopic variability of naevi or how naevi are affected by melanoma-linked variants of the melanocortin 1 receptor ( MC1R ) gene. Clinical and dermoscopic features of 448 AMN in 115 patients from the Han ethnic group in mainland China were described. Germline polymorphisms in MC1R were determined for 98 of these patients. AMN were predominantly found on the head and neck. Dermoscopic patterns observed were nonspecific, reticular, globular, and parallel furrow, with most AMN having a nonspecific pattern. There were no associations between MC1R polymorphisms and clinical or dermoscopic features of AMN. Our results provide evidence that AMN in the Han population in China have similar dermoscopic patterns to those in European populations, but are present in much lower numbers. As there were no associations between clinical or dermoscopic features of AMN and MC1R polymorphisms, further studies should focus on candidate gene associations with AMN features and the risk of melanoma, with larger s le sizes and comparisons to AMN in other populations.
Publisher: Oxford University Press (OUP)
Date: 1997
DOI: 10.1093/OXFORDJOURNALS.EPIREV.A017935
Abstract: TeenCovidLife is part of Generation Scotland's CovidLife projects, a set of longitudinal observational studies designed to assess the psychosocial and health impacts of the COVID-19 pandemic. TeenCovidLife focused on how adolescents in Scotland were coping during the pandemic. As of September 2021, Generation Scotland had conducted three TeenCovidLife surveys. Participants from previous surveys were invited to participate in the next, meaning the age ranges shifted over time. TeenCovidLife Survey 1 consists of data from 5,543 young people age 12 to 17, collected from 22 May to 5 July 2020, during the first school closures period in Scotland. TeenCovidLife Survey 2 consists of data from 2,245 young people aged 12 to 18, collected from 18 August to 14 October 2020, when the initial lockdown measures were beginning to ease, and schools reopened in Scotland. TeenCovidLife Survey 3 consists of data from 597 young people age 12 to 19, collected from 12 May to 27 June 2021, a year after the first survey, after the schools returned following the second lockdown in 2021. A total of 316 participants took part in all three surveys. TeenCovidLife collected data on general health and well-being, as well as topics specific to COVID-19, such as adherence to COVID-19 health guidance, feelings about school closures, and the impact of exam cancellations. Limited work has examined the impact of the COVID-19 pandemic on young people. TeenCovidLife provides relevant and timely data to assess the impact of the pandemic on young people in Scotland. The dataset is available under authorised access from Generation Scotland see the Generation Scotland website for more information.
Publisher: Springer Science and Business Media LLC
Date: 07-08-2007
DOI: 10.1007/S10519-007-9163-2
Abstract: Age at menarche (AAM), time of first menstrual period, is an important developmental milestone in females. Follow-up data from 1,302 adolescent twins and their sisters were used to partition the normal variation in AAM. The proportion of censoring was 14.1%. Both a standard and a survival analysis method were used. The best fitting model from the survival analysis method was an ACE model, where 57% and 23% of the variance in AAM was explained by additive genetic and environmental effects, respectively. The best fitting model when using a standard variance decomposition method was an AE model, where 82% of the variance was explained by additive genetic effects. The lack of correspondence between the results of the two methods was an artefact of the different ascertainment of AAM reports from siblings and twins. After the removal of the sibling s le, both methods indicated that an ACE model was the most likely. Standard and survival analysis methods estimated the proportion of variance explained by additive effects to be 0.50 and 0.54, and common environmental effects to be 0.31 and 0.29, respectively. We conclude that variation in AAM can be explained by additive genetic and common environmental components.
Publisher: Wiley
Date: 03-2005
DOI: 10.1111/J.1365-2222.2005.02189.X
Abstract: IL-16 is an immunomodulatory cytokine whose expression is increased in the bronchial mucosa, bronchoalveolar lavage fluid and induced sputum of asthmatic patients. It has been suggested that IL-16 has a regulatory role in the pathophysiology of asthma. A single-nucleotide polymorphism (T(-295)C) has been described in the promoter region of the gene and it has been hypothesized that this polymorphism may be associated with altered levels of IL-16 expression, and account for the increased levels of IL-16 seen in the asthmatic airway. To determine the association between the T(-295)C promoter polymorphism and asthma, disease severity and atopy in a large Australian Caucasian population. We used PCR and restriction fragment length polymorphism analysis to establish the allele frequency of the T(-295)C promoter polymorphism in a random Australian Caucasian population (n=176) and to characterize the polymorphism in a large Australian Caucasian population of mild (n=273), moderate (n=230) and severe (n=77) asthmatic patients, and non-asthmatic controls (n=455). Genotype association analyses were performed using chi(2) tests. The polymorphic C allele was present in 19% of the asthmatic population and 21% of the non-asthmatic population. There was no association between the polymorphism and asthma (P=0.153) nor with asthma severity (P=0.417) or atopy (P=0.157) in this population. Although it has been hypothesized that the T(-295)C promoter polymorphism may be associated with increased IL-16 gene expression, it is not associated with asthma, disease severity or atopy in this Australian population.
Publisher: Wiley
Date: 13-04-2008
DOI: 10.1111/J.1365-2222.2008.02986.X
Abstract: Cyclooxygenase (COX)-2 is an inducible enzyme responsible for catalysing the formation of prostaglandins (PGs) in settings of inflammation. Single nucleotide polymorphisms (SNPs) of the COX-2 gene may influence gene transcription and PG production in the asthmatic airway. To evaluate the frequencies of COX-2 SNPs in an Australian Caucasian population, and determine potential associations between common COX-2 promoter SNPs and asthma, asthma severity and aspirin-intolerant asthma (AIA). The frequencies of 25 COX-2 SNPs were determined in a random population (n=176). The SNPs with a minor allele frequency of >10% were then studied in asthmatic (n=663), non-asthmatic controls (n=513) and AIA subjects (n=58). Genotype, allele and haplotype associations were assessed. Functional assessment of SNPs was performed by transfection into HeLa cells measured using the luciferase dual-reporter assay system. Eighteen COX-2 SNPs were not detected, five were rare and two promoter SNPs, -1195G>A (rs689465), and -1290A>G (rs689466), were further studied. The A allele of the -1195 SNP was present at a significantly higher frequency among all asthmatic subjects (P=0.012). Over 60% of the asthmatic in iduals were -1195A homozygotes compared with 54.6% of the control subjects (odds ratio, 1.35 95% CI, 1.06-1.72, P=0.03). After classifying for severity, the mild asthmatics represented 64.6% of -1195AA in iduals, the highest of all the asthma groups compared with 54.6% of the control subjects (odds ratio, 1.5 95% CI, 1.12-2.02, P=0.02). The -1290A/-1195G/-765G haplotype was associated with a reduced incidence of asthma (odds ratio, 0.76 95% CI, 0.61-0.95, P=0.017). The -1195G>A polymorphism appears to be associated with asthma, and in particular with mild asthma.
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.UROLOGY.2007.03.068
Abstract: To assess the radical prostatectomy findings in patients with a minute focus of adenocarcinoma on prostate needle biopsy in current practice in Australia. A total of 58 patients with a 0.5-mm focus or less of Gleason score 6 adenocarcinoma on needle biopsy who had been treated by radical prostatectomy were selected. At each biopsy, 6 to 20 cores (mean 11, median 13) were taken. Significant tumors were those with a Gleason score of 6 or more and tumor volume of 0.5 cm3 or larger. The 58 patients (mean age 50 years, median 58, range 44 to 69) had a mean prostate-specific antigen (PSA) level of 6.9 ng/mL (range 0.7 to 16, median 6). Of the 58 men, 48 (82.75%) had pathologically significant tumor, with 8 (13.8%) showing extraprostatic extension. No statistically significant association was found between significant carcinoma and age, mean PSA level, PSA density greater than 0.15, prior negative biopsy, coexistent atypical glands, or the number of tissue cores per biopsy. A prostate weight greater than 40 g correlated significantly with insignificant cancer on both univariate (P = 0.03) and multivariate (P = 0.02) analyses. In 14 (29.2%) of 48 patients with significant tumor, the largest cancer focus in the radical prostatectomy was anterior, lateral, or anterolateral. In patients without atypical glands, 37 (78.72%) of 47 had significant carcinoma, a risk not significantly lower than that of the entire group. The results of our study have shown that in populations without PSA screening, a minute focus of prostate cancer on needle biopsy, even with extended biopsy cores, does not mean insignificant carcinoma in most cases. Patients with larger glands had a greater chance of insignificant cancer.
Publisher: Wiley
Date: 1995
Abstract: In this paper, we explore the use of a variety of familial transmission tests (and case-control analyses) to screen for allelic associations in simulated marker data of a quality (2 cM map) that will feasibly arise from genomic scans within the next 5-10 years. We demonstrate a form of the transmission-disequilibrium test extended to multiallele systems. The methods used were log-linear and related models implemented largely using standard statistical packages.
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: Informa UK Limited
Date: 11-2013
DOI: 10.1080/00480169.2013.817295
Abstract: To investigate, in a pilot study, a possible genetic component to type 2 diabetes mellitus (T2D) in Burmese cats in New Zealand by analysing pedigree data. Pedigrees were obtained for 305 Burmese cats living in New Zealand diabetes was diagnosed in 19 of these due to presence of polyuria and polydipsia, persistent concentrations of glucose in plasma >16 mmol/L and glucosuria prior to insulin treatment. Pedigrees were also submitted for 16 cats with no clinical signs of T2D. The remaining 270 cats were unobserved relatives of these in iduals. Inbreeding coefficients and heritability were calculated, and a single major locus model segregation analysis was conducted using pedigree analysis software. Nineteen cats were diagnosed with T2D. Males (n = 14) and females (n = 5) were both affected, suggesting that the gene or genes causing diabetes are autosomal rather than sex-linked. Examination of the pedigree revealed few signs of fully penetrant dominant gene action: diabetes was ostensibly rarely seen in sequential generations and nearly always skipped at least one and often more generations apparently unaffected offspring of apparently unaffected parents sometimes produced affected progeny. The mean relatedness of the affected animals within the core pedigree (16 diabetic cats) was 0.049, and mean inbreeding 0.033. Based on 100,000 permutations of the trait values, the expected relatedness of a random s le of 16 animals taken from the phenotyped animals would be 0.013 (SD 0.007) (permutation p = 0.0009). The observed inbreeding was also significant (permutation p= 0.02). Heritability was estimated to be 9 (95% CI = 0-57)% assuming all animals with unknown status were unaffected. The best fitting genetic model was a major gene model with dominant expression with the risk allele frequency at 15% with 60% penetrance. In this pilot study the increased inbreeding in the cases, lack of likely s ling bias, the increased frequency of T2D in Burmese, and small number of breed founders are consistent with the involvement of a major locus in diabetes in Burmese cats with a significant risk allele prevalence. However, low case numbers meant this could not be unambiguously confirmed. A genome-wide association study may be useful for investigating the genetic cause of T2D.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2004
Publisher: Cambridge University Press (CUP)
Date: 02-2006
DOI: 10.1375/TWIN.9.1.46
Abstract: Simultaneous analysis of handedness data from 35 s les of twins (with a combined s le size of 21,127 twin pairs) found a small but significant additive genetic effect accounting for 25.47% of the variance (95% confidence interval [CI] 15.69–29.51%). No common environmental influences were detected (C = 0.00 95% CI 0.00–7.67%), with the majority of the variance, 74.53%, explained by factors unique to the in idual (95% CI 70.49–78.67%). No significant heterogeneity was observed within studies that used similar methods to assess handedness, or across studies that used different methods. At an in idual level the majority of studies had insufficient power to reject a purely unique environmental model due to insufficient power to detect familial aggregation. This lack of power is seldom mentioned within studies, and has contributed to the misconception that twin studies of handedness are not informative.
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: Wiley
Date: 2006
DOI: 10.1002/GEPI.20124
Abstract: The additional statistical power of association studies for quantitative traits was derived when ungenotyped relatives with phenotypes are included in the analysis. It was shown that the extra power is a simple function of the coefficient of additive genetic relationship and the phenotypic correlation coefficient between the genotyped and ungenotyped relatives. For close relatives, such as pairs of fullsibs and identical twin pairs, gains in power in the range of 10 to 30% are achieved if only one of the pair is genotyped. The theoretical results were verified by simulations. It was shown that ignoring the error in estimating the genotype of the ungenotyped relative has little impact on the estimates and on statistical power, consistent with results from quantitative trait loci (QTL) linkage studies. For genome-wide association studies in which not all relatives with phenotypes can be genotyped, our study provides a prediction of the additional power of an analysis that includes phenotypes on ungenotyped in iduals, and can be used in experimental design. We show that a two-step procedure, in which missing genotypes are imputed and subsequently an association analysis is performed, is efficient and powerful.
Publisher: Oxford University Press (OUP)
Date: 16-08-2011
Abstract: Immunoglobulin E (IgE)-mediated hypersensitivity against environmental allergens, commonly including Dermatophagoides farinae, is associated with atopic diseases in both humans and dogs. We have recently identified a family of clinically healthy West Highland white terriers (WHWTs) with high-serum D. farinae-IgE levels. In this study, we investigated the genetic mechanism controlling IgE responsiveness in dogs by performing a genome-wide association study (GWAS) using the Affymetrix V2 Dog SNP array in 31 high-IgE and 24 low-IgE responder WHWTs. A gene-dropping simulation method, using SIB-PAIR software, showed significant allelic association between serum D. farinae-specific IgE levels and a 2.3-Mb area on CFA35 (best empirical P = 1 × 10(-5)). A nearby candidate gene, CD83, encodes a protein which has important immunological functions in antigen presentation and regulation of humoral immune responses. We sequenced this gene in 2 high-IgE responders and 2 low-IgE responders and identified an intronic polymorphic repeat sequence with a predicted functional effect, but the association was insufficient to explain the GWAS association signal in this population (P = 1 × 10(-3)). Further studies are necessary to investigate the significance of these findings for IgE responsiveness and atopic disease in the dog.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2018
DOI: 10.1007/S10519-018-9905-3
Abstract: The extent to which correlations between personality domains and physical and psychological health generalize cross-culturally is unclear. We compared the strength of associations between the personality domains and somatic and psychological distress in Chinese (N = 2069) and a genetically informative s le of Australian (N = 2936) adolescents. We also examined the genetic and environmental etiology between personality, somatic and psychological distress in an Australian s le of 390 monozygotic twins and 698 dizygotic twins. In both populations, personality was assessed using the Junior Eysenck Personality Questionnaire. Somatic and psychological distress was assessed using the Somatic and Psychological Health Report. We found significant cultural differences in the relationship between adolescents' personality traits and somatic and psychological distress. Extraversion was positively associated with somatic distress in the Chinese but not in Australian adolescents. In the Australian twins, genetic covariation between neuroticism and somatic and psychological distress was stronger compared to the genetic associations between either psychoticism or extraversion with psychological distress.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1038/JID.2013.272
Abstract: A germline polymorphism of the microphthalmia transcription factor (MITF) gene encoding a SUMOylation-deficient E318K-mutated protein has recently been described as a medium-penetrance melanoma gene. In a clinical assessment of nevi from 301 volunteers taken from Queensland, we identified six in iduals as MITF E318K mutation carriers. The phenotype for 5 of these in iduals showed a commonality of fair skin, body freckling that varied over a wide range, and total nevus count between 46 and 430 in addition, all were multiple primary melanoma patients. The predominant dermoscopic signature pattern of nevi was reticular, and the frequency of globular nevi in carriers varied, which does not suggest that the MITF E318K mutation acts to force the continuous growth of nevi. Excised melanocytic lesions were available for four MITF E318K carrier patients and were compared with a matched range of wild-type (WT) melanocytic lesions. The MITF staining pattern showed a predominant nuclear signal in all sections, with no significant difference in the nuclear/cytoplasmic ratio between mutation-positive or -negative s les. A high incidence of amelanotic melanomas was found within the group, with three of the five melanomas from one patient suggesting a genetic interaction between the MITF E318K allele and an MC1R homozygous red hair color (RHC) variant genotype.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 30-12-2015
Abstract: Primary lens luxation (PLL) in dogs is an inherited disease in which the lens is displaced from its normal position. A truncating mutation in the ADAMTS17 orthologue on CFA03 is reported to cause PLL in several breeds, mostly terriers. However, the complex inheritance pattern of PLL in miniature bull terriers (MBTs) suggests that other loci may have a modifying effect on the ADAMTS17 mutation. This study aimed to detect such loci increasing risk of PLL in Australian MBTs. More than 170,000 single-nucleotide polymorphisms (SNPs) across the canine genome were genotyped in 23 PLL-affected and 73 normal Australian MBTs, and association between the PLL phenotype and the genetic markers was investigated by using general mixed effects Cox model survival analysis. The highest association peaks, other than that associated with the ADAMTS17 mutation (P = 2.2e-05), were SNP BICF2G630420272 located at 62.2 Mb on chromosome 15 (P = 7.8e-05) and the region between 30 Mb and 32.5 Mb on chromosome 1 (P = 9.3e-05). Joint analysis showed that the PLL-associated allele of the BICF2G630420272 SNP increased risk of PLL in the presence of the ADAMTS17 mutation (P = 8.117e-04). Candidate genes in the two regions of interest included CPE on chromosome 15 and CTGF on chromosome 1. The ADAMTS17 mutation was also associated with abnormal foot and nail shapes, pedal hyperkeratosis, and persistent pupillary membranes. Two loci with potentially enhancing effects on the ADAMTS17 mutation were associated with PLL in Australian MBTs. Association of the ADAMTS17 mutation with possible pedal skeletal abnormalities in MBTs supports PLL in this breed and Weill-Marchesani syndrome-like disease in humans as being homologous diseases.
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1086/505031
Publisher: Elsevier BV
Date: 09-1998
DOI: 10.1016/S0091-6749(98)70134-4
Abstract: We have recently conducted a genome-wide screening for genes influencing Dermatophagoides pteronyssinus-specific IgE responsiveness as a part of the Collaborative Study on the Genetics of Asthma (CSGA), which showed evidence for linkage in some regions, including chromosomes 5131-q33 and 11q13 in African American families. To clarify relative contributions of these regions to atopy in the same African American population, we have conducted further genetic linkage studies of specific IgE responses toward common inhaled allergens. We studied 328 in iduals in 58 African American families participating in the CSGA. Specific IgE responses toward Dermatophagoides farinae, cat, dog, American cockroach, rye grass, and Bermuda grass, as measured by skin tests, were used for multipoint linkage analysis with polymorphic markers on chromosomes 5q31-q33 and 11q13. Specific IgE response toward American cockroach showed evidence for linkage to chromosomes 5q31-q33 (P = .0050) and 11q13 (P = .017). Specific IgE response toward dog showed evidence for linkage with chromosome 5q31-q33 (P = .0043). Evidence for linkage with chromosome 11q13 was obtained for specific IgE responses toward Dermatophagoides farinae (P = .012), cat (P = .035), and Bermuda grass (P = .017). The presence of a positive ST response for at least 1 of 30 common allergens showed evidence for linkage to chromosomes 5q31-q33 (P = .017) and 11q13 (P = .00058). These data support that genes on both chromosomes 5q31-q33 and 11q13 confer susceptibility to upregulated IgE-mediated immune responses in this African American population. The putative genes on chromosomes 5q31-q33 and 11q13, however, showed contrasting effects on atopy, which may result from strong gene-environmental interactions.
Publisher: Springer Science and Business Media LLC
Date: 12-2011
Abstract: Canine atopic dermatitis (AD) is a common inflammatory skin disease associated with defects in the epidermal barrier, particularly in West Highland white terriers (WHWTs). It shares many similarities with human AD, and so may be a useful animal model for this disease. Epidermal dysfunction in human AD can be caused by mutations in the gene encoding the epidermal protein filaggrin ( FLG ) and, in some atopic patients, be associated with altered FLG mRNA and protein expression in lesional and/or non-lesional skin. In experimental models of canine AD, mRNA expression of the orthologous canine filaggrin gene may be reduced in non-lesional skin compared with healthy controls. However, there is no published data on canine filaggrin mRNA expression in the skin of dogs with naturally-occurring AD. Hence, the aim of this pilot study was to develop a reverse transcriptase real-time PCR assay to compare filaggrin mRNA expression in the skin of atopic (n = 7) and non-atopic dogs (n = 5) from five breeds, including eight WHWTs. Overall, filaggrin mRNA expression in non-lesional atopic skin was decreased compared to non-lesional non-atopic skin (two fold change) however this difference was only statistically significant in the subgroup of WHWTs ( P = 0.03). Although limited by the small s le size, these results indicate that, comparable to some cases of human AD, altered filaggrin mRNA expression may exist in the skin of some atopic dogs with naturally-occurring disease. Additional studies, including larger s le numbers, will be necessary to confirm this finding and to investigate whether mutations in the filaggrin gene exist and contribute to epidermal lesions of AD in dogs.
Publisher: Wiley
Date: 20-10-2006
Publisher: Elsevier BV
Date: 2009
Publisher: Oxford University Press (OUP)
Date: 05-03-2023
DOI: 10.1093/BJD/LJAD041
Abstract: Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored. To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K– in iduals. Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ in iduals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/– cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank). The cohort comprised 1165 MITF E318K– and 322 E318K+ in iduals. In E318K– cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P & 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P & 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67–2.49) P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54–1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20–1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P & 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ in iduals. RHC alleles/genotypes modify melanoma risk differently in MITF E318K– and E318K+ in iduals. Specifically, although all RHC alleles increase risk relative to wt in E318K– in iduals, only MC1R R increases melanoma risk in E318K+ in iduals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ in iduals.
Publisher: Wiley
Date: 11-09-2007
DOI: 10.1002/AJMG.B.30413
Abstract: The expansion of unstable trinucleotide CAG repeat polymorphisms of a number of genes causes several neurodegenerative disorders with decreased cognitive function, the severity of the disorder being related to allele length at the triplet repeat locus. While the effects of repeat length have been well studied in clinical s les, there has been little investigation of the effects of triplet repeat variation in the normal range for these genes. We have, therefore, examined linkage and association for three CAG triplet repeat markers (Spinocerebellar Ataxia Type 1, SCA1 Machado-Joseph Disease, MJD Dentatorubro-pallidoluysian Atrophy, DRPLA) to assess their contribution to variation in cognitive ability (IQ, reading ability, processing speed) in a normal, unselected s le of adolescent twins (248 dizygotic (DZ) sibling pairs, aged 16 years). Association tests, performed in Mx and QTDT, showed a consistent positive association of SCA1 with Arithmetic (P = 0.04). While association was supported between SCA1 and Cambridge reading scores and between DRPLA and inspection time, results were inconsistent across software packages. Given the number of statistical tests performed, it is unlikely that trinucleotide repeat variation in the normal range for these genes influences variation in normal cognition.
Publisher: Elsevier BV
Date: 12-2005
Publisher: Wiley
Date: 1999
DOI: 10.1002/(SICI)1098-2272(1999)16:1<54::AID-GEPI5>3.0.CO;2-S
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1086/302494
Publisher: Wiley
Date: 03-2010
DOI: 10.1002/AJMG.A.33274
Abstract: A large Australian family affected with long QT syndrome (LQTS) was studied. The medical characteristics of the 16 clinically affected members were consistent with LQT1. A previously identified mutation in KCNQ1 was found in 12 affected in iduals and 1 unaffected infant but absent in 4 affected family members. A haplotype consisting of specific alleles for microsatellites flanking in KCNQ1 was associated with the mutation. This was absent from the four affected in iduals without the mutation, who had three different haplotypes in this region, indicating that LQTS is unlikely to be segregating with KCNQ1 in these anomalous family members. A genome scan revealed 12 regions where all four of these in iduals shared alleles. One region on chromosome 21 contained the KCNE1, KCNE2, KCNJ6, and KCNJ15 genes. A common variant of KCNE1 was segregating in the family but did not explain the anomalous cases. A candidate region on chromosome 7 contained the AKAP9 and KCND2 genes. A previously reported mutation in the N-terminal Yotiao region of AKAP9 was absent from the family. No evidence was found implicating any other known or suspected LQTS gene. This family shows that there remain unidentified genetic causes of LQTS which are clinically significant and highlights the difficulties associated with genetic testing in LQTS, since we cannot rule out risk in in iduals who are negative for the known mutation in KCNQ1 without knowing the second disease locus.
Publisher: Public Library of Science (PLoS)
Date: 08-07-2010
Publisher: BMJ
Date: 10-1993
Abstract: The occurrence of respiratory symptoms and abnormal lung function in children is known to be influenced by genetic and many environmental factors. The association between specific respiratory symptoms in children of school age and their parents has been examined. Respiratory symptoms and ventilatory function were recorded for 4549 schoolchildren in Queensland, Australia. The cumulative prevalence of wheezing was 23.1% of 8 year olds and 20.8% of 12 year olds, and the prevalence of wheezing within the previous 12 months was 13.9% and 10.5% respectively. A parental history of asthma or wheeze and hayfever was associated with wheeze in the child, but did not affect either the age of onset or frequency of episodes. A history of frequent cough in children who had never wheezed was associated with a parental history of frequent bronchitis, but less strongly with parental wheeze. These familial aggregations were not mediated by common exposure to cigarette smoke. Both a history of parental wheeze and maternal cigarette use were associated with a decrease in FEF25-75 in the child and these effects were additive. The association of specific symptoms (wheeze and cough without wheeze) in parent and offspring is interpreted as evidence for different mechanisms of familial transmission, which may be genetic.
Publisher: Elsevier BV
Date: 08-2011
Publisher: Elsevier BV
Date: 11-2009
Publisher: Wiley
Date: 2004
DOI: 10.1002/GEPI.10311
Abstract: Latent class and genetic analyses were used to identify subgroups of migraine sufferers in a community s le of 6,265 Australian twins (55% female) aged 25-36 who had completed an interview based on International Headache Society (IHS) criteria. Consistent with prevalence rates from other population-based studies, 703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins satisfied the criteria for migraine with aura (MA) as indicated by visual symptoms. Latent class analysis (LCA) of IHS symptoms identified three major symptomatic classes, representing 1) a mild form of recurrent nonmigrainous headache, 2) a moderately severe form of migraine, typically without visual aura symptoms (although 40% of in iduals in this class were positive for aura), and 3) a severe form of migraine typically with visual aura symptoms (although 24% of in iduals were negative for aura). Using the LCA classification, many more in iduals were considered affected to some degree than when using IHS criteria (35% vs. 13%). Furthermore, genetic model fitting indicated a greater genetic contribution to migraine using the LCA classification (heritability, h(2)=0.40 95% CI, 0.29-0.46) compared with the IHS classification (h(2)=0.36 95% CI, 0.22-0.42). Exploratory latent class modeling, fitting up to 10 classes, did not identify classes corresponding to either the IHS MO or MA classification. Our data indicate the existence of a continuum of severity, with MA more severe but not etiologically distinct from MO. In searching for predisposing genes, we should therefore expect to find some genes that may underlie all major recurrent headache subtypes, with modifying genetic or environmental factors that may lead to differential expression of the liability for migraine.
Publisher: Elsevier BV
Date: 04-1998
DOI: 10.1016/S0091-6749(98)70356-2
Abstract: Although some studies have shown genetic control of specific IgE responses to purified grass allergens, studies with other allergens have not supported this. The extent of such control for house dust mite (HDM) (Dermatophagoides pteronyssinus) allergens is unclear. We sought to determine the extent to which genetic factors control the specificity of IgE responses to in idual HDM allergens by comparing the immunoblot patterns of IgE binding of serum from monozygotic and dizygotic members of a large cohort of Australian twins. HDM proteins separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis were immunoblotted with sera from 317 twin pairs in which at least one twin had at least a weak HDM skin test response. Concordance levels for IgE binding to the in idual HDM components were compared in the subset of 142 pairs of twins in which both twins were allergic to HDMs (skin prick test wheal diameter, > 3 mm). Over all 36 blotted bands, the mean case-wise concordance was 41% for monozygotic twins and 17% for dizygotic twins. Of the components detected, only those of molecular weights 23 kd and 16 kd were significantly different between the groups (p < 0.01). Differences observed between the monozygotic and dizygotic twins could be partly explained by overall IgE hyperresponsiveness. Evidence for genetic control of IgE responses to 36 IgE-binding HDM components from a large s le of twins showed significant differences in concordance for two components and nonsignificant differences for several others. In the monozygotic twins, concordance never exceeded 67% for any band, and most monozygotic in iduals recognized components their co-twin did not. Genetic control of overall atopy in monozygotic twins is far stronger than that controlling specific sensitization to HDM allergens.
Publisher: Oxford University Press (OUP)
Date: 22-01-2016
DOI: 10.1111/BJD.14291
Abstract: Heritability of naevi counts is widely acknowledged as a potential surveillance parameter for prevention purposes. The contribution of heritability to the changes seen in naevus number and morphology over time and their corresponding dermoscopic characteristics is unknown, but is important to understand in order to account for adequate prevention measures. To identify naevus characteristics that are strongly influenced by heritability. This cross-sectional study included 220 in iduals [76 monozygotic (MZ), 144 dizygotic (DZ)], recruited from the Brisbane Twin Naevus Study. Participants received full body imaging and dermoscopy of naevi ≥ 5 mm in diameter. Dermoscopic type, total naevus count (TNC), change in TNC with age, and naevus distribution, size, colour and profile were compared between MZ and DZ twins. Heritability of these traits was assessed via Falconer's estimate. Significant differences were found in comparing MZ and DZ twins for TNC, numbers of naevi 5·0-7·9 mm in diameter, counts of light-brown naevi, naevi on the back and sun-protected sites, and naevi with the 'nonspecific' dermoscopic pattern. This study strongly supports a heritable component to TNC, as well as changes in TNC, and the number of medium-sized naevi, light-brown naevi, specific sites and certain dermoscopic features in adults. These characteristics should be taken into account by naevus surveillance programmes and further studied to identify candidate gene associations for clinical and dermoscopic patterns in conjunction with melanoma risk stratification.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2006
Abstract: The ADAM33 gene has recently been identified as being a potentially important asthma candidate gene, and polymorphisms in this gene have been shown to be associated with asthma and bronchial hyperresponsiveness in Caucasian in iduals from several populations. We performed chip-based matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry using the MassARRAY system and multiplexed genotyping assays to investigate the association between 10 single nucleotide polymorphisms (SNPs) in the ADAM33 gene (F_+1, Q_-1, S_1, ST_+4, ST_+7, V_-2, V_-1, V_2, V_4, V_5) and asthma and asthma severity in a large Australian Caucasian population of nonasthmatic controls (n = 473), and patients with mild (n = 292), moderate (n = 238) and severe (n = 82) asthma. No significant association was found between any one of the 10 SNPs and asthma or asthma severity, however, there was a significant global haplotypic association with asthma (P = 0.0002) and disease severity (P = 0.0001), driven by the combination of two key SNPs, V_-1 and ST_+7. A meta-analysis of all the genetic studies conducted to date found significant between-study heterogeneity, likely to reflect population stratification. Our analysis of ADAM33 haplotypes further suggests a likely role for ADAM33 in the asthma phenotype, although it does not exclude an association with another locus in linkage disequilibrium with ADAM33.
Publisher: Oxford University Press (OUP)
Date: 05-02-2020
DOI: 10.1111/BJD.18777
Abstract: Skin phenotype, host genotype and ultraviolet (UV) damage play a role in the development of melanoma. To ascertain whether the level of UV damage at the site of melanomas was associated with genetic polymorphisms. Deep phenotyping was performed on 1244 in iduals 281 with multiple primary melanomas (MPMs), 304 with single primary melanoma (SPM) and 659 convenience controls. Genotype data was generated using the Illumina CoreExome microarray platform, assaying over 500 000 single-nucleotide polymorphisms. A subset of variants were combined to assess a polygenic risk score (PRS) for melanoma. Most MPM cases were diagnosed in patients aged > 40 years, in sites with visible chronic UV damage. Women and those diagnosed at age ≤ 40 years were less likely to have perilesional UV damage. Patients with MPM had higher frequencies of MITF E318K, MC1R R-alleles and the ASIP risk haplotype. In iduals who had melanoma in a visibly UV-damaged site were more likely to carry MC1R rs75570604 [odds ratio (OR) 2·5], 9q31.2 rs10816595 (OR 1·4) and MTAP rs869329 (OR 1·4). These same alleles were more common in patients with MPM who were diagnosed at age ≤ 40 years. The mean PRS was significantly higher in MPM than in SPM and controls. Naevus count was comparable in early-onset MPM cases and those diagnosed at age > 40 years. Our cohort demonstrated higher frequencies of previously reported alleles associated with melanoma. MPM melanomas more commonly occur in UV-damaged areas, and these in iduals are more likely to carry MC1R red hair colour alleles. Awareness of the interplay of genetic vulnerability with UV damage can stratify risk and guide recommendations for melanoma screening. What's already known about this topic? Skin phenotype, host genotype and ultraviolet (UV) damage all play a role in melanoma development. One of the main risk factors is a personal history of melanoma second and subsequent primary melanomas account for over 20% of all melanomas registered in Queensland. Multiple loci are associated with melanoma risk, including many low-penetrance loci, which may have a cumulatively significant risk. Population-wide screening programmes for melanoma are not yet economically viable. What does this study add? Patients diagnosed with melanoma at age ≤ 40 years were more likely than older patients to have melanomas in non-UV-damaged sites. Patients with multiple melanomas had higher frequencies of MITF E318K, MC1R R-alleles, and the ASIP extended risk haplotype than patients with single melanoma. CDKN2A, MC1R and MTAP variants were more frequent in patients who developed melanomas at a younger age, but also in those whose melanomas were all on visibly UV-damaged sites. What is the translational message? Incorporating these genetic findings into the known risk factors of skin phenotype and visible UV damage may allow for a more customized and economically feasible approach to early detection of melanoma, particularly in younger patients. Plain language summary available online.
Publisher: Wiley
Date: 27-02-2008
DOI: 10.1111/J.1440-1681.2008.04882.X
Abstract: 1. There are two types of familial hyperaldosteronism (FH): FH-I and FH-II. FH-I is caused by a hybrid CYP11B1/CYP11B2 gene mutation. The genetic cause of FH-II, which is more common, is unknown. Adrenal hyperplasia and adenomas are features. We previously reported linkage of FH-II to a approximately 5 Mb region on chromosome 7p22. We subsequently reported finding no causative mutations in the retinoblastoma-associated Kruppel-associated box gene (RBaK), a candidate at 7p22 involved in tumorigenesis and cell cycle control. 2. In the current study we investigated RBaK regulatory regions and two other candidate genes: postmeiotic segregation increased 2 (PMS2, involved in DNA mismatch repair and tumour predisposition) and guanine nucleotide-binding protein alpha-12 (GNA12, a transforming oncogene). 3. The GNA12 and PMS2 genes were examined in two affected (A1, A2) and two unaffected (U1, U2) subjects from a large 7p22-linked FH-II family (family 1). No mutations were found. 4. The RBaK and PMS2 distal promoters were sequenced to -2150 bp from the transcription start site for RBaK and-2800 bp for PMS2. Five unreported single nucleotide polymorphisms (SNPs) were found in subjects A1, A2 but not in U1 or U2 A(-2031 bp)T, T(-2030 bp)G, G(-834 bp)C, C(-821 bp)G in RBaK and A(-876 bp)G in PMS2. Additional affected and unaffected subjects from family 1 and from two other 7p22-linked FH-II families and 58 unrelated normotensive control subjects were genotyped for these SNPs. 5. The five novel SNPs were found to be present in a significant proportion of normotensive controls. The four RBaK promoter SNPs were found to be in linkage disequilibrium in the normal population. The RBaK promoter (-)2031T/2030G/834C/821T allele was found to be in linkage disequilibrium with the causative mutation in FH-II family 1, but not in families 2 and 3. The PMS2 promoter (-)876G allele was also found to be linked to affected phenotypes in family 1. 6. The RBaK and PMS2 promoter SNPs alter the binding sites for several transcription factors. Although present in the normal population, it is possible that the RBaK (-)2031T/2030G/834C/821T and PMS2 (-)876G alleles may have functional roles contributing to the FH-II phenotype in family 1.
Publisher: Springer New York
Date: 29-11-2016
DOI: 10.1007/978-1-4939-6613-4_11
Abstract: Although the term quantitative trait locus (QTL) strictly refers merely to a genetic variant that causes changes in a quantitative phenotype such as height, QTL analysis more usually describes techniques used to study oligogenic or polygenic traits where each identified locus contributes a relatively small amount to the genetic determination of the trait, which may be categorical in nature. Originally, too, it would be clear that it covered segregation and genetic linkage analysis, but now genetic association analysis in a genome-wide SNP or sequencing experiment would be the commonest application. The same biometrical genetic statistical apparatus used in this setting-analysis of variance, linear or generalized linear mixed models-can actually be applied to categorical phenotypes, as well as to multiple traits simultaneously, dealing with and taking advantage of genetic pleiotropy. Most recently, they are being used to make inferences about population and evolutionary genetics, with applications ranging from human disease to control of disease-causing organisms. Several computer software packages make it relatively straightforward to fit these statistically complex models to the large amounts of genotype and phenotype data routinely collected today.
Publisher: Oxford University Press (OUP)
Date: 27-06-2007
DOI: 10.1093/HMG/DDM177
Abstract: The human melanocortin-1 receptor (MC1R) is a G-protein coupled receptor involved in the regulation of pigmentation. Several MC1R variant alleles are associated with red hair, fair skin and increased skin cancer risk. We have performed a systematic functional analysis of nine common MC1R variants and correlated these results with the strength of the genetic association of each variant allele with pigmentation phenotypes. In vitro expression studies revealed that variant receptors with reduced cell surface expression, including V60L, D84E, R151C, I155T, R160W and R163Q, showed a corresponding impairment in cAMP coupling. The R142H and D294H variants demonstrated normal cell surface expression, but had reduced functional responses, indicating that altered G-protein coupling may be responsible for this loss of function. The V92M variant cAMP activation was equal to or higher than that for wild-type MC1R. In co-expression studies, the D84E, R151C, I155T and R160W variants showed a dominant negative effect on wild-type receptor cell surface expression, which was reflected in a decreased ability to elevate intracellular cAMP levels. The D294H variant also demonstrated a dominant negative effect on wild-type MC1R cAMP signalling, but had no effect on wild-type surface expression. Importantly, comparison of the in vitro receptor characteristics with skin and hair colour data of in iduals both homozygous and heterozygous for MC1R variant alleles revealed parallels between variant MC1R cell surface expression, functional ability, dominant negative activity and their effects on human pigmentation. These findings show the first direct correlations between variant MC1R biochemical properties and pigmentation phenotype.
Publisher: Wiley
Date: 26-02-2018
DOI: 10.1111/PCMR.12691
Publisher: European Respiratory Society (ERS)
Date: 08-2005
DOI: 10.1183/09031936.05.00140104
Abstract: Cyclooxygenase-1 (COX-1) regulates the biosynthesis of prostaglandins, which are important mediators in asthma. The possible association of COX-1 gene polymorphisms with asthma has not been investigated. The allele frequencies of 20 COX-1 polymorphisms were determined in a random Australian Caucasian population using MassARRAY technology. Informative and potentially functional promoter (c.8592C > T, c.1676C > T) and coding region (c.22C > T, c.50C > T) polymorphisms were investigated in carefully phenotyped patients with mild (n = 316), moderate (n = 241), severe (n = 86) or aspirin-intolerant asthma (AIA) (n = 58), and in nonasthmatic subjects (n = 477). There were no allelic, genotypic or haplotypic associations between these four polymorphisms and asthma or asthma severity. Over-representation of the c.50TT genotype among AIA patients (3.4%) compared with aspirin-tolerant patients (0.8%), and a global haplotype association with AIA did not reach statistical significance. The c.22TT genotype was less frequent among atopic (0.1%) rather than nonatopic in iduals (1.2% odds ratio = 9.05, 95% confidence interval 1.01-81.29). In conclusion, the present investigation of cyclooxygenase-1 polymorphisms in asthma indicates that they do not appear to play a substantial role in genetic pre-disposition for asthma or asthma severity. However, the c.22TT genotype confers a small protective effect against atopy. Potential associations with aspirin-intolerant asthma were identified and warrant further investigation in a larger population of aspirin-intolerant asthma patients.
Publisher: Elsevier BV
Date: 10-2004
Publisher: Cambridge University Press (CUP)
Date: 06-1998
DOI: 10.1375/136905298320566375
Abstract: We examined the cumulative prevalences of 22 symptoms thought to reflect immune system function reported in a questionnaire mailed to 7616 Australian twins. The associations between symptoms and demographic variables were expressed in terms of polychoric or polyserial correlations, and a principal components analysis performed. Factors representing underlying propensities respectively to allergic disease, various minor infections, diseases associated with aging such as arthritis, skin disease, and respiratory tract infection were extracted. Possible processes underlying these symptom clusters and the relative strengths and weaknesses of this type of analysis are discussed.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2012
DOI: 10.1007/S00251-011-0577-X
Abstract: Canine atopic dermatitis (AD) is an allergic inflammatory skin disease that shares similarities with AD in humans. Canine AD is likely to be an inherited disease in dogs and is common in West Highland white terriers (WHWTs). We performed a genome-wide association study using the Affymetrix Canine SNP V2 array consisting of over 42,800 single nucleotide polymorphisms, on 35 atopic and 25 non-atopic WHWTs. A gene-dropping simulation method, using SIB-PAIR, identified a projected 1.3 Mb area of association (genome-wide P = 6 × 10(-5) to P = 7 × 10(-4)) on CFA 17. Nineteen genes on CFA 17, including 1 potential candidate gene (PTPN22), were located less than 0.5 Mb from the interval of association identified on the genome-wide association analysis. Four haplotypes within this locus were differently distributed between cases and controls in this population of dogs. These findings suggest that a major locus for canine AD in WHWTs may be located on, or in close proximity to an area on CFA 17.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2018
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: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2019
Publisher: Wiley
Date: 09-2002
DOI: 10.1046/J.1365-2745.2002.01447.X
Abstract: The fungus Alternaria alternata contains potent allergens, and sensitization to these allergens is associated with a high risk of respiratory disease. The influence of genetic regulation on sensitization to Alternaria is unknown. To determine the influence of genetic factors on IgE responses to specific allergens of Alternaria. The concordance of skin prick test (SPT), radioallergosorbent test (RAST) and IgE-binding profiles of sera were examined from a large cohort of monozygotic and dizygotic twins. Casewise concordance for a positive SPT response was monozygous (MZ) 66%: dizygous (DZ) 40% (P = 0.002). Logistic regression confirmed that casewise concordance was significantly stronger between MZ than DZ pairs. Immunoblotting against an Alternaria extract revealed 19 allergenic bands. The differences in concordance between the different bands were not significant for either the MZ (P = 0.97) or DZ (P = 0.84) groups. The pooled MZ : DZ difference in concordance was just significant (P = 0.049), suggesting an overall genetic effect on the response to Alternaria. This was reinforced by the comparison of the MZ and DZ correlations for total number of bands recognized (MZ r = 0.65 DZ r = 0.37, P = 0.015). Overall, there was a moderate correlation between the in idual SPT weal size and RAST score (r(2) = 0.41) and a substantial correlation between the number of immunoblotted bands and RAST scores (r(2) = 0.79). There is a strong genetic influence on IgE response to the mixture of Alternaria allergens and a lesser effect on IgE response to in idual allergens.
Publisher: Wiley
Date: 2005
DOI: 10.1002/SIM.2010
Abstract: Although population-based molecular association studies are becoming increasingly popular, methodology for the meta-analysis of these studies has been neglected, particularly with regard to two issues: testing Hardy-Weinberg equilibrium (HWE), and pooling results in a manner that reflects a biological model of gene effect. We propose a process for pooling results from population-based molecular association studies which consists of the following steps: (1) checking HWE using chi-square goodness of fit we suggest performing sensitivity analysis with and without studies that are in HWE. (2) Heterogeneity is then checked, and if present, possible causes are explored. (3) If no heterogeneity is present, regression analysis is used to pool data and to determine the gene effect. (4) If there is a significant gene effect, pairwise group differences are analysed and these data are allowed to 'dictate' the best genetic model. (5) Data may then be pooled using this model. This method is easily performed using standard software, and has the advantage of not assuming an a priori genetic model.
Publisher: Springer Science and Business Media LLC
Date: 09-2005
DOI: 10.1007/S10519-005-3851-6
Abstract: After ingestion of a standardized dose of ethanol, alcohol concentrations were assessed, over 3.5 hours from blood (six readings) and breath (10 readings) in a s le of 412 MZ and DZ twins who took part in an Alcohol Challenge Twin Study (ACTS). Nearly all participants were subsequently genotyped on two polymorphic SNPs in the ADH1B and ADH1C loci known to affect in vitro ADH activity. In the DZ pairs, 14 microsatellite markers covering a 20.5 cM region on chromosome 4 that includes the ADH gene family were assessed, Variation in the timed series of autocorrelated blood and breath alcohol readings was studied using a bivariate simplex design. The contribution of a quantitative trait locus (QTL) or QTL's linked to the ADH region was estimated via a mixture of likelihoods weighted by identity-by-descent probabilities. The effects of allelic substitution at the ADH1B and ADH1C loci were estimated in the means part of the model simultaneously with the effects sex and age. There was a major contribution to variance in alcohol metabolism due to a QTL which accounted for about 64% of the additive genetic covariation common to both blood and breath alcohol readings at the first time point. No effects of the ADH1B*47His or ADH1C*349Ile alleles on in vivo metabolism were observed, although these have been shown to have major effects in vitro. This implies that there is a major determinant of variation for in vivo alcohol metabolism in the ADH region that is not accounted for by these polymorphisms. Earlier analyses of these data suggested that alcohol metabolism is related to drinking behavior and imply that this QTL may be protective against alcohol dependence.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2009
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1038/JID.2011.322
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.IJPARA.2015.02.002
Abstract: Marteilia sydneyi (Phylum Paramyxea, Class Marteiliidea, Order Marteiliida) (the causative agent of QX disease) is recognised as the most severe parasite to infect Saccostrea glomerata, the Sydney rock oyster, on the east coast of Australia. Despite its potential impact on industry (>95% mortality), research towards lessening these effects has been hindered by the lack of an experimental laboratory model of infection as a consequence of our incomplete understanding of the life cycle of this parasite. Here, we explored the presence of this parasite in hosts other than a bivalve mollusc from two study sites on the Hawkesbury River, New South Wales, Australia. We employed PCR-based in situ hybridisation and sequence analysis of a portion of the first internal transcribed spacer of rDNA in an attempt to detect M. sydneyi DNA in 21 species of polychaete worm. Marteilia DNA was detected in 6% of 1247 s les examined by PCR the analysis of all licons defined one distinct sequence type for first internal transcribed spacer, representing M. sydneyi. Of the polychaete operational taxonomic units test-positive in PCR, we examined 116 s les via in situ hybridisation DNA probe staining and identified M. sydneyi DNA in the epithelium of the intestine of two specimens of Nephtys australiensis. Two differing morphological forms were identified: a 'primordial' cell that contained a well-defined nucleus but had little differentiation in the cytoplasm, and a 'plasmodial' cell that showed an apparent syncytial structure. This finding represents the first known record of the identification of M. sydneyi being parasitic in an organism other than an oyster, and only the third record of any species of Marteilia identified from non-molluscan hosts. Future work aims at determining if N. australiensis and S. glomerata are the only hosts in the life cycle of this paramyxean, and the development of experimental models to aid the production of QX disease-resistant oysters.
Publisher: Elsevier BV
Date: 11-1997
Abstract: Linkage of asthma and high total serum IgE levels to chromosome 12q15-q24.1 has been recently described. To evaluate this region further in regard to total IgE responsiveness, we genotyped 52 unrelated German children with persistently "high" total serum IgE (selected from a noninterventional prospective multicenter cohort study) and their parents. We carefully defined a most extreme IgE phenotype and analyzed it as a dichotomous trait. We tested for linkage between high total IgE concentrations and nine polymorphic microsatellite markers on chromosome 12q15-q24.1 using the transmission/disequilibrium test. Evidence for linkage and allelic association for high total IgE was observed for four markers in this region. This study demonstrates the value of using extreme phenotypes in genetic analysis of a complex quantitative trait.
Publisher: Wiley
Date: 1994
Publisher: Springer Science and Business Media LLC
Date: 12-2011
Abstract: Canine atopic dermatitis is an allergic inflammatory skin disease common in West Highland white terriers. A genome-wide association study for atopic dermatitis in a population of West Highland white terriers identified a 1.3 Mb area of association on CFA17 containing canine protein tyrosine phosphatase non-receptor type 22 (lymphoid) PTPN22 . This gene is a potential candidate gene for canine atopic dermatitis as it encodes a lymphoid-specific signalling mediator that regulates T-cell and possibly B-cell activity. Sequencing of PTPN22 in three atopic and three non-atopic West Highland white terriers identified 18 polymorphisms, including five genetic variants with a bioinformatically predicted functional effect. An intronic polymorphic repeat sequence variant was excluded as the cause of the genome-wide association study peak signal, by large-scale genotyping in 72 West Highland white terriers (gene-dropping simulation method, P = 0.01). This study identified 18 genetic variants in PTPN22 that might be associated with atopic dermatitis in West Highland white terriers. This preliminary data may direct further study on the role of PTPN22 in this disease. Large scale genotyping and complementary genomic and proteomic assays would be required to assess this possibility.
Publisher: Elsevier BV
Date: 07-2010
Publisher: Oxford University Press (OUP)
Date: 06-04-2018
DOI: 10.1111/BJD.16323
Abstract: Iris naevi and iris freckles have a frequency of 4% and 50% in the European population, respectively. They are associated with dysplastic naevi, but few studies have examined their link to cutaneous melanoma. To assess whether iris pigmented lesions are a predictive indicator for cutaneous melanoma. This is a melanoma case-control study of 1254 European-background Australians. Sun exposure and melanoma history, a saliva s le for DNA analysis and eye photographs taken with a digital camera were collected from 1117 participants. Iris images were assessed by up to four trained observers for the number of iris pigmented lesions. The data were analysed for correlations between iris pigmented lesions and melanoma history. Case participants over the age of 40 had similar numbers of iris pigmented lesions to age matched controls (mean 5·7 vs. 5·2, P = 0·02), but in younger case and control participants there was a greater difference (mean 3·96 vs. 2·19, P = 0·004). A logistic regression adjusted for age, sex, skin, hair and eye colour, skin freckling and naevus count found that the presence of three or more iris pigmented lesions increases the melanoma risk 1·45-fold [95% confidence interval (CI) 1·07-1·95]. HERC2/OCA2 rs12913832 and IRF4 rs12203592 influenced both eye colour and the number of iris pigmented lesions. On the HERC2/OCA2 A/A and A/G genotype background there was an increasing proportion of blue eye colour when carrying the IRF4 T allele (P = 3 × 10 Iris pigmented lesion count provides additional predictive information for melanoma risk above that from conventional risk factors.
Publisher: Wiley
Date: 1994
Abstract: A recent multivariate extension of the classical twin study in theory allows the inference of the direction of causation between correlated traits solely using cross-sectional data. In this paper we briefly review this model and assess its usefulness by applying it to a number of pairs of biological and psychological variables between which the nature of the causative relationship is already known. We conclude that the method has a number of biases and limitations. If a causative relationship at the phenotypic level exists between two traits, the correct direction of causation is usually identifiable, providing the reliability and validity of the measures are known. Failure to correctly specify a measurement model can lead to incorrect tests of hypotheses. Difficulties can also occur when discriminating between a direct causative relationship and a correlation due to common genetic or environmental determinants, but these occur in predictable situations. If these considerations are taken into account in interpretation of results, the true nature of the association between traits can often be correctly identified, or at least included in a subgroup of best fitting models.
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.JACI.2010.06.017
Abstract: Although the genetics of asthma susceptibility have been frequently explored, little is known about genetic factors that influence the age at onset of asthma. To study the variation in the age at onset of asthma attributable to genetic and environmental factors. Data on the age at onset and predictors of asthma were collected in 2002 via a multidisciplinary questionnaire study of 34,782 Danish twins 20 to 71 years of age. Survival analytic methods were applied to partition variation in the age at onset of asthma into genetic and environmental components. Sex, hay fever, atopic dermatitis, smoking, and exposure to passive smoking in childhood were significant risk factors, whereas BCG vaccination was protective for asthma. The risk of asthma in the co-twin of an affected twin was higher in monozygotic than in dizygotic twins (hazard ratio, 2.59 95% CI, 1.83-3.68 P < .001). The risk of asthma in the co-twin decreased with increasing age at onset of asthma in the index twin (hazard ratio per ten years, 0.86 95% CI, 0.76-0.98 P = .019). The effect was attenuated in dizygotic twins relative to monozygotic twins (P = .005). Genetic factors explained 34% of the variation in the age at onset of asthma, and environmental factors accounted for 66%. Host-related differences in genetic makeup cause different in iduals to develop asthma at different ages. Better understanding of the causes for variation in the age at onset of disease may ultimately lead the way to targeted treatments.
Publisher: Elsevier BV
Date: 10-2015
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: Elsevier BV
Date: 02-2002
DOI: 10.1086/338626
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2003
DOI: 10.1097/00008390-200308000-00011
Abstract: Germline variants in the melanocortin 1 receptor gene (MC1R) and the p16 gene (CDKN2A) are associated with an increased risk of cutaneous melanoma. The frequency of these germline variants was examined in a population-based, incident series of 62 ocular melanoma cases and ethnicity-matched population controls. In both cases and controls, 59% of in iduals carried at least one MC1R variant and there were no significant differences in the frequency of any of the five most common variants of MC1R. We also found no significant differences between cases and controls in the frequency of any of the four most common variants of CDKN2A, and no melanoma case carried a deleterious germline CDKN2A mutation. Our findings argue against an important predisposing effect of the MC1R and CDKN2A genes for ocular melanoma.
Publisher: Wiley
Date: 15-03-2019
DOI: 10.1111/JDV.15446
Abstract: Amelanotic/hypomelanotic melanoma is associated with poorer outcomes due to a more advanced disease stage at diagnosis. To determine phenotypic risks and genotypic associations with amelanotic/hypomelanotic melanoma to develop a clinical and genetic profile that could assist in identifying high-risk in iduals. The Brisbane Naevus Morphology Study conducted from 2009 to 2016 has recruited a core of 1254 participants. Participants were drawn from a combination of volunteers from dermatology outpatient clinics, private dermatology clinics, the Brisbane Longitudinal Twin Study and QSkin study. Case participants had a personal history of melanoma and control participants no personal history of melanoma. We specifically examined seven known candidate pigmentation and melanoma genes and pigmentary phenotypic characteristics in participants with amelanotic/hypomelanotic melanoma compared to pigmented melanomas. This assayed single nucleotide polymorphisms in MC1R, TYR, HERC/OCA2, IRF4, MTAP, PLA2G6 and MITF. Forty-seven participants had at least one amelanotic/hypomelanotic melanoma, and 389 had pigmented melanomas, with amelanotic/hypomelanotic melanoma patients significantly older than pigmented melanoma participants (63.3 ± 13.0 vs. 54.6 ± 15.3 years P < 0.001). Amelanotic/hypomelanotic melanoma patients were more likely than pigmented melanoma patients to have red hair (34% vs. 15% P = 0.01), severe hand freckling (13% vs. 5% P = 0.01) and propensity to sunburn (63% vs. 44% P = 0.01). MC1R R/R genotype was much more frequent in our amelanotic/hypomelanotic melanoma population (31.1% vs. 11% P < 0.001 OR 26.4 vs. 5.9 control 1.0). Amelanotic/hypomelanotic melanoma was associated with TYR rs1126809*A/A [OR (CI 95%) 2.7 (1.1-6.8) vs. 1.2 (0.8-1.9)] and PLA2G6 rs11570734*A/A [OR (CI 95%) 3.7 (1.0-13.6) vs. 1.3 (0.9-2.0)]. The MTAP melanoma risk SNP genotype, associated with darker pigmentation, (rs4636294*A/A) was less common in amelanotic/hypomelanotic melanoma patients [OR (CI 95%) 0.8 (0.3-2.1) vs. 2.0 (1.3-3.1)]. Knowledge of phenotypic and genotypic associations of amelanotic/hypomelanotic melanoma can help predict risks and associations of this difficult to diagnose melanoma, which may ultimately assist clinical management and patient skin self-examination.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Oxford University Press (OUP)
Date: 18-06-2014
DOI: 10.1093/HMG/DDU312
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: Elsevier BV
Date: 08-1999
DOI: 10.1016/S0091-6749(99)70398-2
Abstract: Asthma is a complex disease characterized by a high prevalence of allergic diathesis and the almost ubiquitous presence of upper airway disease (eg, rhinitis). Previously, we observed linkage of asthma among Afro-Caribbean families to markers in chromosome 12q, which contains a number of genes encoding for products closely related to allergic airway inflammation and disease. To identify susceptibility loci in chromosome 12q contributing to the genetics of upper and lower airway diseases and to expand the region to include genes encoding IFN-gamma (IFNG ) and one of the signal transducers and activators of transcription (STAT6 ), we conducted further linkage studies among 33 multiplex families. We characterized 528 subjects from Barbados for asthma 82% were characterized for allergic rhinitis. Two-point and multipoint linkage analysis of 22 microsatellite markers (spanning approximately 79 centimorgan) was performed. Affected sib-pair analysis revealed significant evidence for linkage to asthma over approximately 30 cM (P <.05 to.002), with the best evidence for linkage at a CA repeat polymorphism in the first intron of IFNG in 12q21.1 (P =.002). Evidence of linkage to allergic rhinitis was observed in the same region (D12S313, P = 0.006, and IFNGCA, P =.01, respectively). Multipoint linkage analysis also provided evidence for linkage to asthma, with the best nonparametric linkage analysis score at D12S326 (nonparametric linkage score = 3.8, P =.0008). Modest evidence for linkage to allergic rhinitis was observed next to D12S326 at D12S1052 (P =.036). Our findings suggest that (1) one or more loci in the chromosome 12q13. 12-q23.3 region are contributing to the expression of the clinical phenotype asthma and the strongest evidence for linkage is in a region near the gene encoding IFNG and (2) a susceptibility locus for both asthma and allergic rhinitis maps to this region.
Publisher: Environmental Health Perspectives
Date: 08-2007
DOI: 10.1289/EHP.8847
Publisher: Elsevier BV
Date: 03-2001
Publisher: Public Library of Science (PLoS)
Date: 16-05-2008
Publisher: Springer Science and Business Media LLC
Date: 30-10-2017
DOI: 10.1038/NG.3985
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: Oxford University Press (OUP)
Date: 03-03-1999
Abstract: Mutations in the CDKN2A gene confer susceptibility to cutaneous malignant melanoma (CMM) however, the population incidence of such mutations is unknown. Polymorphisms in CDKN2A have also been described, but it is not known whether they influence melanoma risk. We investigated the association of CDKN2A mutations and polymorphisms with melanoma risk in a population-based s le of families ascertained through probands with melanoma. The 482 Queensland, Australia, families in our s le were characterized previously as having high, intermediate, or low family risk of CMM. Unrelated in iduals (n = 200 families/in iduals) drawn from the Australian Twin Registry served as control subjects. For in iduals in the high-risk group, the entire CDKN2A gene coding region was screened for mutations by use of the polymerase chain reaction, agarose gel electrophoresis, allele-specific oligonucleotide (ASO) hybridization, and single-strand conformation polymorphism analysis. The intermediate- and low-risk families and control subjects were analyzed by ASO hybridization for a total of six recurring mutations as well as for polymorphisms at nucleotides (Nts) 442, 500, and 540. CDKN2A mutations were found only in the high-risk families (nine [10.3%] of 87). The prevalence of the Nt500G (guanosine) polymorphism increased linearly with increasing familial risk (two-sided P = .02) and was highest in the nine (primarily Celtic) families with CDKN2A mutations. After adjustment for ethnic origin, the relationship between risk group and the frequency of the Nt500G allele was weakened (P = .25) however, there was no relationship between ethnic origin and Nt500-polymorphism frequency among the control subjects. CDKN2A mutations are rare in this population (approximately 0.2% of all melanoma cases in Queensland) and appear to be associated with melanoma in only the most affected families. The Nt500G allele appears to be associated with familial risk, but this association probably reflects Celtic ancestry.
No related grants have been discovered for David Duffy.