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Hundreds of variants clustered in genomic loci and biological pathways affect human height

Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

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Figure 1: Phenotypic variance explained by common variants.
Figure 2: Example of a locus with a secondary signal before (a) and after (b) conditioning.
Figure 3: Loci associated with height contain genes related to each other.

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Acknowledgements

Several participating studies are members of the CHARGE and ENGAGE consortia. We acknowledge funding from the following organizations: the Academy of Finland (104781, 117797, 120315, 121584, 126925, 129269, 129494, 129680, 213506); Affymetrix for genotyping services (N02-HL-6-4278); Agency for Science, Technology and Research of Singapore; ALF/LUA Gothenburg; Althingi (the Icelandic Parliament); Amgen; AstraZeneca AB; Australian National Health and Medical Research Council (241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672); Australian Research Council (DP0770096); Biocentrum Helsinki; Boston Obesity Nutrition Research Center (DK46200); British Diabetes Association; British Heart Foundation (PG/02/128); British Heart Foundation Centre for Research Excellence, Oxford; CamStrad; Cancer Research UK; Centre for Neurogenomics and Cognitive Research; Chief Scientist Office of the Scottish Government (CZB/4/279); Council of Health of the Academy of Finland; DIAB Core project of the German Network of Diabetes; Diabetes UK; Donald W. Reynolds Foundation; Emil and Vera Cornell Foundation; Erasmus MC; Estonian Government (SF0180142s08); European Commission (201413, ECOGENE:205419, BBMRI:212111, OPENGENE:245536, ENGAGE:HEALTH-F4-2007-201413, EURODIA:LSHG-CT-2004-518153, EU/WLRT-2001-01254, HEALTH-F2-2008-ENGAGE, HEALTH-F4-2007-201550, LSH-2006-037593, LSHG-CT-2006-018947, LSHG-CT-2006-01947, Procardis:LSHM-CT-2007-037273, POLYGENE:LSHC-CT-2005, QLG1-CT-2000-01643, QLG2-CT-2002-01254, DG XII, Marie Curie Intra-European Fellowship); Eve Appeal; Finnish Ministry of Education; Finnish Diabetes Research Foundation; Finnish Diabetes Research Society; Finnish Foundation for Cardiovascular Research; Finnish Medical Society; Finska Läkaresällskapet; Folkhälsan Research Foundation; Fondation LeDucq; Foundation for Life and Health in Finland; Foundation for Strategic Research; GEN-AU-Programme ‘GOLD’; Genetic Association Information Network; German Bundesministerium fuer Forschung und Technology (01 AK 803 A-H, 01 IG 07015 G); German Federal Ministry of Education and Research (01GS0831); German Ministry for Health, Welfare and Sports; German Ministry of Cultural Affairs; German Ministry of Education, Culture and Science; German National Genome Research Net (01GS0823, 01ZZ0103, 01ZZ0403, 01ZZ9603, 03ZIK012); German Research Council (KFO-152); GlaxoSmithKline; Göteborg Medical Society; Gyllenberg Foundation; Helmholtz Center Munich; Juvenile Diabetes Research Foundation International (U01 DK062418); Karolinska Institute; Knut and Alice Wallenberg Foundation; Lundberg Foundation; March of Dimes (6-FY-09-507); MC Health; Medical Research Council UK (G0000649, G0000934, G0500539, G0600331, G0601261, G9521010D, PrevMetSyn); Microarray Core Facility of the Interdisciplinary Centre for Clinical Research (B27); Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488); Ministry of Health and Department of Educational Assistance (South Tyrol, Italy); Ministry of Science, Education and Sport of the Republic of Croatia (216-1080315-0302); Montreal Heart Institute Foundation; Närpes Health Care Foundation; National Cancer Institute; National Institute for Health Research Cambridge Biomedical Research Centre; National Institute for Health Research Oxford Biomedical Research Centre; National Institute for Health Research Comprehensive Biomedical Research Centre; National Institutes of Health (263-MA-410953, AA014041, AA07535, AA10248, AA13320, AA13321, AA13326, CA047988, CA49449, CA50385, CA65725, CA67262, CA87969, DA12854, DK062370, DK063491, DK072193, DK079466, DK080145, DK58845, HG002651, HG005214, HG005581, HL043851, HL084729, HL69757, HL71981, K08-AR055688, K23-DK080145, K99-HL094535, M01-RR00425, MH084698, N01-AG12100, N01-AG12109, N01-HC15103, N01-HC25195, N01-HC35129, N01-HC45133, N01-HC55015, N01-HC55016, N01-HC55018–N01-HC55022, N01-HC55222, N01-HC75150, N01-HC85079–N01-HC85086, N01-HG65403, R01-AG031890, R01 CA104021, R01-DK068336, R01-DK073490, R01-DK075681, R01-DK075787, R01-HL086694, R01-HL087641, R01-HL087647, R01-HL087652, R01-HL087676, R01-HL087679, R01-HL087700, R01-HL088119, R01-HL59367, R01-MH059160, R01-MH59565, R01-MH59566, R01-MH59571, R01-MH59586, R01-MH59587, R01-MH59588, R01-MH60870, R01-MH60879, R01-MH61675, R01-MH63706, R01-MH67257, R01-MH79469, R01-MH81800, RL1-MH083268, T32-HG00040, U01-CA098233, U01-GM074518, U01-HG004399, U01-HG004402, U01-HL080295, U01-HL084756, U01-HL72515, U01-MH79469, U01-MH79470, U54-RR020278, UL1-RR025005, Z01-AG00675, Z01-AG007380, Z01-HG000024; contract HHSN268200625226C; ADA Mentor-Based Postdoctoral Fellowship; Pew Scholarship for the Biomedical Sciences); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (investment number 175.010.2005.011, 911-03-012); Netherlands Organization for the Health Research and Development (10-000-1002); Netherlands Scientific Organization (904-61-090, 904-61-193, 480-04-004, 400-05-717, Center for Medical Systems Biology (NOW Genomics), SPI 56-464-1419) ; NIA Intramural Research Program; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklén Foundation; Petrus and Augusta Hedlunds Foundation; Queensland Institute of Medical Research; Radboud University Nijmegen Medical Centre; Research Institute for Diseases in the Elderly (014-93-015); Royal Swedish Academy of Science; Sahlgrenska Center for Cardiovascular and Metabolic Research (A305:188); Siemens Healthcare, Erlangen, Germany; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; Social Ministry of the Federal State of Mecklenburg-West Pomerania; South Tyrolean Sparkasse Foundation; Stockholm County Council (560183); Support for Science Funding programme; Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society; Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation; Swedish Medical Research Council (K2007-66X-20270-01-3, 8691); Swedish National Cancer Institute; Swedish Research Council; Swedish Society of Medicine; Swiss National Science Foundation (33CSCO-122661); Torsten and Ragnar Söderberg’s Foundation; Vandervell Foundation; Västra Götaland Foundation; Wellcome Trust (072960, 075491, 079557, 079895, 083270, 068545/Z/02, 076113/B/04/Z, 076113/C/04/Z, 076113/C/04/Z, 077016/Z/05/Z, 081682/Z/06/Z, 084183/Z/07/Z, 085301/Z/08/Z, 086596/Z/08/Z, 091746/Z/10/Z; Wellcome Trust Research Career Development Fellowship); Western Australian Genetic Epidemiology Resource and the Western Australian DNA Bank (both National Health and Medical Research Council of Australia Enabling Facilities). A detailed list of acknowledgements by study is given in the Supplementary Information.

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This work was done under the auspices of the Genetic Investigation of ANthropocentric Traits (GIANT) Consortium. Author contributions and roles are listed in the Supplementary Information.

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Correspondence to Michael N. Weedon, Gonçalo R. Abecasis, Kari Stefansson, Timothy M. Frayling or Joel N. Hirschhorn.

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Supplementary Information

This file contains Supplementary Methods, additional references, Supplementary Tables 1-13, Supplementary Figures 1-3 with legends, Supplementary Methods Tables 1-3 and Supplementary Notes comprising author contributions and acknowledgments. (PDF 6588 kb)

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Lango Allen, H., Estrada, K., Lettre, G. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010). https://doi.org/10.1038/nature09410

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