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 alreadydiscovered 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.
| Original language | English |
|---|---|
| Pages (from-to) | 832-838 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 467 |
| Issue number | 7317 |
| DOIs | |
| State | Published - Oct 14 2010 |
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In: Nature, Vol. 467, No. 7317, 14.10.2010, p. 832-838.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Hundreds of variants clustered in genomic loci and biological pathways affect human height
AU - Allen, Hana Lango
AU - Estrada, Karol
AU - Lettre, Guillaume
AU - Berndt, Sonja I.
AU - Weedon, Michael N.
AU - Rivadeneira, Fernando
AU - Willer, Cristen J.
AU - Jackson, Anne U.
AU - Vedantam, Sailaja
AU - Raychaudhuri, Soumya
AU - Ferreira, Teresa
AU - Wood, Andrew R.
AU - Weyant, Robert J.
AU - Segrè, Ayellet V.
AU - Speliotes, Elizabeth K.
AU - Wheeler, Eleanor
AU - Soranzo, Nicole
AU - Park, Ju Hyun
AU - Yang, Jian
AU - Gudbjartsson, Daniel
AU - Heard-Costa, Nancy L.
AU - Randall, Joshua C.
AU - Qi, Lu
AU - Smith, Albert Vernon
AU - Mägi, Reedik
AU - Pastinen, Tomi
AU - Liang, Liming
AU - Heid, Iris M.
AU - Luan, Jian'An
AU - Thorleifsson, Gudmar
AU - Winkler, Thomas W.
AU - Goddard, Michael E.
AU - Lo, Ken Sin
AU - Palmer, Cameron
AU - Workalemahu, Tsegaselassie
AU - Aulchenko, Yurii S.
AU - Johansson, Åsa
AU - Zillikens, M. Carola
AU - Feitosa, Mary F.
AU - Esko, Toñu
AU - Johnson, Toby
AU - Ketkar, Shamika
AU - Kraft, Peter
AU - Mangino, Massimo
AU - Prokopenko, Inga
AU - Absher, Devin
AU - Albrecht, Eva
AU - Ernst, Florian
AU - Glazer, Nicole L.
AU - Hayward, Caroline
AU - Hottenga, Jouke Jan
AU - Jacobs, Kevin B.
AU - Knowles, Joshua W.
AU - Kutalik, Zoltán
AU - Monda, Keri L.
AU - Polasek, Ozren
AU - Preuss, Michael
AU - Rayner, Nigel W.
AU - Robertson, Neil R.
AU - Steinthorsdottir, Valgerdur
AU - Tyrer, Jonathan P.
AU - Voight, Benjamin F.
AU - Wiklund, Fredrik
AU - Xu, Jianfeng
AU - Zhao, Jing Hua
AU - Nyholt, Dale R.
AU - Pellikka, Niina
AU - Perola, Markus
AU - Perry, John B.
AU - Surakka, Ida
AU - Tammesoo, Mari Liis
AU - Altmaier, Elizabeth L.
AU - Amin, Najaf
AU - Aspelund, Thor
AU - Bhangale, Tushar
AU - Boucher, Gabrielle
AU - Chasman, Daniel I.
AU - Chen, Constance
AU - Coin, Lachlan
AU - Cooper, Matthew N.
AU - Dixon, Anna L.
AU - Gibson, Quince
AU - Grundberg, Elin
AU - Hao, Ke
AU - Junttila, M. Juhani
AU - Kaplan, Lee M.
AU - Kettunen, Johannes
AU - König, Inke R.
AU - Kwan, Tony
AU - Lawrence, Robert W.
AU - Levinson, Douglas F.
AU - Lorentzon, Mattias
AU - McKnight, Barbara
AU - Morris, Andrew P.
AU - Müller, Martina
AU - Ngwa, Julius Suh
AU - Purcell, Shaun
AU - Rafelt, Suzanne
AU - Salem, Rany M.
AU - Salvi, Erika
AU - Sanna, Serena
AU - Shi, Jianxin
AU - Sovio, Ulla
AU - Thompson, John R.
AU - Turchin, Michael C.
AU - Vandenput, Liesbeth
AU - Verlaan, Dominique J.
AU - Vitart, Veronique
AU - White, Charles C.
AU - Ziegler, Andreas
AU - Almgren, Peter
AU - Balmforth, Anthony J.
AU - Campbell, Harry
AU - Citterio, Lorena
AU - De Grandi, Alessandro
AU - Dominiczak, Anna
AU - Duan, Jubao
AU - Elliott, Paul
AU - Elosua, Roberto
AU - Eriksson, Johan G.
AU - Freimer, Nelson B.
AU - Geus, Eco J.C.
AU - Glorioso, Nicola
AU - Haiqing, Shen
AU - Hartikainen, Anna Liisa
AU - Havulinna, Aki S.
AU - Hicks, Andrew A.
AU - Hui, Jennie
AU - Igl, Wilmar
AU - Illig, Thomas
AU - Jula, Antti
AU - Kajantie, Eero
AU - Kilpeläinen, Tuomas O.
AU - Koiranen, Markku
AU - Kolcic, Ivana
AU - Koskinen, Seppo
AU - Kovacs, Peter
AU - Laitinen, Jaana
AU - Liu, Jianjun
AU - Lokki, Marja Liisa
AU - Marusic, Ana
AU - Maschio, Andrea
AU - Meitinger, Thomas
AU - Mulas, Antonella
AU - Paré, Guillaume
AU - Parker, Alex N.
AU - Peden, John F.
AU - Petersmann, Astrid
AU - Pichler, Irene
AU - Pietiläinen, Kirsi H.
AU - Pouta, Anneli
AU - Ridderstråle, Martin
AU - Rotter, Jerome I.
AU - Sambrook, Jennifer G.
AU - Sanders, Alan R.
AU - Schmidt, Carsten Oliver
AU - Sinisalo, Juha
AU - Smit, Jan H.
AU - Stringham, Heather M.
AU - Walters, G. Bragi
AU - Widen, Elisabeth
AU - Wild, Sarah H.
AU - Willemsen, Gonneke
AU - Zagato, Laura
AU - Zgaga, Lina
AU - Zitting, Paavo
AU - Alavere, Helene
AU - Farrall, Martin
AU - McArdle, Wendy L.
AU - Nelis, Mari
AU - Peters, Marjolein J.
AU - Ripatti, Samuli
AU - Van Meurs, Joyce B.J.
AU - Aben, Katja K.
AU - Ardlie, Kristin G.
AU - Beckmann, Jacques S.
AU - Beilby, John P.
AU - Bergman, Richard N.
AU - Bergmann, Sven
AU - Collins, Francis S.
AU - Cusi, Daniele
AU - Den Heijer, Martin
AU - Eiriksdottir, Gudny
AU - Gejman, Pablo V.
AU - Hall, Alistair S.
AU - Hamsten, Anders
AU - Huikuri, Heikki V.
AU - Iribarren, Carlos
AU - Kähönen, Mika
AU - Kaprio, Jaakko
AU - Kathiresan, Sekar
AU - Kiemeney, Lambertus
AU - Kocher, Thomas
AU - Launer, Lenore J.
AU - Lehtimäki, Terho
AU - Melander, Olle
AU - Mosley, Tom H.
AU - Musk, Arthur W.
AU - Nieminen, Markku S.
AU - O'Donnell, Christopher J.
AU - Ohlsson, Claes
AU - Oostra, Ben
AU - Palmer, Lyle J.
AU - Raitakari, Olli
AU - Ridker, Paul M.
AU - Rioux, John D.
AU - Rissanen, Aila
AU - Rivolta, Carlo
AU - Schunkert, Heribert
AU - Shuldiner, Alan R.
AU - Siscovick, David S.
AU - Stumvoll, Michael
AU - Tönjes, Anke
AU - Tuomilehto, Jaakko
AU - Van Ommen, Gert Jan
AU - Viikari, Jorma
AU - Heath, Andrew C.
AU - Martin, Nicholas G.
AU - Montgomery, Grant W.
AU - Province, Michael A.
AU - Kayser, Manfred
AU - Arnold, Alice M.
AU - D.Atwood, Larry
AU - Boerwinkle, Eric
AU - Chanock, Stephen J.
AU - Deloukas, Panos
AU - Gieger, Christian
AU - Grönberg, Henrik
AU - Hall, Per
AU - Hattersley, Andrew T.
AU - Hengstenberg, Christian
AU - Hoffman, Wolfgang
AU - Lathrop, G. Mark
AU - Salomaa, Veikko
AU - Schreiber, Stefan
AU - Uda, Manuela
AU - Waterworth, Dawn
AU - Wright, Alan F.
AU - Assimes, Themistocles L.
AU - Barroso, Inês
AU - Hofman, Albert
AU - Mohlke, Karen L.
AU - Boomsma, Dorret I.
AU - Caulfield, Mark J.
AU - Cupples, L. Adrienne
AU - Erdmann, Jeanette
AU - Fox, Caroline S.
AU - Gudnason, Vilmundur
AU - Gyllensten, Ulf
AU - Harris, Tamara B.
AU - Hayes, Richard B.
AU - Jarvelin, Marjo Riitta
AU - Mooser, Vincent
AU - Munroe, Patricia B.
AU - Ouwehand, Willem H.
AU - Penninx, Brenda W.
AU - Pramstaller, Peter P.
AU - Quertermous, Thomas
AU - Rudan, Igor
AU - Samani, Nilesh J.
AU - Spector, Timothy D.
AU - Völzke, Henry
AU - Watkins, Hugh
AU - Wilson, James F.
AU - Groop, Leif C.
AU - Haritunians, Talin
AU - Hu, Frank B.
AU - Kaplan, Robert C.
AU - Metspalu, Andres
AU - North, Kari E.
AU - Schlessinger, David
AU - Wareham, Nicholas J.
AU - Hunter, David J.
AU - O'Connell, Jeffrey R.
AU - Strachan, David P.
AU - Wichmann, H. Erich
AU - Borecki, Ingrid B.
AU - Van Duijn, Cornelia M.
AU - Schadt, Eric E.
AU - Thorsteinsdottir, Unnur
AU - Peltonen, Leena
AU - Uitterlinden, André G.
AU - Visscher, Peter M.
AU - Chatterjee, Nilanjan
AU - Loos, Ruth J.F.
AU - Boehnke, Michael
AU - McCarthy, Mark I.
AU - Ingelsson, Erik
AU - Lindgren, Cecilia M.
AU - Abecasis, Gonçalo R.
AU - Stefansson, Kari
AU - Frayling, Timothy M.
AU - Hirschhorn, Joel N.
N1 - Funding Information: 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.
PY - 2010/10/14
Y1 - 2010/10/14
N2 - 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 alreadydiscovered 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.
AB - 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 alreadydiscovered 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.
UR - http://www.scopus.com/inward/record.url?scp=77957947562&partnerID=8YFLogxK
U2 - 10.1038/nature09410
DO - 10.1038/nature09410
M3 - Article
C2 - 20881960
AN - SCOPUS:77957947562
SN - 0028-0836
VL - 467
SP - 832
EP - 838
JO - Nature
JF - Nature
IS - 7317
ER -