Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic, pulse pressure) to date in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing (WGS) data. We demonstrate using simulations based on WGS data that ~97% and ~68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ~17M imputed variants explain 56% (s.e. = 2.3%) of variance for height and 27% (s.e. = 2.5%) for body mass index (BMI), and find evidence that height- and BMI-associated variants have been under natural selection. Considering imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60–70% for height and 30–40% for BMI. Therefore, missing heritability is small for both traits. For further gene discovery of complex traits, a design with SNP arrays followed by imputation is more cost-effective than WGS at current prices.
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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