ORCID Profile
0000-0003-0663-4621
Current Organisation
University of Queensland
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Genetics | Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
Immune System and Allergy | Expanding Knowledge in the Medical and Health Sciences |
Publisher: Informa UK Limited
Date: 02-01-2019
Publisher: Springer Science and Business Media LLC
Date: 12-08-2004
Publisher: Public Library of Science (PLoS)
Date: 29-03-2012
Publisher: Wiley
Date: 20-06-2013
DOI: 10.1111/GBB.12053
Publisher: Springer Science and Business Media LLC
Date: 04-07-2023
DOI: 10.1038/S42003-023-04869-0
Abstract: Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis ( n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci ( ZIC1 , PRKAR1A , AZIN1/ATP6V1C1 , GLRX3 ), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.
Publisher: Elsevier BV
Date: 07-2014
Publisher: Springer Science and Business Media LLC
Date: 15-07-2017
Publisher: Oxford University Press (OUP)
Date: 12-04-2018
DOI: 10.1093/HMG/DDY121
Publisher: The Endocrine Society
Date: 08-2010
DOI: 10.1210/JC.2010-0025
Publisher: Oxford University Press (OUP)
Date: 23-05-2013
DOI: 10.1093/HMG/DDT231
Publisher: BMJ
Date: 29-08-2018
DOI: 10.1136/BMJ.K3225
Abstract: To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk. Meta-analysis of genome wide association studies (GWAS) and a two-s le mendelian randomisation approach. 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data. A discovery set of 37 857 fracture cases and 227 116 controls with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as in iduals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a two-s le mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor. Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2016
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1086/340850
Publisher: Wiley
Date: 2020
DOI: 10.1002/DAD2.12108
Publisher: Oxford University Press (OUP)
Date: 29-05-2013
DOI: 10.1093/HMG/DDT239
Publisher: F1000 Research Ltd
Date: 06-2020
DOI: 10.12688/WELLCOMEOPENRES.15846.1
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent in iduals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P x10 -8 ) interactions with sex on lung function, and 21 showed suggestive interactions (P x10 -6 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1 ) (P=3.15x10 -15 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP ) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6 ), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
Publisher: F1000 Research Ltd
Date: 24-05-2021
DOI: 10.12688/WELLCOMEOPENRES.15846.2
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent in iduals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P x10 -8 ) interactions with sex on lung function, and 21 showed suggestive interactions (P x10 -6 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1 ) (P=3.15x10 -15 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP ) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6 ), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
Publisher: Wiley
Date: 20-01-2015
DOI: 10.1111/ADD.12822
Publisher: Elsevier BV
Date: 04-2016
Publisher: Springer Science and Business Media LLC
Date: 04-05-2016
Abstract: Ankylosing spondylitis (AS) is a common chronic immune-mediated arthropathy affecting primarily the spine and pelvis. The condition is strongly associated with HLA-B*27 as well as other human leukocyte antigen variants and at least 47 in idual non-MHC-associated variants. However, substantial additional heritability remains as yet unexplained. To identify further genetic variants associated with the disease, we undertook an association study of AS in 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. A novel association achieving genome-wide significance was noted at CDKAL1 . Suggestive associations were demonstrated with common variants in FAM118A , C7orf72 and FAM114A1 and with a low-frequency variant in PNPLA1. Two of the variants have been previously associated with inflammatory bowel disease (IBD CDKAL1 and C7orf72 ). These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having similar aetiopathogenesis.
Publisher: Cambridge University Press (CUP)
Date: 08-2020
DOI: 10.1017/THG.2020.60
Abstract: Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740 . 1 noncoding RNA, was significantly associated with septic shock ( p = 1.05 × 10 –10 ) however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated ( p 1.00 × 10 –6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality ( p = 3.04 × 10 –3 p = 2.29 × 10 –3 ), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock ( p = 1.44 × 10 –3 ). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic in iduals.
Publisher: Elsevier BV
Date: 02-2010
Publisher: Springer Science and Business Media LLC
Date: 28-09-2016
DOI: 10.1038/NATURE19806
Publisher: Public Library of Science (PLoS)
Date: 18-11-2010
Publisher: Elsevier BV
Date: 09-2018
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NCOMMS10495
Abstract: To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 in iduals. Twelve loci reached genome-wide significance ( P × 10 −8 ), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14 , IGF2BP1 , PLA2G6 , CRTC1 ) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
Publisher: Public Library of Science (PLoS)
Date: 17-07-2014
Publisher: Springer Science and Business Media LLC
Date: 02-01-2021
Publisher: Cambridge University Press (CUP)
Date: 02-2004
Publisher: Springer Science and Business Media LLC
Date: 16-01-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2022
DOI: 10.1161/HYPERTENSIONAHA.121.17701
Abstract: Observational epidemiological studies have reported that higher maternal blood pressure (BP) during pregnancy is associated with increased future risk of offspring cardiometabolic disease. However, it is unclear whether this association represents a causal relationship through intrauterine mechanisms. We used a Mendelian randomization (MR) framework to examine the relationship between unweighted maternal genetic scores for systolic BP and diastolic BP and a range of cardiometabolic risk factors in the offspring of up to 29 708 genotyped mother-offspring pairs from the UKB study (UK Biobank) and the HUNT study (Trøndelag Health). We conducted similar analyses in up to 21 423 father-offspring pairs from the same cohorts. We confirmed that the BP-associated genetic variants from the general population s le also had similar effects on maternal BP during pregnancy in independent cohorts. We did not detect any association between maternal (or paternal) unweighted genetic scores and cardiometabolic offspring outcomes in the meta-analysis of UKB and HUNT after adjusting for offspring genotypes at the same loci. We find little evidence to support the notion that maternal BP is a major causal risk factor for adverse offspring cardiometabolic outcomes in later life.
Publisher: Cold Spring Harbor Laboratory
Date: 06-2012
Abstract: The power of a statistical test is the probability that it will yield a statistically significant result given that the null hypothesis is false. In other words, it represents the chance that the study will be successful in detecting a true effect and is dependent on a number of factors, including the magnitude of the effect, the s le size and study design, and the specified false-positive rate. Power calculations are primarily performed during the planning stages of a study, most typically in determining the s le size required. Consideration of statistical power can also sometimes shed light on the results of completed studies, particularly in the interpretation of negative results. In this article, we review the fundamentals of statistical power, discuss how power is calculated (using a genetic case/control study as an ex le), and consider the most pertinent factors that influence power in genetic studies. Finally, we focus on power in the context of modern whole-genome association studies, in which issues of coverage, multiple testing, and staged designs are paramount.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2016
DOI: 10.1038/SREP25853
Abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry s les (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4 P = 6.3E–04).
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: Informa UK Limited
Date: 03-04-2017
Publisher: Oxford University Press (OUP)
Date: 23-07-2019
DOI: 10.1093/IJE/DYZ160
Abstract: The intrauterine environment is critical for fetal growth and development. However, observational associations between maternal gestational lipid concentrations and offspring birth weight (BW) have been inconsistent and ascertaining causality is challenging. We used a novel two-s le Mendelian randomization (MR) approach to estimate the causal effect of maternal gestational high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride concentrations on offspring BW. Single nucleotide polymorphisms (SNPs) associated with serum HDL-C, LDL-C and triglyceride concentrations identified in the Global Lipids Genetics Consortium genome-wide association study meta-analysis (n = 188 577 European-ancestry in iduals s le 1) were selected as instrumental variables. The effects of these SNPs on offspring BW were estimated using a structural equation model in the UK Biobank and Early Growth Genetics consortium (n = 230 069 European-ancestry in iduals s le 2) that enabled partitioning of the genetic associations into maternal- (intrauterine) and fetal-specific effects. We found no evidence for a causal effect of maternal gestational HDL-C, LDL-C or triglyceride concentrations on offspring BW [standard deviation change in BW per standard deviation higher in HDL-C = −0.005 (95% confidence interval: −0.039, 0.029), LDL-C = 0.014 (−0.017, 0.045), and triglycerides = 0.014 (−0.025, 0.052)]. Our findings suggest that maternal gestational HDL-C, LDL-C and triglyceride concentrations play a limited role in determining offspring BW. However, we cannot comment on the impact of these and other lipid fractions on fetal development more generally. Our study illustrates the power and flexibility of two-s le MR in assessing the causal effect of maternal environmental exposures on offspring outcomes.
Publisher: eLife Sciences Publications, Ltd
Date: 06-07-2022
Publisher: Springer Science and Business Media LLC
Date: 13-02-2021
Publisher: Research Square Platform LLC
Date: 12-04-2021
DOI: 10.21203/RS.3.RS-375556/V1
Abstract: We report the first epigenome-wide association study of left-handedness, a trait with low heritability for which epigenetic mechanisms have been proposed as an underlying etiological mechanism. A region-based meta-analysis of whole blood genome-wide DNA methylation data from two cohorts (3,914 adults) identified differentially methylated regions annotated to BLCAP (20q11.23), a negative regulator of cell growth involved in apoptosis, NNAT (20q11.23), involved in brain development, and IAH1 (2p25.1), which encodes an acyl esterase. CpGs located in proximity to the SNPs from the largest GWAS of handedness were more strongly associated with left-handedness than other differentially methylated positions. In longitudinal whole blood s les, cord blood, and buccal cells from children (N = 1,967), the association with handedness displayed moderate stability across age, but little consistency across cell types. These findings suggest new candidate loci associated with handedness.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2013
DOI: 10.1158/1055-9965.EPI-12-1248
Abstract: Background: Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D. Methods: We created a tanning, a skin color, and a freckling score as combinations of single nucleotide polymorphisms that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and prostate-specific antigen detected prostate cancer in 3,123 White British in iduals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study. Results: The freckling score was inversely associated with 25(OH)D levels [change in 25(OH)D per score unit −0.27 95% CI, −0.52% to −0.01%], and the tanning score was positively associated with prostate cancer risk (OR = 1.05 95% CI, 1.02–1.09), after adjustment for population stratification and potential confounders. Conclusions: In iduals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer. Impact: The use of pigmentation-related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk. Cancer Epidemiol Biomarkers Prev 22(4) 597–606. ©2013 AACR.
Publisher: Springer Science and Business Media LLC
Date: 04-09-2017
DOI: 10.1038/NG.3949
Publisher: Springer Science and Business Media LLC
Date: 26-11-2018
Publisher: The Endocrine Society
Date: 02-12-2022
Abstract: Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown. This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity. We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-s le Mendelian randomization. In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] −0.19 [−0.21 to −0.17]), body fat (−0.12 [−0.14 to −0.10), and fasting C-peptide (−2.04 [−2.46 to −1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose cl in 2 independent clinical studies (−0.5 [−0.7 to −0.4] and −0.5 [−0.6 to −0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-s le Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, −1.72 [−2.86 to −0.58], and −0.20 [−0.36 to −0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-s le Mendelian randomization suggested no causal effect of fasting glucose on sOb-R. BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 03-01-2017
DOI: 10.1038/MP.2016.198
Publisher: Elsevier BV
Date: 08-2013
Publisher: Wiley
Date: 29-08-2014
DOI: 10.1111/GBB.12158
Publisher: Springer Science and Business Media LLC
Date: 03-2004
Publisher: Cold Spring Harbor Laboratory
Date: 26-10-2005
DOI: 10.1101/GR.4217605
Abstract: As part of a recent high-density linkage disequilibrium (LD) study of chromosome 20, we obtained genotypes for ∼30,000 SNPs at a density of 1 SNP/2 kb on four different population s les (47 CEPH founders 91 UK unrelateds [unrelated white in iduals of western European ancestry] 97 African Americans 42 East Asians). We observed that ∼50% of SNPs had at least one genetically indistinguishable partner i.e., for every in idual considered, their genotype at the first locus was identical to their genotype at the second locus, or in LD terms, the SNPs were in “perfect” LD (r 2 = 1.0). These “genetically indistinguishable SNPs” (giSNPs) formed into clusters of varying size. The larger the cluster, the greater the tendency to be located within genes and to overlap with giSNP clusters in other population s les. As might be expected for this map density, many giSNPs were located close to one another, thus reflecting local regions of undetected recombination or haplotype blocks. However, ∼1/3 of giSNP clusters had intermingled, non-indistinguishable SNPs with incomplete LD (D′ and r 2 ), sometimes spanning hundreds of kilobases, comprising up to 70 indistinguishable markers and overlapping multiple haplotype blocks. These long-range, nonconsecutive giSNPs have implications for disease gene localization by allelic association as evidence for association at one locus will be indistinguishable from that at another locus, even though both loci may be situated far apart. We describe the distribution of giSNPs on this map of chromosome 20 and illustrate the potential impact they can have on association mapping.
Publisher: Oxford University Press (OUP)
Date: 03-2005
Publisher: Cold Spring Harbor Laboratory
Date: 13-07-2023
DOI: 10.1101/2023.07.13.23292588
Abstract: We propose TetraHer, a method for estimating the liability heritability of binary phenotypes. TetraHer has five key features. Firstly, it can be applied to data from complex pedigrees, that contain multiple types of relationships. Secondly, it can correct for ascertainment of cases or controls. Thirdly, it can accommodate covariates. Fourthly, it can model the contribution of common environment. Fifthly, it produces a likelihood, that can be used for significance testing. We first demonstrate the validity of TetraHer on simulated data. We then use TetraHer to estimate liability heritability for 229 codes from the tenth International Classification of Diseases (ICD-10). We identify 118 codes with significant heritability (P .05/229), which can be used in future analyses for investigating the genetic architecture of human diseases.
Publisher: Rockefeller University Press
Date: 26-10-2021
DOI: 10.1084/JEM.20211872
Abstract: Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a−/− demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB–mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation.
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: Oxford University Press (OUP)
Date: 27-02-2019
DOI: 10.1093/IJE/DYZ019
Abstract: There is considerable interest in estimating the causal effect of a range of maternal environmental exposures on offspring health-related outcomes. Previous attempts to do this using Mendelian randomization methodologies have been h ered by the paucity of epidemiological cohorts with large numbers of genotyped mother–offspring pairs. We describe a new statistical model that we have created which can be used to estimate the effect of maternal genotypes on offspring outcomes conditional on offspring genotype, using both in idual-level and summary-results data, even when the extent of s le overlap is unknown. We describe how the estimates obtained from our method can subsequently be used in large-scale two-s le Mendelian randomization studies to investigate the causal effect of maternal environmental exposures on offspring outcomes. This includes studies that aim to assess the causal effect of in utero exposures related to fetal growth restriction on future risk of disease in offspring. We illustrate our framework using ex les related to offspring birthweight and cardiometabolic disease, although the general principles we espouse are relevant for many other offspring phenotypes. We advocate for the establishment of large-scale international genetics consortia that are focused on the identification of maternal genetic effects and committed to the public sharing of genome-wide summary-results data from such efforts. This information will facilitate the application of powerful two-s le Mendelian randomization studies of maternal exposures and offspring outcomes.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2022
DOI: 10.1007/S10519-022-10116-9
Abstract: The Barker Hypothesis posits that adverse intrauterine environments result in fetal growth restriction and increased risk of cardiometabolic disease through developmental compensations. Here we introduce a new statistical model using the genomic SEM software that is capable of simultaneously partitioning the genetic covariation between birthweight and cardiometabolic traits into maternally mediated and offspring mediated contributions. We model the covariance between birthweight and later life outcomes, such as blood pressure, non-fasting glucose, blood lipids and body mass index in the Norwegian HUNT study, consisting of 15,261 mother-eldest offspring pairs with genetic and phenotypic data. Application of this model showed some evidence for maternally mediated effects of systolic blood pressure on offspring birthweight, and pleiotropy between birthweight and non-fasting glucose mediated through the offspring genome. This underscores the importance of genetic links between birthweight and cardiometabolic phenotypes and offer alternative explanations to environmentally based hypotheses for the phenotypic correlation between these variables.
Publisher: Wiley
Date: 20-11-2019
DOI: 10.1111/CEN.14119
Publisher: Public Library of Science (PLoS)
Date: 13-05-2014
Publisher: Springer Science and Business Media LLC
Date: 25-07-2017
DOI: 10.1038/S41467-017-00108-3
Abstract: Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34–52%) for TBLH-BMD, and 39% (95% CI: 30–48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29–56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4 , GALNT3 , MEPE , CPED1/WNT16 , TNFSF11 , RIN3 , and PPP6R3/LRP5 . Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2020
Publisher: Springer Science and Business Media LLC
Date: 03-2018
Publisher: Oxford University Press (OUP)
Date: 05-2020
DOI: 10.1093/IJE/DYAA069
Publisher: Springer Science and Business Media LLC
Date: 31-05-2019
DOI: 10.1038/S41588-019-0446-3
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2013
DOI: 10.1038/NG.2610
Publisher: Elsevier BV
Date: 04-2015
Publisher: Oxford University Press (OUP)
Date: 09-06-2022
DOI: 10.1093/IJE/DYAC121
Abstract: Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized–controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR). A two-s le MR study was performed using summary results data from a genome-wide association meta-analysis of coffee consumption (N = 91 462) from the Coffee and Caffeine Genetics Consortium. Outcomes included self-reported miscarriage (N = 49 996 cases and 174 109 controls from a large meta-analysis) the number of stillbirths [N = 60 453 from UK Biobank (UKBB)] gestational age and pre-term birth (N = 43 568 from the 23andMe, Inc cohort) and birthweight (N = 297 356 reporting own birthweight and N = 210 248 reporting offspring’s birthweight from UKBB and the Early Growth Genetics Consortium). Additionally, a one-s le genetic risk score (GRS) analysis of coffee consumption in UKBB women (N up to 194 196) and the Avon Longitudinal Study of Parents and Children (N up to 6845 mothers and 4510 children) and its relationship with offspring outcomes was performed. Both the two-s le MR and one-s le GRS analyses showed no change in risk of sporadic miscarriages, stillbirths, pre-term birth or effect on gestational age connected to coffee consumption. Although both analyses showed an association between increased coffee consumption and higher birthweight, the magnitude of the effect was inconsistent. Our results suggest that coffee consumption during pregnancy might not itself contribute to adverse outcomes such as stillbirth, sporadic miscarriages and pre-term birth or lower gestational age or birthweight of the offspring.
Publisher: Cold Spring Harbor Laboratory
Date: 06-08-2021
DOI: 10.1101/2021.08.04.455178
Abstract: Maternal genetic effects can be defined as the effect of a mother’s genotype on the phenotype of her offspring, independent of the offspring’s genotype. Maternal genetic effects can act via the intrauterine environment during pregnancy and/or via the postnatal environment. In this manuscript, we present a simple extension to the basic adoption design that uses structural equation modelling (SEM) to partition maternal genetic effects into prenatal and postnatal effects. We assume that in biological families, offspring phenotypes are influenced prenatally by their mother’s genotype and postnatally by both parents’ genotypes, whereas adopted in iduals’ phenotypes are influenced prenatally by their biological mother’s genotype and postnatally by their adoptive parents’ genotypes. Our SEM framework allows us to model the (potentially) unobserved genotypes of biological and adoptive parents as latent variables, permitting us in principle to leverage the thousands of adopted singleton in iduals in the UK Biobank. We examine the power, utility and type I error rate of our model using simulations and asymptotic power calculations. We apply our model to polygenic scores of educational attainment and birth weight associated variants, in up to 5178 adopted singletons, 983 trios, 3650 mother-offspring pairs, 1665 father-offspring pairs and 350330 singletons from the UK Biobank. Our results show the expected pattern of maternal genetic effects on offspring birth weight, but unexpectedly large prenatal maternal genetic effects on offspring educational attainment. Sensitivity and simulation analyses suggest this result may be at least partially due to adopted in iduals in the UK Biobank being raised by their biological relatives. We show that accurate modelling of these sorts of cryptic relationships is sufficient to bring type I error rate under control and produce unbiased estimates of prenatal and postnatal maternal genetic effects. We conclude that there would be considerable value in following up adopted in iduals in the UK Biobank to determine whether they were raised by their biological relatives, and if so, to precisely ascertain the nature of these relationships. These adopted in iduals could then be incorporated into informative statistical genetics models like the one described in our manuscript to further elucidate the genetic architecture of complex traits and diseases.
Publisher: Wiley
Date: 05-2020
DOI: 10.1002/AJMG.B.32784
Publisher: Public Library of Science (PLoS)
Date: 19-04-2012
Publisher: Hindawi Limited
Date: 14-08-2018
DOI: 10.1155/2018/2624981
Abstract: Rheumatoid arthritis (RA) is a disease of chronic systemic inflammation (SI). In the present study, we used four datasets to explore whether methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) might be a marker of SI in new onset, untreated, and treated prevalent RA cases and/or a marker of treatment response to the tumour necrosis factor inhibitor (TNFi) etanercept. mdNLR was associated with increased odds of being a new onset RA case (OR = 2.32, 95% CI = 1.95–2.80, P 2 × 10 − 16 ) and performed better in distinguishing new onset RA cases from controls compared to covariates: age, gender, and smoking status. In untreated preclinical RA cases and controls, mdNLR at baseline was associated with diagnosis of RA in later life after adjusting for batch (OR = 4.30, 95% CI = 1.52–21.71, P = 0.029 ) although no association was observed before batch correction. When prevalent RA cases were treated, there was no association with mdNLR in s les before and after batch correction (OR = 0.34, 95% CI = 0.05–1.82, P = 0.23 ), and mdNLR was not associated with treatment response to etanercept (OR = 1.10, 95% CI = 0.75–1.68, P = 0.64 ). Our results indicate that SI measured by DNA methylation data is indicative of the recent onset of RA. Although preclinical RA was associated with mdNLR, there was no difference in the mean mdNLR between preclinical RA cases and controls. mdNLR was not associated with RA case status if treatment for RA has commenced, and it is not associated with treatment response. In the future, mdNLR estimates may be used as a valuable research tool to reliably estimate SI in the absence of freshly collected blood s les.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2010
Publisher: Cold Spring Harbor Laboratory
Date: 11-06-2018
DOI: 10.1101/338863
Abstract: Osteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 in iduals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M in iduals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10 −75 ). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P 0.0001). In-depth analysis of one such Target Gene, DAAM2 , showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.
Publisher: Public Library of Science (PLoS)
Date: 22-12-2015
Publisher: Frontiers Media SA
Date: 21-11-2019
Publisher: Elsevier BV
Date: 08-2012
Publisher: Elsevier BV
Date: 2010
Publisher: Oxford University Press (OUP)
Date: 30-10-2201
Publisher: Elsevier BV
Date: 02-2010
Publisher: Springer Science and Business Media LLC
Date: 10-11-2017
DOI: 10.1038/S41598-017-11852-3
Abstract: Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-in idual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
Publisher: Cold Spring Harbor Laboratory
Date: 19-09-2020
DOI: 10.1101/2020.09.17.302208
Abstract: Higher birth weight is associated with higher adult body mass index (BMI). If genetic variants can be identified with alleles that predispose to both greater fetal growth and to greater adult adiposity, such shared genetic effects might indicate biological processes important in the early patterning of adiposity. However, variants identified in genome-wide association studies of adult BMI have overall been only weakly associated with birth weight. Genetic variants have recently been identified where one allele is associated with higher adult body fat percentage, but lower risk of metabolic disease, likely due to a favourable body fat distribution. The effect of these adult metabolically favourable adiposity alleles on an in idual’s own birth weight is unknown. We aimed to test the effect on birth weight of a fetal genetic predisposition to higher metabolically favourable adult adiposity and to compare this with the effects of a fetal genetic predisposition to higher adult BMI. We also aimed to examine the effects of a genetic predisposition to higher metabolically favourable adult adiposity or BMI on other birth anthropometric traits (length, ponderal index, head circumference and skinfold thickness) and on cord-blood insulin, leptin and adiponectin. We used published GWAS data from up to 406,063 in iduals to estimate the fetal effects on birth weight of alleles that are robustly associated with higher metabolically favourable adult adiposity or BMI. We additionally used 9,350 mother-child pairs from four cohorts to test the effects of the same alleles on other birth anthropometric traits and cord-blood markers. In all analyses, we adjusted for potential confounding due to the maternal genotype. We used inverse-variance weighted meta-analyses to combine summary data across SNPs. Fetal genetic predisposition to higher metabolically favourable adult adiposity was associated with higher birth weight (10 grams (95% CI: 7 to 13) higher mean birth weight per 1 SD pooled “genetic score”). Fetal genetic predisposition to higher adult BMI was also associated with higher birth weight, but with a smaller magnitude of effect (4 grams (95% CI: 0 to 8) higher mean birth weight per 1 SD pooled “genetic score”) and with higher heterogeneity across SNPs. Effects on other birth anthropometric outcomes were consistent with the effect on birth weight but with wider confidence intervals. There was no strong evidence for an effect on cord-blood markers. Some genetic variants previously linked to adult adiposity influence birth weight. Alleles that predispose to higher metabolically favourable adult adiposity collectively have a stronger effect on birth weight than those predisposing to higher BMI. This suggests that the early accumulation of a metabolically favourable fat distribution might underlie part of the observed association between higher birth weight and higher adult BMI. Larger s les are needed to clarify the effects on other birth anthropometric measures and cord-blood markers.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2019
DOI: 10.1038/S41588-019-0415-X
Abstract: In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article.
Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 04-05-2008
DOI: 10.1038/NG.140
Publisher: American Diabetes Association
Date: 17-01-2012
DOI: 10.2337/DB11-1039
Abstract: Rapid postnatal growth is associated with increased risk of childhood adiposity. The aim of this study was to establish whether this pathway is mediated by altered DNA methylation and gene expression. Two distinct cohorts, one preterm (n = 121) and one term born (n = 6,990), were studied. Exploratory analyses were performed using microarrays to identify differentially expressed genes in whole blood from children defined as “slow” (n = 10) compared with “rapid” (n = 10) postnatal (term to 12 weeks corrected age) growers. Methylation within the identified TACSTD2 gene was measured in both cohorts, and rs61779296 genotype was determined by Pyrosequencing or imputation and analyzed in relation to body composition at 9–15 years of age. In cohort 1, TACSTD2 expression was inversely correlated with methylation (P = 0.016), and both measures were associated with fat mass (expression, P = 0.049 methylation, P = 0.037). Although associated with gene expression (cohort 1, P = 0.008) and methylation (cohort 1, P = 2.98 × 10−11 cohort 2, P = 3.43 × 10−15), rs61779296 was not associated with postnatal growth or fat mass in either cohort following multiple regression analysis. Hence, the lack of association between fat mass and a methylation proxy SNP suggests that reverse causation or confounding may explain the initial association between fat mass and gene regulation. Noncausal methylation patterns may still be useful predictors of later adiposity.
Publisher: Springer Science and Business Media LLC
Date: 10-2007
DOI: 10.1038/NATURE06250
Publisher: Public Library of Science (PLoS)
Date: 02-10-2015
Publisher: Public Library of Science (PLoS)
Date: 12-08-2021
Publisher: Springer Science and Business Media LLC
Date: 26-11-2015
DOI: 10.1038/GENE.2015.49
Abstract: Acute anterior uveitis (AAU) involves inflammation of the iris and ciliary body of the eye. It occurs both in isolation and as a complication of ankylosing spondylitis (AS). It is strongly associated with HLA-B*27, but previous studies have suggested that further genetic factors may confer additional risk. We sought to investigate this using the Illumina Exomechip microarray, to compare 1504 cases with AS and AAU, 1805 with AS but no AAU and 21 133 healthy controls. We also used a heterogeneity test to test the differences in effect size between AS with AAU and AS without AAU. In the analysis comparing AS+AAU+ cases versus controls, HLA-B*27 and HLA-A*02:01 were significantly associated with the presence of AAU (P<10(-300) and P=6 × 10(-8), respectively). Secondary independent association with PSORS1C3 (P=4.7 × 10(-5)) and TAP2 (P=1.1 × 10(-5)) were observed in the major histocompatibility complex. There was a new suggestive association with a low-frequency variant at zinc-finger protein 154 in the AS without AAU versus control analysis (zinc-finger protein 154 (ZNF154), P=2.2 × 10(-6)). Heterogeneity testing showed that rs30187 in ERAP1 has a larger effect on AAU compared with that in AS alone. These findings also suggest that variants in ERAP1 have a differential impact on the risk of AAU when compared with AS, and hence the genetic risk for AAU differs from AS.
Publisher: Public Library of Science (PLoS)
Date: 07-07-2022
DOI: 10.1371/JOURNAL.PGEN.1010247
Abstract: Estimating effects of parental and sibling genotypes (indirect genetic effects) can provide insight into how the family environment influences phenotypic variation. There is growing molecular genetic evidence for effects of parental phenotypes on their offspring (e.g. parental educational attainment), but the extent to which siblings affect each other is currently unclear. Here we used data from s les of unrelated in iduals, without (singletons) and with biological full-siblings (non-singletons), to investigate and estimate sibling effects. Indirect genetic effects of siblings increase (or decrease) the covariance between genetic variation and a phenotype. It follows that differences in genetic association estimates between singletons and non-singletons could indicate indirect genetic effects of siblings if there is no heterogeneity in other sources of genetic association between singletons and non-singletons. We used UK Biobank data to estimate polygenic score (PGS) associations for height, BMI and educational attainment in self-reported singletons (N = 50,143) and non-singletons (N = 328,549). The educational attainment PGS association estimate was 12% larger (95% C.I. 3%, 21%) in the non-singleton s le than in the singleton s le, but the height and BMI PGS associations were consistent. Birth order data suggested that the difference in educational attainment PGS associations was driven by in iduals with older siblings rather than firstborns. The relationship between number of siblings and educational attainment PGS associations was non-linear PGS associations were 24% smaller in in iduals with 6 or more siblings compared to the rest of the s le (95% C.I. 11%, 38%). We estimate that a 1 SD increase in sibling educational attainment PGS corresponds to a 0.025 year increase in the index in idual’s years in schooling (95% C.I. 0.013, 0.036). Our results suggest that older siblings may influence the educational attainment of younger siblings, adding to the growing evidence that effects of the environment on phenotypic variation partially reflect social effects of germline genetic variation in relatives.
Publisher: Oxford University Press (OUP)
Date: 09-06-2023
DOI: 10.1093/IJE/DYAD079
Abstract: Previous Mendelian randomization (MR) studies using population s les (population MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. MR using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis. Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used in idual-level data on 72 932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including & 000 in iduals. Both population and within-sibship MR estimates provided evidence that educational attainment decreased BMI, cigarette smoking and SBP. Genetic variant–outcome associations attenuated in the within-sibship model, but genetic variant–educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. These results provide evidence of beneficial in idual-level effects of education (or liability to education) on adulthood health, independently of potential demographic and family-level confounders.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2018
DOI: 10.1038/S41467-018-03109-Y
Abstract: Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.
Publisher: Springer Science and Business Media LLC
Date: 02-2022
DOI: 10.1186/S12916-021-02216-W
Abstract: Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW N = 9339) and BMI at age 1 and 4 years ( N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years ( N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10–18 years ( N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates ( P difference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 05-2019
Publisher: Oxford University Press (OUP)
Date: 14-07-2011
DOI: 10.1093/HMG/DDR309
Publisher: Oxford University Press (OUP)
Date: 13-02-2018
DOI: 10.1093/IJE/DYY015
Publisher: Cambridge University Press (CUP)
Date: 04-2020
DOI: 10.1017/THG.2020.31
Abstract: Blood cell concentrations for most cell types are highly heritable. Data from Nick Martin’s twin registry provided much of the data for the early heritability and linkage studies of blood cell related traits and have contributed significantly to more recent genomewide association studies that have successfully identified in idual genetic loci.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1093/AJCN/NQY101
Abstract: Several observational studies have shown that low serum vitamin B-12 is associated with increased body mass index (BMI) and adverse cardiometabolic outcomes. However, it is unclear if these associations reflect a causal effect of vitamin B-12 on cardiometabolic risk factors and diseases, latent confounding, or reverse causality. The aims of this study were to investigate 1) the possible causal relation between vitamin B-12 and indicators of body fat, lipid, and glucose variables type 2 diabetes (T2D) and cardiovascular disease by using a 2-s le Mendelian randomization (MR) method and 2) the possible pleiotropic role of fucosyltransferase 2 (FUT2). We selected 11 single nucleotide polymorphisms (SNPs) robustly associated with serum concentrations of vitamin B-12 in a previous genomewide association study (GWAS) in 45,576 in iduals. We performed 2-s le MR analyses of the relation between vitamin B-12 and cardiometabolic risk factors and diseases with the use of publicly available GWAS summary statistics for 15 outcomes in ≤339,224 in iduals. The robustness of results was tested with sensitivity analyses by using MR Egger regression and weighted-median estimation, and by performing additional analyses excluding a variant in the FUT2 gene, which may be pleiotropic. We found a suggestive causal relation between vitamin B-12 and fasting glucose and β cell function [homeostatic model assessment (HOMA) of β cell function (HOMA-B)]. However, we found no evidence that serum concentrations of vitamin B-12 were causally related to BMI, waist-to-hip ratio, plasma leptin, body fat, fasting insulin, insulin resistance (from HOMA of insulin resistance), glycated hemoglobin, triglycerides, T2D, coronary artery disease, or HDL, LDL, or total cholesterol. We found no evidence that serum concentrations of vitamin B-12 are causally related to body weight or the majority of cardiometabolic outcomes investigated. However, vitamin B-12 may have a causal effect on fasting glucose and HOMA-B, although these results will require replication in large independent data sets. This trialwas registered at www.isrctn.com/ISRCTN47414943 as ISRCTN47414943.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2014
DOI: 10.1038/MP.2012.184
Publisher: The Royal Society
Date: 27-07-2005
Abstract: Recent large-scale studies of common genetic variation throughout the human genome are making it feasible to conduct whole genome studies of genotype–phenotype associations. Such studies have the potential to uncover novel contributors to common complex traits and thus lead to insights into the aetiology of multifactorial phenotypes. Despite this promise, it is important to recognize that the availability of genetic markers and the ability to assay them at realistic cost does not guarantee success of this approach. There are a number of practical issues that require close attention, some forms of allelic architecture are not readily amenable to the association approach with even the most rigorous design, and doubtless new hurdles will emerge as the studies begin. Here we discuss the promise and current challenges of the whole genome approach, and raise some issues to consider in interpreting the results of the first whole genome studies.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2014
DOI: 10.1038/NCOMMS5831
Abstract: Twin studies suggest that expressive vocabulary at ~24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology consortium, analysing an early (15–18 months, ‘one-word stage’, N Total =8,889) and a later (24–30 months, ‘two-word stage’, N Total =10,819) phase of language acquisition. For the early phase, one single-nucleotide polymorphism (rs7642482) at 3p12.3 near ROBO2 , encoding a conserved axon-binding receptor, reaches the genome-wide significance level ( P =1.3 × 10 −8 ) in the combined s le. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by genome-wide complex trait analysis (meta-GCTA h 2 15–18-months =0.13, meta-GCTA h 2 24–30-months =0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h 2 24-months =0.20).
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
DOI: 10.1038/NCOMMS11008
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry in iduals, we identify six novel loci ( FAM150B-ACP1 , LINC00340 , FBN1 , DIS3L-MAP2K1 , ARID2-SNAT1 and SLC14A2 ) associated with refractive error. In Asian populations, three genome-wide significant loci AREG , GABRR1 and PDE10A also exhibit strong interactions with education ( P .5 × 10 −5 ), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Publisher: Oxford University Press (OUP)
Date: 18-08-2009
DOI: 10.1093/HMG/DDP371
Publisher: Springer Science and Business Media LLC
Date: 31-12-2018
Publisher: Oxford University Press (OUP)
Date: 27-03-2015
DOI: 10.1093/HMG/DDV112
Publisher: Wiley
Date: 18-03-2019
DOI: 10.1002/JBMR.3697
Abstract: Observations that insulin and adiponectin levels are related to cortical bone size in adolescents, independently of body composition, suggest factors related to fat metabolism directly influence skeletal development. To explore this question, we examined associations between a metabolic screen focusing on fat metabolism, and peripheral quantitative computed tomography (pQCT) measures of the mid-tibia, in 15-year-olds from the Avon Longitudinal Study of Parents and Children. Metabolic profiles were generated by proton nuclear magnetic resonance spectroscopy, from blood s les obtained at the same time as pQCT scans. Ordinary least squares linear regression was used to investigate relationships between metabolic measures and periosteal circumference (PC), cortical thickness (CT), and cortical bone mineral density (BMD
Publisher: Springer Science and Business Media LLC
Date: 28-05-2018
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1038/NG.2385
Publisher: Public Library of Science (PLoS)
Date: 02-02-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2021
Publisher: Oxford University Press (OUP)
Date: 21-12-2020
DOI: 10.1093/IJE/DYAA256
Abstract: Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal. We performed two-s le Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 in iduals (s le 1) and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 in iduals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (s le 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels. We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [−0.051 (−0.100, −0.003)]. Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.
Publisher: Public Library of Science (PLoS)
Date: 12-09-2013
Publisher: Elsevier BV
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 27-05-2021
Publisher: Wiley
Date: 18-06-2015
DOI: 10.1002/AJMG.B.32333
Abstract: In idual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest s le exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed s le and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total s le. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total s le identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.
Publisher: Oxford University Press (OUP)
Date: 17-05-2018
DOI: 10.1093/JNCI/DJY081
Publisher: Springer Science and Business Media LLC
Date: 14-12-2008
DOI: 10.1038/NG.287
Publisher: American Thoracic Society
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 28-09-2020
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.PNPBP.2017.01.011
Abstract: Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait. Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole s le or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756). No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in in idual studies or a meta-analysis. Stratifying by antidepressant did not alter the results. We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2008
Abstract: Several studies involving genome-wide scans of non-synonymous SNPs (nsSNPs) have successfully identified loci contributing to common complex diseases. We were interested in the extent to which these small scans involving a few thousand non-synonymous markers might complement the results from denser genome-wide association studies. We assessed the degree to which three commercially available genome-wide marker panels tagged nsSNPs on the Illumina HumanNS-12 BeadChip, a product specifically designed to capture non-synonymous variation. We demonstrate that commercially available genome-wide panels already tag the majority of common non-synonymous variants on the NS-12 BeadChip, indicating that with respect to capturing common non-synonymous variation, information from the NS-12 BeadChip is largely redundant. In contrast, genome-wide panels fail to capture most of the rare SNPs present on the NS-12 BeadChip. Power calculations reveal that non-synonymous scans involving s le sizes typical of the current wave of genome-wide association studies are unlikely to identify rare variants of small effect, but could conceivably identify rare variants of intermediate penetrance. We conclude that non-synonymous scans may facilitate the identification of rare variants of intermediate penetrance that would not otherwise be detectable using dense genome-wide panels, but are unlikely to uniquely identify common variants contributing to complex disease variation.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2021
Publisher: Springer Science and Business Media LLC
Date: 12-07-2017
DOI: 10.1038/NCOMMS16015
Abstract: Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined s le of 195,180 in iduals and identify 16 loci associated with grip strength ( P × 10 −8 ) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres ( ACTG1 ), neuronal maintenance and signal transduction ( PEX14, TGFA, SYT1 ), or monogenic syndromes with involvement of psychomotor impairment ( PEX14, LRPPRC and KANSL1 ). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
Publisher: Cambridge University Press (CUP)
Date: 04-2004
Publisher: Public Library of Science (PLoS)
Date: 05-07-2012
Publisher: Elsevier
Date: 2011
Publisher: Springer Science and Business Media LLC
Date: 31-03-2016
Publisher: Wiley
Date: 2004
DOI: 10.1002/GEPI.20045
Abstract: The International Haplotype Mapping Project (HapMap) aims to characterize the distribution and extent of linkage disequilibrium (LD) throughout the human genome, thereby facilitating genome-wide association analysis and the search for the genetic determinants of complex diseases. Implicit in the rationale behind the project is the expectation that hidden (unobserved) disease-causing variants will be in significant LD with surrounding typed markers and will thus be amenable to detection using association-based mapping approaches. In order to investigate the validity of this assumption, we examined more than 5,000 SNPs across a 10-MB region of chromosome 20 in a s le of 96 unrelated African-American and 96 unrelated Caucasian in iduals. We treated observed loci as surrogates for hidden SNPs by pretending that in iduals' genotypes were unknown. We then attempted to predict these genotypes at the surrogate hidden SNP by using information about LD in the region and genotypes at surrounding observed loci. Our method is based on finding the most likely genotype for each in idual, given all possible haplotype pairs consistent with observed genotypes for that in idual at surrounding loci, and given the frequencies of those haplotypes in an independent s le. Our method performs extremely well in predicting genotypes in areas of high LD. Furthermore, in areas of low LD, our method results in substantial gains in predictive accuracy as compared to pair-wise strategies. These results suggest that pair-wise tests of disease-marker association may be inferior to multipoint methods, which take advantage of the information contained within multi-locus haplotypes.
Publisher: Informa UK Limited
Date: 02-01-2023
Publisher: Public Library of Science (PLoS)
Date: 21-02-2013
Publisher: Elsevier BV
Date: 04-2011
Abstract: High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background. The objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight. A meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (n(max) = 14,060) 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (n(max) = 10,623) and 3) all published data (n(max) = 14,837). Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (β ± SE: -13 ± 5 g/allele P = 0.012 n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (β ± SE: 11 ± 4 g/allele P = 0.013 n = 28,219). These results were not significant after correction for multiple testing. Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity.
Publisher: Annual Reviews
Date: 24-08-2015
DOI: 10.1146/ANNUREV-GENOM-090314-050016
Abstract: Mendelian randomization (MR) is an approach that uses genetic variants associated with a modifiable exposure or biological intermediate to estimate the causal relationship between these variables and a medically relevant outcome. Although it was initially developed to examine the relationship between modifiable exposures/biomarkers and disease, its use has expanded to encompass applications in molecular epidemiology, systems biology, pharmacogenomics, and many other areas. The purpose of this review is to introduce MR, the principles behind the approach, and its limitations. We consider some of the new applications of the methodology, including informing drug development, and comment on some promising extensions, including two-step, two-s le, and bidirectional MR. We show how these new methods can be combined to efficiently examine causality in complex biological networks and provide a new framework to data mine high-dimensional studies as we transition into the age of hypothesis-free causality.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2010
Publisher: Public Library of Science (PLoS)
Date: 10-07-2014
Publisher: Oxford University Press (OUP)
Date: 22-09-2015
DOI: 10.1093/HMG/DDV378
Publisher: Cambridge University Press (CUP)
Date: 04-12-2020
DOI: 10.1017/S2040174420001105
Abstract: Recent studies have used Mendelian randomization (MR) to investigate the observational association between low birth weight (BW) and increased risk of cardiometabolic outcomes, specifically cardiovascular disease, glycemic traits, and type 2 diabetes (T2D), and inform on the validity of the Barker hypothesis. We used simulations to assess the validity of these previous MR studies, and to determine whether a better formulated model can be used in this context. Genetic and phenotypic data were simulated under a model of no direct causal effect of offspring BW on cardiometabolic outcomes and no effect of maternal genotype on offspring cardiometabolic risk through intrauterine mechanisms where the observational relationship between BW and cardiometabolic risk was driven entirely by horizontal genetic pleiotropy in the offspring (i.e. offspring genetic variants affecting both BW and cardiometabolic disease simultaneously rather than a mechanism consistent with the Barker hypothesis). We investigated the performance of four commonly used MR analysis methods (weighted allele score MR (WAS-MR), inverse variance weighted MR (IVW-MR), weighted median MR (WM-MR), and MR-Egger) and a new approach, which tests the association between maternal genotypes related to offspring BW and offspring cardiometabolic risk after conditioning on offspring genotype at the same loci. We caution against using traditional MR analyses, which do not take into account the relationship between maternal and offspring genotypes, to assess the validity of the Barker hypothesis, as results are biased in favor of a causal relationship. In contrast, we recommend the aforementioned conditional analysis framework utilizing maternal and offspring genotypes as a valid test of not only the Barker hypothesis, but also to investigate hypotheses relating to the Developmental Origins of Health and Disease more broadly.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2007
DOI: 10.1038/NATURE05911
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1086/429274
Publisher: Oxford University Press (OUP)
Date: 30-01-2021
DOI: 10.1093/HMG/DDAB023
Abstract: Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) in iduals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all s les. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2019
DOI: 10.1038/S41467-018-07863-X
Abstract: Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53 , with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2012
DOI: 10.1038/NG.2247
Publisher: Oxford University Press (OUP)
Date: 13-10-2023
DOI: 10.1093/IJE/DYAD142
Publisher: Wiley
Date: 20-07-2015
DOI: 10.1002/OBY.21147
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 07-03-2013
Publisher: Public Library of Science (PLoS)
Date: 11-12-2009
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: 16-12-2010
DOI: 10.1002/AJMG.B.31149
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/NATURE14878
Publisher: Public Library of Science (PLoS)
Date: 31-10-2013
Publisher: Public Library of Science (PLoS)
Date: 15-09-2011
Publisher: Oxford University Press (OUP)
Date: 04-2015
DOI: 10.1093/IJE/DYV077
Publisher: Wiley
Date: 2019
DOI: 10.1002/PRA2.17
Publisher: Springer Science and Business Media LLC
Date: 25-07-2014
Publisher: Public Library of Science (PLoS)
Date: 02-07-2020
Publisher: Oxford University Press (OUP)
Date: 04-05-2015
DOI: 10.1093/HMG/DDV143
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0301-0511(02)00051-0
Abstract: Biometrical genetics is the science concerned with the inheritance of quantitative traits. In this review we discuss how the analytical methods of biometrical genetics are based upon simple Mendelian principles. We demonstrate how the phenotypic covariance between related in iduals provides information on the relative importance of genetic and environmental factors influencing that trait, and how factors such as assortative mating, gene-environment correlation and genotype-environment interaction complicate such interpretations. Twin and adoption studies are discussed as well as their assumptions and limitations. Structural equation modeling (SEM) is introduced and we illustrate how this approach may be applied to genetic problems. In particular, we show how SEM can be used to address complicated issues such as analyzing the causes of correlation between traits or determining the direction of causation (DOC) between variables.
Publisher: Wiley
Date: 08-05-2017
DOI: 10.1002/JBMR.3148
Publisher: Cold Spring Harbor Laboratory
Date: 25-02-2020
DOI: 10.1101/2020.02.21.959114
Abstract: Indirect parental genetic effects may be defined as the influence of parental genotypes on offspring phenotypes over and above that which results from the transmission of genes from parents to children. However, given the relative paucity of large-scale family-based cohorts around the world, it is difficult to demonstrate parental genetic effects on human traits, particularly at in idual loci. In this manuscript, we illustrate how parental genetic effects on offspring phenotypes, including late onset diseases, can be estimated at in idual loci in principle using large-scale genome-wide association study (GWAS) data, even in the absence of parental genotypes. Our strategy involves creating “virtual” mothers and fathers by estimating the genotypic dosages of parental genotypes using physically genotyped data from relative pairs. We then utilize the expected dosages of the parents, and the actual genotypes of the offspring relative pairs, to perform conditional genetic association analyses to obtain asymptotically unbiased estimates of maternal, paternal and offspring genetic effects. We develop a freely available web application that quantifies the power of our approach using closed form asymptotic solutions. We implement our methods in a user-friendly software package IMPISH ( IM puting P arental genotypes I n S iblings and H alf-Siblings) which allows users to quickly and efficiently impute parental genotypes across the genome in large genome-wide datasets, and then use these estimated dosages in downstream linear mixed model association analyses. We conclude that imputing parental genotypes from relative pairs may provide a useful adjunct to existing large-scale genetic studies of parents and their offspring.
Publisher: Public Library of Science (PLoS)
Date: 08-09-2011
Publisher: Springer Science and Business Media LLC
Date: 17-12-2014
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
DOI: 10.1038/NG0613-712B
Publisher: Cambridge University Press (CUP)
Date: 04-10-2022
DOI: 10.1017/S2040174422000538
Abstract: One of the longstanding debates in life-course epidemiology is whether an adverse intrauterine environment, often proxied by birth weight, causally increases the future risk of cardiometabolic disease. The use of a discordant twin study design, which controls for the influence of shared genetic and environmental confounding factors, may be useful to investigate whether this relationship is causal. We conducted a discordant twin study of 120 monozygotic (MZ) and 148 dizygotic (DZ) twin pairs from the UK Biobank to explore the potential causal relationships between birth weight and a broad spectrum of later-life cardiometabolic risk factors. We used a linear mixed model to investigate the association between birth weight and later-life cardiometabolic risk factors for twins, allowing for both within-pair differences and between-pair differences in birth weight. Of primary interest is the within-pair association between differences in birth weight and cardiometabolic risk factors, which could reflect an intrauterine effect on later-life risk factors. We found no strong evidence of association in MZ twins between the within-pair differences in birth weight and most cardiometabolic risk factors in later life, except for nominal associations with C-reactive protein and insulin-like growth factor 1. However, these associations were not replicated in DZ twin pairs. Our study provided no strong evidence for intrauterine effects on later-life cardiometabolic risk factors, which is consistent with previous large-scale studies of singletons testing the potential causal relationship. It does not support the hypothesis that adverse intrauterine environments increase the risk of cardiometabolic disease in later life.
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: 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: 02-12-2012
DOI: 10.1038/NG.2477
Publisher: Springer Science and Business Media LLC
Date: 02-11-2017
Publisher: Oxford University Press (OUP)
Date: 03-10-2023
DOI: 10.1093/IJE/DYAC186
Abstract: Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight. We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH n = 872) and UK Biobank (UKB n = 133 187). We conducted two-s le MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs) n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-s le MR in UKB women (n = 199 768). Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: –50, 6) P = 0.13] and UKB [–28 g (95% CI: –31, –25) P = 1.8 × 10–75]. The MR causal effect estimate was directionally consistent, but smaller [–11 g (95% CI: –25, 3) PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1) P = 7.8 × 10–22], consistent with that previously published in women and men. The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweight. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.
Publisher: eLife Sciences Publications, Ltd
Date: 13-07-2022
DOI: 10.7554/ELIFE.73671
Abstract: Maternal genetic effects can be defined as the effect of a mother’s genotype on the phenotype of her offspring, independent of the offspring’s genotype. Maternal genetic effects can act via the intrauterine environment during pregnancy and/or via the postnatal environment. In this manuscript, we present a simple extension to the basic adoption design that uses structural equation modelling (SEM) to partition maternal genetic effects into prenatal and postnatal effects. We examine the power, utility and type I error rate of our model using simulations and asymptotic power calculations. We apply our model to polygenic scores of educational attainment and birth weight associated variants, in up to 5,178 adopted singletons, 943 trios, 2687 mother-offspring pairs, 712 father-offspring pairs and 347,980 singletons from the UK Biobank. Our results show the expected pattern of maternal genetic effects on offspring birth weight, but unexpectedly large prenatal maternal genetic effects on offspring educational attainment. Sensitivity and simulation analyses suggest this result may be at least partially due to adopted in iduals in the UK Biobank being raised by their biological relatives. We show that accurate modelling of these sorts of cryptic relationships is sufficient to bring type I error rate under control and produce asymptotically unbiased estimates of prenatal and postnatal maternal genetic effects. We conclude that there would be considerable value in following up adopted in iduals in the UK Biobank to determine whether they were raised by their biological relatives, and if so, to precisely ascertain the nature of these relationships. These adopted in iduals could then be incorporated into informative statistical genetics models like the one described in our manuscript to further elucidate the genetic architecture of complex traits and diseases.
Publisher: Wiley
Date: 11-2003
DOI: 10.1046/J.1529-8817.2003.00069.X
Abstract: Williams & Blangero (1999) derived closed form expressions for the power of a univariate variance components test of linkage for a variety of pedigree structures. We have extended their results by investigating the effect of including monozygotic twins in the design on the power to detect linkage. Specifically, we determined the power associated with a pedigree of size three, where in iduals one and two were monozygotic twins and in idual three was a full sibling to the twins. The power of this s ling unit was uniformly greater than the power obtained from a sib-pair under the same genetic model. The reason for this was that addition of a second monozygotic twin provided another estimate of the sibling correlation for the particular IBD class. In addition, when the total heritability of the trait was <50%, the number of in iduals that needed to be phenotyped was less than that with sib-pairs alone. However, a pedigree consisting of a monozygotic pair and sibling was never as informative as a sib-trio, presumably because the sib-trio provided information about allele sharing between three in iduals, whereas the monozygotic twins and sibling unit only provided one such relationship. We conclude that including a monozygotic twin in the analysis is an economical strategy, since only one twin needs to be genotyped.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2019
DOI: 10.1007/S10519-019-09969-4
Abstract: There is increasing interest within the genetics community in estimating the relative contribution of parental genetic effects on offspring phenotypes. Here we describe the user-friendly M-GCTA software package used to estimate the proportion of phenotypic variance explained by maternal (or alternatively paternal) and offspring genotypes on offspring phenotypes. The tool requires large studies where genome-wide genotype data are available on mother- (or alternatively father-) offspring pairs. The software includes several options for data cleaning and quality control, including the ability to detect and automatically remove cryptically related pairs of in iduals. It also allows users to construct genetic relationship matrices indexing genetic similarity across the genome between parents and offspring, enabling the estimation of variance explained by maternal (or alternatively paternal) and offspring genetic effects. We evaluated the performance of the software using a range of data simulations and estimated the computing time and memory requirements. We demonstrate the use of M-GCTA on previously analyzed birth weight data from two large population based birth cohorts, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Norwegian Mother and Child Cohort Study (MoBa). We show how genetic variation in birth weight is predominantly explained by fetal genetic rather than maternal genetic sources of variation.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 18-03-2023
DOI: 10.1038/S41398-023-02348-Y
Abstract: Parental genes may indirectly influence offspring psychiatric outcomes through the environment that parents create for their children. These indirect genetic effects, also known as genetic nurture, could explain in idual differences in common internalising and externalising psychiatric symptoms during childhood. Advanced statistical genetic methods leverage data from families to estimate the overall contribution of parental genetic nurture effects. This study included up to 10,499 children, 5990 mother–child pairs, and 6,222 father–child pairs from the Norwegian Mother Father and Child Study. Genome-based restricted maximum likelihood (GREML) models were applied using software packages GCTA and M-GCTA to estimate variance in maternally reported depressive, disruptive, and attention-deficit hyperactivity disorder (ADHD) symptoms in 8-year-olds that was explained by direct offspring genetic effects and maternal or paternal genetic nurture. There was no strong evidence of genetic nurture in this s le, although a suggestive paternal genetic nurture effect on offspring depressive symptoms (variance explained (V) = 0.098, standard error (SE) = 0.057) and a suggestive maternal genetic nurture effect on ADHD symptoms (V = 0.084, SE = 0.058) was observed. The results indicate that parental genetic nurture effects could be of some relevance in explaining in idual differences in childhood psychiatric symptoms. However, robustly estimating their contribution is a challenge for researchers given the current paucity of large-scale s les of genotyped families with information on childhood psychiatric outcomes.
Publisher: American Diabetes Association
Date: 21-05-2011
DOI: 10.2337/DB10-1575
Abstract: To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9–16 years. We performed meta-analyses to test associations of in idual SNPs and a weighted risk score of the 16 loci with fasting glucose. Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase [β (95% CI)] in fasting glucose level of 0.026 mmol/L (0.021–0.031) for each unit increase in the score. Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interin idual differences in glucose levels from childhood onwards.
Publisher: Elsevier BV
Date: 02-2014
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: Massachusetts Medical Society
Date: 27-06-2019
DOI: 10.1056/NEJMC1905282
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-09-2019
Publisher: Springer Science and Business Media LLC
Date: 04-04-2022
DOI: 10.1038/S41598-022-08998-0
Abstract: Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites ( P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children ( N = 1737), we observed moderately stable associations across age (correlation range [0.355–0.578]), but inconsistent across tissues (correlation range [− 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.
Publisher: Oxford University Press (OUP)
Date: 24-06-2009
DOI: 10.1093/HMG/DDP295
Abstract: The current paradigm within genetic diagnostics is to test in iduals only at loci known to affect risk of complex disease-yet the technology exists to genotype an in idual at thousands of loci across the genome. We investigated whether information from genome-wide association studies could be harnessed to improve discrimination of complex disease affection status. We employed genome-wide data from the Wellcome Trust Case Control Consortium to test this hypothesis. Each disease cohort together with the same set of controls were split into two s les-a 'Training Set', where thousands of SNPs that might predispose to disease risk were identified and a 'Prediction Set', where the discriminatory ability of these SNPs was assessed. Genome-wide scores consisting of, for ex le, the total number of risk alleles an in idual carries was calculated for each in idual in the prediction set. Case-control status was regressed on this score and the area under the receiver operator characteristic curve (AUC) estimated. In most cases, a liberal inclusion of SNPs in the genome-wide score improved AUC compared with a more stringent selection of top SNPs, but did not perform as well as selection based upon established variants. The addition of genome-wide scores to known variant information produced only a limited increase in discriminative accuracy but was most effective for bipolar disorder, coronary heart disease and type II diabetes. We conclude that this small increase in discriminative accuracy is unlikely to be of diagnostic or predictive utility at the present time.
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2020
DOI: 10.1101/2020.05.15.097840
Abstract: Indirect genetic effects from relatives may result in misleading quantifications of heritability, but can also be of interest in their own right. In this paper we propose Trio-GCTA, a model for separating direct and indirect genetic effects when genome-wide single nucleotide polymorphism data have been collected from parent-offspring trios. The model is applicable to phenotypes obtained from any of the family members. We discuss appropriate parameter interpretations and apply the method to four exemplar phenotypes offspring birth weight, offspring temperament, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).
Publisher: Springer Science and Business Media LLC
Date: 06-03-2015
DOI: 10.1038/NCOMMS6681
Abstract: Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project ( N =2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 ( N =16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P =6.15 × 10 −9 ) and a new independent variant in PDE8B (MAF=10.4%, P =5.94 × 10 −14 ). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P =1.27 × 10 −9 ) tagging a rare TTR variant (MAF=0.4%, P =2.14 × 10 −11 ). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF %) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.
Publisher: Elsevier BV
Date: 02-2023
Publisher: Elsevier BV
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
DOI: 10.1038/NG0613-713A
Publisher: Oxford University Press (OUP)
Date: 19-05-2015
DOI: 10.1093/IJE/DYV072
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/NATURE14962
Publisher: Wiley
Date: 05-07-2014
DOI: 10.1002/AJMG.B.32254
Abstract: The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent s le of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale.
Publisher: BMJ
Date: 06-07-2007
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/NATURE17671
Publisher: Springer Science and Business Media LLC
Date: 18-09-2013
Abstract: Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. We performed a genome-wide association study on parent-reported social communication problems using items of the children’s communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a s le of children with comparable measures from Western Australia (RAINE, N = 1364). Two of our seven independent top signals ( P- discovery .0E-05) were replicated (0.009 P- replication ≤0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta- P = 2.5E-07) and 14q22.1 (rs2352908, meta- P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27 . This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region. Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h 2 (SE) = 0.18(0.066), P = 0.0027). Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.
Publisher: Springer Science and Business Media LLC
Date: 2023
Publisher: Springer Science and Business Media LLC
Date: 10-05-2009
DOI: 10.1038/NG.361
Publisher: Springer Science and Business Media LLC
Date: 06-04-2008
DOI: 10.1038/NG.121
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-06-2013
Abstract: Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 s les, Rietveld et al. (p. 1467 , published online 30 May see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.
Publisher: Wiley
Date: 29-10-2008
DOI: 10.1111/J.1467-6494.2008.00527.X
Abstract: We report the first genome-wide scan of adolescent personality. We conducted a genome-wide scan to detect linkage for measures of adolescent Psychoticism, Extraversion, Neuroticism, and Lie from the Junior Eysenck Personality Questionnaire. Data are based on 1,280 genotyped Australian adolescent twins and their siblings. The highest linkage peaks were found on chromosomes 16 and 19 for Neuroticism, on chromosomes 1, 7, 10, 13 m, and 18 for Psychoticism, and on chromosomes 2 and 3 for Extraversion.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2014
DOI: 10.1158/1055-9965.EPI-13-0889
Abstract: Background: Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls. Methods: We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls) meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls) investigated associations of SNPs with prostate cancer using either “low” (PSA & 0.5 ng/mL) or “high” (PSA ≥ 3 ng/mL, biopsy negative) PSA controls and investigated associations of SNPs with PSA. Results: The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates & 0.04). We found a novel inverse association of rs9311171-T with circulating PSA. Conclusions: Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA. Impact: These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria. Cancer Epidemiol Biomarkers Prev 23(7) 1356–65. ©2014 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2009
DOI: 10.1158/1055-9965.EPI-09-0544
Abstract: Low levels of plasma vitamin D have been implicated as a possible risk factor for both prostate cancer incidence and advanced disease, and recent phase II trials suggest that vitamin D supplementation might delay progression of prostate cancer. Common polymorphisms in the vitamin D receptor (VDR) are associated with VDR activity and are therefore potentially useful proxies for assessing whether vitamin D is causally related to advanced prostate cancer. We genotyped five well-known VDR polymorphisms in 1,604 men with prostate cancer from the Prostate Testing for Cancer and Treatment study. Our aim was to examine the association between VDR polymorphisms and cancer stage (localized versus advanced) as well as cancer grade (Gleason score & versus ≥7). Moreover, we also carried out a systematic review and meta-analysis of 13 similar studies. As a result of our meta-analysis, we revealed three polymorphisms, BsmI, ApaI, and TaqI, associated with high Gleason score with an overall summary odds ratios (95% confidence intervals) of 1.12 (1.00-1.25 bb versus BB + Bb), 1.25 (1.02-1.53 aa versus AA + Aa), and 0.82 (0.69-0.98 Tt + tt versus TT), respectively. The haplotype analysis revealed that the BsmI (B)-ApaI (A)-TaqI (t) participants compared with BsmI (b)-ApaI (a)-TaqI (T) in iduals were less likely to have high Gleason scores (odds ratio, 0.84 95% confidence interval, 0.71-1.00 Punadjusted = 0.050 Padjusted = 0.014). Our finding provides some support for the hypothesis that low levels of vitamin D may increase the risk of prostate cancer progression. (Cancer Epidemiol Biomarkers Prev 2009 (11):2874–81)
Publisher: Public Library of Science (PLoS)
Date: 10-07-2014
Publisher: Springer Science and Business Media LLC
Date: 11-2022
DOI: 10.1186/S12916-022-02585-W
Abstract: Observational epidemiological studies suggest a link between several factors related to ovulation and reproductive function and endometrial cancer (EC) risk however, it is not clear whether these relationships are causal, and whether the risk factors act independently of each other. The aim of this study was to investigate putative causal relationships between the number of live births, age at last live birth, and years ovulating and EC risk. We conducted a series of observational analyses to investigate various risk factors and EC risk in the UK Biobank (UKBB). Additionally, multivariate analysis was performed to elucidate the relationship between the number of live births, age at last live birth, and years ovulating and other related factors such as age at natural menopause, age at menarche, and body mass index (BMI). Secondly, we used Mendelian randomization (MR) to assess if these observed relationships were causal. Genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from previous studies of woman’s number of live births, age at menopause and menarche, and BMI. We conducted a genome-wide association analysis using the UKBB to identify SNPs associated with years ovulating, years using the contraceptive pill, and age at last live birth. We found evidence for a causal effect of the number of live births (inverse variance weighted (IVW) odds ratio (OR): 0.537, p = 0.006), the number of years ovulating (IVW OR: 1.051, p = 0.014), in addition to the known risk factors BMI, age at menarche, and age at menopause on EC risk in the univariate MR analyses. Due to the close relationships between these factors, we followed up with multivariable MR (MVMR) analysis. Results from the MVMR analysis showed that number of live births had a causal effect on EC risk (OR: 0.783, p = 0.036) independent of BMI, age at menarche and age at menopause. MVMR analysis showed that the number of live births causally reduced the risk of EC.
Publisher: Springer Netherlands
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NATURE08979
Publisher: Springer Science and Business Media LLC
Date: 28-07-2004
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 06-02-2017
DOI: 10.1038/NG.3787
Publisher: Wiley
Date: 21-07-2014
DOI: 10.1002/OBY.20840
Publisher: Public Library of Science (PLoS)
Date: 22-09-2006
Publisher: Public Library of Science (PLoS)
Date: 26-02-2010
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: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1038/NG.3529
Publisher: Springer Science and Business Media LLC
Date: 23-07-2018
Publisher: Springer Science and Business Media LLC
Date: 05-10-2023
Publisher: Springer Science and Business Media LLC
Date: 12-2012
DOI: 10.1038/NATURE11677
Publisher: F1000 Research Ltd
Date: 14-02-2017
DOI: 10.12688/WELLCOMEOPENRES.10567.1
Abstract: Mendelian randomization (MR), the use of genetic variants as instrumental variables (IVs) to test causal effects, is increasingly used in aetiological epidemiology. Few of the methodological developments in MR have considered the specific situation of using genetic IVs to test the causal effect of exposures in pregnant women on postnatal offspring outcomes. In this paper, we describe specific ways in which the IV assumptions might be violated when MR is used to test such intrauterine effects. We highlight the importance of considering the extent to which there is overlap between genetic variants in offspring that influence their outcome with genetic variants used as IVs in their mothers. Where there is overlap, and particularly if it generates a strong association of maternal genetic IVs with offspring outcome via the offspring genotype, the exclusion restriction assumption of IV analyses will be violated. We recommend a set of analyses that ought to be considered when MR is used to address research questions concerned with intrauterine effects on post-natal offspring outcomes, and provide details of how these can be undertaken and interpreted. These additional analyses include the use of genetic data from offspring and fathers, examining associations using maternal non-transmitted alleles, and using simulated data in sensitivity analyses (for which we provide code). We explore the extent to which new methods that have been developed for exploring violation of the exclusion restriction assumption in the two-s le setting (MR-Egger and median based methods) might be used when exploring intrauterine effects in one-s le MR. We provide a list of recommendations that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes and use an illustrative ex le with real data to demonstrate how our recommendations can be applied and subsequent results appropriately interpreted.
Publisher: Elsevier BV
Date: 10-2004
DOI: 10.1086/424696
Publisher: Oxford University Press (OUP)
Date: 23-08-2016
DOI: 10.1093/HMG/DDW264
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2020
DOI: 10.1101/2020.05.25.20112441
Abstract: Higher maternal BMI during pregnancy results in higher offspring birth weight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity coupled with a favourable metabolic profile, in a Mendelian Randomisation (MR) study comparing the effect of maternal “metabolically favourable adiposity” on offspring birth weight with the effect of maternal general adiposity (as indexed by BMI). To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birth weight, we performed two s le MR. We used variants identified in large genetic association studies as associated with either higher adiposity and a favourable metabolic profile, or higher BMI (N = 442,278 and N = 322,154 for metabolically favourable adiposity and BMI, respectively). We then used data from the same variants in a large genetic study of maternal genotype and offspring birth weight independent of fetal genetic effects (N = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total N = 9,323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birth weight and cord-blood biomarkers. Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birth weight (−94 (95% CI: −150 to −38) grams per 1 SD (6.5%) higher maternal metabolically favourable adiposity). By contrast, higher maternal BMI was associated with higher offspring birth weight (35 (95% CI: 16 to 53) grams per 1 SD (4 kg/m 2 ) higher maternal BMI). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures and their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels whilst maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birth weight, but the smaller s le sizes for these analyses meant the effects were imprecisely estimated. We also found evidence to suggest that maternal metabolically favourable adiposity decreases cord-blood leptin whilst maternal BMI increases it. Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birth weight. Higher maternal adiposity can lead to lower offspring birth weight if accompanied by a favourable metabolic profile. Studies in non-pregnant people with obesity suggest many people can have a “metabolically healthy” form of obesity, but effects in pregnancy and on offspring are not known. Multiple lines of evidence show that higher maternal BMI is causally associated with higher offspring birth weight, and that this may be mediated by the fetal insulin response to higher maternal gestational glucose. Recently, genetic variants have been identified, where one allele is associated with higher adiposity but lower risk of type II diabetes and favourable metabolic profile, including lower insulin and glucose levels, so called “metabolically favourable adiposity” the mechanism is thought to be due to greater subcutaneous adipose storage capacity that leads to higher insulin sensitivity. What is the effect of maternal metabolically favourable adiposity on birth weight, and how does it compare with the effect of maternal BMI on birth weight? Higher maternal adiposity can lead to lower, not higher birth weight, if it is also associated with a metabolically favourable profile this contrasts with the effect of higher maternal general adiposity (BMI), on higher birth weight. Higher maternal metabolically favourable adiposity causes lower maternal fasting plasma glucose levels, most likely due to higher insulin sensitivity in contrast higher maternal general adiposity leads to higher maternal fasting plasma glucose levels, most likely due to lower insulin sensitivity. Identifying ways of stratifying overweight and obese pregnant women into those with and without metabolically favourable adiposity could allow for targeted management to obtain healthy fetal growth and birth weight.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2020
DOI: 10.1038/S41467-020-16592-Z
Abstract: Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3 , which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.
Publisher: Public Library of Science (PLoS)
Date: 19-06-2014
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/307542
Abstract: Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference ( P .05 ). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers ( P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.
Publisher: Oxford University Press (OUP)
Date: 06-2018
DOI: 10.1093/HMG/DDY206
Publisher: Springer Science and Business Media LLC
Date: 30-06-2013
DOI: 10.1038/NG.2686
Publisher: Springer Science and Business Media LLC
Date: 05-05-2021
DOI: 10.1038/S41467-021-22517-1
Abstract: Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders ( P = 2.4 × 10 −22 ) and are associated with the polygenic diseases osteoporosis ( P = 1.8 × 10 −13 ) and osteoarthritis ( P = 1.6 × 10 −7 ). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2021
Publisher: Oxford University Press (OUP)
Date: 22-09-2016
DOI: 10.1093/BIOINFORMATICS/BTW613
Abstract: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large s le sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously. In this manuscript, we describe LD Hub - a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies. The web interface and instructions for using LD Hub are available at ldsc.broadinstitute.org/ Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Oxford University Press (OUP)
Date: 10-05-2019
DOI: 10.1093/IJE/DYZ095
Abstract: Maternal pre-pregnancy body mass index (BMI) is positively associated with offspring birth weight (BW) and BMI in childhood and adulthood. Each of these associations could be due to causal intrauterine effects, or confounding (genetic or environmental), or some combination of these. Here we estimate the extent to which the association between maternal BMI and offspring body size is explained by offspring genotype, as a first step towards establishing the importance of genetic confounding. We examined the associations of maternal pre-pregnancy BMI with offspring BW and BMI at 1, 5, 10 and 15 years, in three European birth cohorts (n ≤11 498). Bivariate Genomic-relatedness-based Restricted Maximum Likelihood implemented in the GCTA software (GCTA-GREML) was used to estimate the extent to which phenotypic covariance was explained by offspring genotype as captured by common imputed single nucleotide polymorphisms (SNPs). We merged in idual participant data from all cohorts, enabling calculation of pooled estimates. Phenotypic covariance (equivalent here to Pearson’s correlation coefficient) between maternal BMI and offspring phenotype was 0.15 [95% confidence interval (CI): 0.13, 0.17] for offspring BW, increasing to 0.29 (95% CI: 0.26, 0.31) for offspring 15 year BMI. Covariance explained by offspring genotype was negligible for BW [–0.04 (95% CI: –0.09, 0.01)], but increased to 0.12 (95% CI: 0.04, 0.21) at 15 years, which is equivalent to 43% (95% CI: 15%, 72%) of the phenotypic covariance. Sensitivity analyses using weight, BMI and ponderal index as the offspring phenotype at all ages showed similar results. Offspring genotype explains a substantial fraction of the covariance between maternal BMI and offspring adolescent BMI. This is consistent with a potentially important role for genetic confounding as a driver of the maternal BMI–offspring BMI association.
Publisher: Public Library of Science (PLoS)
Date: 04-04-2013
Publisher: BMJ
Date: 28-08-2014
Publisher: Elsevier BV
Date: 12-2003
Publisher: Springer Science and Business Media LLC
Date: 05-2022
DOI: 10.1038/S41588-022-01062-7
Abstract: Estimates from genome-wide association studies (GWAS) of unrelated in iduals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For ex le, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for ex le, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
Publisher: Springer International Publishing
Date: 2019
Publisher: IEEE
Date: 11-2013
Publisher: Wiley
Date: 19-03-2014
DOI: 10.1002/JBMR.2093
Publisher: MDPI AG
Date: 10-04-2014
DOI: 10.3390/GENES5020330
Publisher: Cold Spring Harbor Laboratory
Date: 17-12-2021
DOI: 10.1101/2021.12.16.21267808
Abstract: Ankylosing Spondylitis (AS) is a highly heritable inflammatory arthritis which occurs more frequently in men than women. In their recent publication examining sex differences in the genetic aetiology of common complex traits and diseases, Bernabeu et al. (2021) observe differences in heritability of AS between sexes, and a genome-wide significant genotype by sex interaction in risk of AS at the major histocompatability (MHC) locus 1 . The authors then present evidence suggesting that this genotype by sex interaction arises primarily as a result of differential expression of the gene MICA across the sexes in skeletal muscle tissue. Through a series of conditional association analyses in the UK Biobank, reanalysis of the GTEx gene expression resource and RNASeq experiments on peripheral blood cells from AS cases and controls, we show that the genotype by sex interaction the authors’ report is unlikely to be a result of variation in MICA , but probably reflects a known interaction between the HLA-B gene, sex and risk of AS. We demonstrate that the diagnostic accuracy of AS in the UK Biobank is low, particularly amongst women, likely explaining some of the observed differences in heritability across the sexes and the difficulty in precisely locating association signals in the cohort.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2021
DOI: 10.1038/S41467-021-25723-Z
Abstract: Estimation of direct and indirect (i.e. parental and/or sibling) genetic effects on phenotypes is becoming increasingly important. We compare several multivariate methods that utilize summary results statistics from genome-wide association studies to determine how well they estimate direct and indirect genetic effects. Using data from the UK Biobank, we contrast point estimates and standard errors at in idual loci compared to those obtained using in idual level data. We show that Genomic structural equation modelling (SEM) outperforms the other methods in accurately estimating conditional genetic effects and their standard errors. We apply Genomic SEM to fertility data in the UK Biobank and partition the genetic effect into female and male fertility and a sibling specific effect. We identify a novel locus for fertility and genetic correlations between fertility and educational attainment, risk taking behaviour, autism and subjective well-being. We recommend Genomic SEM be used to partition genetic effects into direct and indirect components when using summary results from genome-wide association studies.
Publisher: Oxford University Press (OUP)
Date: 10-2016
DOI: 10.5665/SLEEP.6170
Publisher: Public Library of Science (PLoS)
Date: 16-10-2012
Publisher: Springer Science and Business Media LLC
Date: 10-02-2013
DOI: 10.1038/NG.2554
Publisher: MDPI AG
Date: 22-01-2018
DOI: 10.3390/GENES9010053
Publisher: Elsevier BV
Date: 11-2009
Publisher: Springer Science and Business Media LLC
Date: 23-06-2013
DOI: 10.1038/NG.2676
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1002/JBMR.3989
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.TIG.2006.05.001
Abstract: A recent study by Cheung et al. demonstrates how to identify expression quantitative trait loci (eQTLs) underlying gene expression phenotypes through a combination of genome-wide linkage analysis and subsequent fine mapping or by genome-wide association (GWA) analysis. This study emphasizes the complexity of human traits, highlighting the challenges faced by investigators--in particular, insufficient linkage disequilibrium between the trait and marker variant, genetic heterogeneity and correcting for multiple testing will all adversely impact the power to detect loci by association. These issues must be considered carefully if the GWA approach is to succeed in mapping complex phenotypes.
Publisher: Wiley
Date: 21-05-2012
Publisher: Springer Science and Business Media LLC
Date: 09-10-2017
DOI: 10.1038/IJO.2017.248
Publisher: eLife Sciences Publications, Ltd
Date: 30-05-2018
DOI: 10.7554/ELIFE.34408
Abstract: Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-s le Mendelian randomization (2SMR) and bypassing the need for in idual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base ( www.mrbase.org ): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2021
DOI: 10.1007/S00125-021-05570-9
Abstract: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal ‘metabolically favourable adiposity’ on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI). To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-s le MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI ( n = 442,278 and n = 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects ( n = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total n = 9323 mother–child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers. Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (−94 [95% CI −150, −38] g per 1 SD [6.5%] higher maternal metabolically favourable adiposity, p = 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 [95% CI 16, 53] g per 1 SD [4 kg/m 2 ] higher maternal BMI, p = 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller s le sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it. Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile. The data for the genome-wide association studies (GWAS) of BMI are available at ollaboration/giant/index.php/GIANT_consortium_data_files . The data for the GWAS of body fat percentage are available at walker05.u.hpc.mssm.edu .
Publisher: Springer Science and Business Media LLC
Date: 16-04-2018
Publisher: Wiley
Date: 15-02-2013
DOI: 10.1002/JBMR.1796
Publisher: Oxford University Press (OUP)
Date: 12-2018
DOI: 10.1530/EJE-18-0478
Abstract: Hyperglycaemia during pregnancy increases the risk of adverse health outcomes in mother and child, but the genetic aetiology is scarcely studied. Our aims were to (1) assess the overlapping genetic aetiology between the pregnant and non-pregnant population and (2) assess the importance of genome-wide polygenic contributions to glucose traits during pregnancy, by exploring whether genetic risk scores (GRSs) for fasting glucose (FG), 2-h glucose (2hG), type 2 diabetes (T2D) and BMI in non-pregnant in iduals were associated with glucose measures in pregnant women. We genotyped 529 Norwegian pregnant women and constructed GRS from known genome-wide significant variants and SNPs weakly associated ( p 5 × 10 −8 ) with FG, 2hG, BMI and T2D from external genome-wide association studies (GWAS) and examined the association between these scores and glucose measures at gestational weeks 14–16 and 30–32. We also performed GWAS of FG, 2hG and shape information from the glucose curve during an oral glucose tolerance test (OGTT). GRS FG explained similar variance during pregnancy as in the non-pregnant population (~5%). GRS BMI and GRS T2D explained up to 1.3% of the variation in the glucose traits in pregnancy. If we included variants more weakly associated with these traits, GRS 2hG and GRS T2D explained up to 2.4% of the variation in the glucose traits in pregnancy, highlighting the importance of polygenic contributions. Our results suggest overlap in the genetic aetiology of FG in pregnant and non-pregnant in iduals. This was less apparent with 2hG, suggesting potential differences in postprandial glucose metabolism inside and outside of pregnancy.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1038/S41467-020-17117-4
Abstract: Estimates from Mendelian randomization studies of unrelated in iduals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated in iduals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from s les of unrelated in iduals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.
Publisher: Springer Science and Business Media LLC
Date: 02-01-2019
Publisher: Springer Science and Business Media LLC
Date: 06-04-2010
DOI: 10.1038/NG.567
Publisher: Springer Science and Business Media LLC
Date: 26-10-2020
DOI: 10.1038/S41467-020-19257-Z
Abstract: There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother–offspring pairs (and 19,792 father–offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based s les of in iduals.
Publisher: MIT Press - Journals
Date: 11-1997
DOI: 10.1162/JOCN.1997.9.6.743
Abstract: Brain electrical activity related to working memory was recorded at 15 scalp electrodes during a visuospatial delayed response task. Participants (N = 18) touched the remembered position of a target on a computer screen after either a 1 or 8 sec delay. These memory trials were compared to sensory trials in which the target remained present throughout the delay and response periods. Distractor stimuli identical to the target were briefly presented during the delay on 30% of trials. Responses were less accurate in memory than sensory trials, especially after the long delay. During the delay slow potentials developed that were significantly more negative in memory than sensory trials. The difference between memory and sensory trials was greater at anterior than posterior electrodes. On trials with distractors, the slow potentials generated by memory trials showed further enhancement of negativity, whereas there were minimal effects on accuracy of performance. The results provide evidence that engagement of visuospatial working memory generates slow wave negativity with a timing and distribution consistent with frontal activation. Enhanced brain activity associated with working memory is required to maintain performance in the presence of distraction.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2021
Publisher: Springer Science and Business Media LLC
Date: 17-04-2021
Publisher: BMJ
Date: 10-11-2011
Abstract: Recent association studies by the Australo-Anglo-American Spondyloarthritis Consortium (TASC) in Caucasian European populations from Australia, North America and the UK have identified a number of genes as being associated with ankylosing spondylitis (AS). A candidate gene study in a Han Chinese population was performed based on these findings to identify associated genes in this population. A case-control study was performed in a Han Chinese population of patients with AS (n = 775) and controls (n = 1587) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The cases and controls were genotyped for 115 single nucleotide polymorphisms (SNPs) tagging IL23R, ERAP1, STAT3, JAK2, TNFRSF1A and TRADD, as well as other confirmation SNPs from the TASC study, using the Sequenom iPlex and the ABI OpenArray platforms. Statistical analysis of genotyped SNPs was performed using the Cochran-Armitage test for trend and meta-analysis was performed using METAL. SNPs in AS-associated genes in this study were then imputed using MaCH, and association with AS tested by logistic regression. SNPs in TNFRSF1A (rs4149577, p = 8.2 × 10⁻⁴), STAT3 (rs2293152, p = 0.0015 rs1053005, p = 0.017) and ERAP1 (rs27038, p = 0.0091 rs27037, p = 0.0092) were significantly associated with AS in Han Chinese. Association was also observed between AS and the intergenic region 2p15 (rs10865331, p = 0.023). The lack of association between AS and IL23R in Han Chinese was confirmed (all SNPs p > 0.1). The study results demonstrate for the first time that genetic polymorphisms in STAT3, TNFRSF1A and 2p15 are associated with AS in Han Chinese, suggesting common pathogenic mechanisms for the disease in Chinese and Caucasian European populations. Furthermore, previous findings demonstrating that ERAP1, but not IL23R, is associated with AS in Chinese patients were confirmed.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2006
DOI: 10.1007/S10519-006-9087-2
Abstract: Transmission distortion refers to deviation from the normal 50:50 transmission of alleles from parents to offspring. Identification of genomic regions which undergo distortion is necessary for the correct interpretation of linkage and association studies, since tests of linkage using affected relative pairs and family based tests of association will yield spurious results in the presence of transmission distortion. With the increasing availability of genome-wide high density SNP data (e.g. from the International HapMap project), identification of these loci is now a real possibility. Here we present an analytical formula which demonstrates that the power to detect transmission distortion is a simple function of the number of heterozygous parents in the s le and the level of distortion at the locus. Our results indicate that whilst it will be possible to identify loci undergoing major levels of distortion using tens or hundreds of trios, large s le sizes in the order of tens of thousands of trios will be necessary to detect minor levels of distortion with appreciable power. The corollary is that genome-wide searches are unlikely to identify loci where the level of distortion is small, although they may serve to identify interesting regions worthy of follow up.
Publisher: Oxford University Press (OUP)
Date: 27-02-2013
DOI: 10.1093/HMG/DDT104
Publisher: Public Library of Science (PLoS)
Date: 07-2014
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 09-12-2014
DOI: 10.1007/S10552-014-0500-5
Abstract: Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer. In a nested case-control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1-T2/T3-T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism. We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04 rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01) there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure. We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).
Publisher: Cambridge University Press (CUP)
Date: 18-07-2016
DOI: 10.1017/S0954579416000572
Abstract: This study sought to identify trajectories of DSM-IV based internalizing (INT) and externalizing (EXT) problem scores across childhood and adolescence and to provide insight into the comorbidity by modeling the co-occurrence of INT and EXT trajectories. INT and EXT were measured repeatedly between age 7 and age 15 years in over 7,000 children and analyzed using growth mixture models. Five trajectories were identified for both INT and EXT, including very low, low, decreasing, and increasing trajectories. In addition, an adolescent onset trajectory was identified for INT and a stable high trajectory was identified for EXT. Multinomial regression showed that similar EXT and INT trajectories were associated. However, the adolescent onset INT trajectory was independent of high EXT trajectories, and persisting EXT was mainly associated with decreasing INT. Sex and early life environmental risk factors predicted EXT and, to a lesser extent, INT trajectories. The association between trajectories indicates the need to consider comorbidity when a child presents with INT or EXT disorders, particularly when symptoms start early. This is less necessary when INT symptoms start at adolescence. Future studies should investigate the etiology of co-occurring INT and EXT and the specific treatment needs of these severely affected children.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Wiley
Date: 26-11-2018
DOI: 10.1002/JBMR.3605
Abstract: We aimed to report the first genomewide association study (GWAS) meta‐analysis of dual‐energy X‐ray absorptiometry (DXA)‐derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant ( p 5 × 10 −9 , adjusted for 10 independent outcomes) single‐nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look‐up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9 , PTHrP , RUNX1 , NKX3‐2 , FGFR4 , DICER1 , and HHIP . The SNP adjacent to DICER1 also showed osteoblast cis‐regulatory activity of GSC , in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD ( r 2 0.5) were identified, which intersected with open chromatin sites as detected by ATAC‐seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
Publisher: Elsevier BV
Date: 11-2018
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2008
End Date: 2011
Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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End Date: 2012
Funder: Medical Research Council
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End Date: 2014
Funder: Biotechnology and Biological Sciences Research Council
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End Date: 2019
Funder: Medical Research Council
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End Date: 2017
Funder: National Health and Medical Research Council
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End Date: 2013
Funder: Medical Research Council
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End Date: 2014
Funder: Wellcome Trust
View Funded ActivityStart Date: 2011
End Date: 2014
Funder: Wellcome Trust
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End Date: 2017
Funder: National Health and Medical Research Council
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End Date: 2020
Funder: National Health and Medical Research Council
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End Date: 2017
Funder: Australian Research Council
View Funded ActivityStart Date: 2013
End Date: 2018
Funder: Medical Research Council
View Funded ActivityStart Date: 2008
End Date: 2010
Funder: Wellcome Trust
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
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End Date: 2014
Funder: National Health and Medical Research Council
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End Date: 2016
Funder: National Health and Medical Research Council
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End Date: 2022
Funder: National Health and Medical Research Council
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End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2008
End Date: 2009
Funder: Wellcome Trust
View Funded ActivityStart Date: 12-2013
End Date: 12-2017
Amount: $823,692.00
Funder: Australian Research Council
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