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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Tuesday,2012-11-06 12:25 America/Los_Angeles — eenright
| Title | Hundreds of variants clustered in genomic loci and biological pathways affect human height. |
| Publication Type | Journal Article |
| Year of Publication | 2010 |
| Authors | Allen, HLango, Estrada, K, Lettre, G, Berndt, SI, Weedon, MN, Rivadeneira, F, Willer, CJ, Jackson, AU, Vedantam, S, Raychaudhuri, S, Ferreira, T, Wood, AR, Weyant, RJ, Segrè, AV, Speliotes, EK, Wheeler, E, Soranzo, N, Park, J-H, Yang, J, Gudbjartsson, D, Heard-Costa, NL, Randall, JC, Qi, L, Smith, AVernon, Mägi, R, Pastinen, T, Liang, L, Heid, IM, Luan, J'an, Thorleifsson, G, Winkler, TW, Goddard, ME, Lo, KSin, Palmer, C, Workalemahu, T, Aulchenko, YS, Johansson, A, Zillikens, CM, Feitosa, MF, Esko, T, Johnson, T, Ketkar, S, Kraft, P, Mangino, M, Prokopenko, I, Absher, D, Albrecht, E, Ernst, F, Glazer, NL, Hayward, C, Hottenga, J-J, Jacobs, KB, Knowles, JW, Kutalik, Z, Monda, KL, Polasek, O, Preuss, M, Rayner, NW, Robertson, NR, Steinthorsdottir, V, Tyrer, JP, Voight, BF, Wiklund, F, Xu, J, Zhao, JH, Nyholt, DR, Pellikka, N, Perola, M, Perry, JRB, Surakka, I, Tammesoo, M-L, Altmaier, EL, Amin, N, Aspelund, T, Bhangale, T, Boucher, G, Chasman, DI, Chen, C, Coin, L, Cooper, MN, Dixon, AL, Gibson, Q, Grundberg, E, Hao, K, M Junttila, J, Kaplan, LM, Kettunen, J, König, IR, Kwan, T, Lawrence, RW, Levinson, DF, Lorentzon, M, McKnight, B, Morris, AP, Müller, M, Ngwa, JSuh, Purcell, S, Rafelt, S, Salem, RM, Salvi, E, Sanna, S, Shi, J, Sovio, U, Thompson, JR, Turchin, MC, Vandenput, L, Verlaan, DJ, Vitart, V, White, CC, Ziegler, A, Almgren, P, Balmforth, AJ, Campbell, H, Citterio, L, De Grandi, A, Dominiczak, A, Duan, J, Elliott, P, Elosua, R, Eriksson, JG, Freimer, NB, Geus, EJC, Glorioso, N, Haiqing, S, Hartikainen, A-L, Havulinna, AS, Hicks, AA, Hui, J, Igl, W, Illig, T, Jula, A, Kajantie, E, Kilpeläinen, TO, Koiranen, M, Kolcic, I, Koskinen, S, Kovacs, P, Laitinen, J, Liu, J, Lokki, M-L, Marusic, A, Maschio, A, Meitinger, T, Mulas, A, Paré, G, Parker, AN, Peden, JF, Petersmann, A, Pichler, I, Pietiläinen, KH, Pouta, A, Ridderstråle, M, Rotter, JI, Sambrook, JG, Sanders, AR, Schmidt, COliver, Sinisalo, J, Smit, JH, Stringham, HM, G Walters, B, Widen, E, Wild, SH, Willemsen, G, Zagato, L, Zgaga, L, Zitting, P, Alavere, H, Farrall, M, McArdle, WL, Nelis, M, Peters, MJ, Ripatti, S, van Meurs, JBJ, Aben, KK, Ardlie, KG, Beckmann, JS, Beilby, JP, Bergman, RN, Bergmann, S, Collins, FS, Cusi, D, Heijer, Mden, Eiriksdottir, G, Gejman, PV, Hall, AS, Hamsten, A, Huikuri, HV, Iribarren, C, Kähönen, M, Kaprio, J, Kathiresan, S, Kiemeney, L, Kocher, T, Launer, LJ, Lehtimäki, T, Melander, O, Mosley, TH, Musk, AW, Nieminen, MS, O'Donnell, CJ, Ohlsson, C, Oostra, B, Palmer, LJ, Raitakari, O, Ridker, PM, Rioux, JD, Rissanen, A, Rivolta, C, Schunkert, H, Shuldiner, AR, Siscovick, DS, Stumvoll, M, Tönjes, A, Tuomilehto, J, van Ommen, G-J, Viikari, J, Heath, AC, Martin, NG, Montgomery, GW, Province, MA, Kayser, M, Arnold, AM, Atwood, LD, Boerwinkle, E, Chanock, SJ, Deloukas, P, Gieger, C, Grönberg, H, Hall, P, Hattersley, AT, Hengstenberg, C, Hoffman, W, Lathrop, MG, Salomaa, V, Schreiber, S, Uda, M, Waterworth, D, Wright, AF, Assimes, TL, Barroso, I, Hofman, A, Mohlke, KL, Boomsma, DI, Caulfield, MJ, Cupples, AL, Erdmann, J, Fox, CS, Gudnason, V, Gyllensten, U, Harris, TB, Hayes, RB, Jarvelin, M-R, Mooser, V, Munroe, PB, Ouwehand, WH, Penninx, BW, Pramstaller, PP, Quertermous, T, Rudan, I, Samani, NJ, Spector, TD, Völzke, H, Watkins, H, Wilson, JF, Groop, LC, Haritunians, T, Hu, FB, Kaplan, RC, Metspalu, A, North, KE, Schlessinger, D, Wareham, NJ, Hunter, DJ, O'Connell, JR, Strachan, DP, Wichmann, H-E, Borecki, IB, van Duijn, CM, Schadt, EE, Thorsteinsdottir, U, Peltonen, L, Uitterlinden, AG, Visscher, PM, Chatterjee, N, Loos, RJF, Boehnke, M, McCarthy, MI, Ingelsson, E, Lindgren, CM, Abecasis, GR, Stefansson, K, Frayling, TM, Hirschhorn, JN |
| Journal | Nature |
| Volume | 467 |
| Issue | 7317 |
| Pagination | 832-8 |
| Date Published | 2010 Oct 14 |
| ISSN | 1476-4687 |
| Keywords | Body Height, Chromosomes, Human, Pair 3, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide |
| Abstract | <p>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 traits, 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 trait. 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.</p> |
| DOI | 10.1038/nature09410 |
| Alternate Journal | Nature |
| PubMed ID | 20881960 |
| PubMed Central ID | PMC2955183 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States R01 MH061675 / MH / NIMH NIH HHS / United States R01 CA050385 / CA / NCI NIH HHS / United States U01-HG004402 / HG / NHGRI NIH HHS / United States R01 MH059587-09 / MH / NIMH NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States R01 MH061675-09 / MH / NIMH NIH HHS / United States R01 HL087679-01 / HL / NHLBI NIH HHS / United States R01-MH67257 / MH / NIMH NIH HHS / United States CZB/4/710 / / Chief Scientist Office / United Kingdom G9521010 / / Medical Research Council / United Kingdom R01 DK073490 / DK / NIDDK NIH HHS / United States K08 AR055688-03 / AR / NIAMS NIH HHS / United States R01-HL088119 / HL / NHLBI NIH HHS / United States R01-MH61675 / MH / NIMH NIH HHS / United States 072856 / / Wellcome Trust / United Kingdom G0000649 / / Medical Research Council / United Kingdom K23 DK080145 / DK / NIDDK NIH HHS / United States N01-G65403 / / PHS HHS / United States R01 MH063706 / MH / NIMH NIH HHS / United States G9521010(63660) / / Medical Research Council / United Kingdom R01 AA007535 / AA / NIAAA NIH HHS / United States R01 DK058845 / DK / NIDDK NIH HHS / United States R01 AA007535-08 / AA / NIAAA NIH HHS / United States N01AG12100 / AG / NIA NIH HHS / United States MH084698 / MH / NIMH NIH HHS / United States R01 MH059565-06 / MH / NIMH NIH HHS / United States R01 CA065725-14 / CA / NCI NIH HHS / United States CZB/4/279 / / Chief Scientist Office / United Kingdom R01-MH60870 / MH / NIMH NIH HHS / United States R56 DK062370 / DK / NIDDK NIH HHS / United States N01-HC15103 / HC / NHLBI NIH HHS / United States R01-HL59367 / HL / NHLBI NIH HHS / United States R01 AA014041 / AA / NIAAA NIH HHS / United States K05 AA017688 / AA / NIAAA NIH HHS / United States N01HG65403 / HG / NHGRI NIH HHS / United States R01 MH084698 / MH / NIMH NIH HHS / United States N01HC55018 / HL / NHLBI NIH HHS / United States G0600331 / / Medical Research Council / United Kingdom N01-HC55021 / HC / NHLBI NIH HHS / United States 079557 / / Wellcome Trust / United Kingdom R01 HL087647 / HL / NHLBI NIH HHS / United States 084183/Z/07/Z / / Wellcome Trust / United Kingdom U01 CA049449-21 / CA / NCI NIH HHS / United States U01 HL084729 / HL / NHLBI NIH HHS / United States U01 HL080295-04 / HL / NHLBI NIH HHS / United States R01 AA014041-05 / AA / NIAAA NIH HHS / United States N01-HC85086 / HC / NHLBI NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States R01-MH59571 / MH / NIMH NIH HHS / United States AA13320 / AA / NIAAA NIH HHS / United States N01-HC85079 / HC / NHLBI NIH HHS / United States R01-MH59586 / MH / NIMH NIH HHS / United States R01-HL087676 / HL / NHLBI NIH HHS / United States P01 CA087969 / CA / NCI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States R01 HL087679 / HL / NHLBI NIH HHS / United States RL1-MH083268 / MH / NIMH NIH HHS / United States R01 CA067262 / CA / NCI NIH HHS / United States R01 HL087676 / HL / NHLBI NIH HHS / United States 086596 / / Wellcome Trust / United Kingdom N01-HC85083 / HC / NHLBI NIH HHS / United States R01 DA012854-09 / DA / NIDA NIH HHS / United States R01 HG002651 / HG / NHGRI NIH HHS / United States R01 DK075681-02 / DK / NIDDK NIH HHS / United States HL69757 / HL / NHLBI NIH HHS / United States R01-MH60879 / MH / NIMH NIH HHS / United States R01 MH067257-04 / MH / NIMH NIH HHS / United States U01-HL080295 / HL / NHLBI NIH HHS / United States R01 HL043851 / HL / NHLBI NIH HHS / United States R01 MH059571-05 / MH / NIMH NIH HHS / United States N01-HC55222 / HC / NHLBI NIH HHS / United States 088885 / / Wellcome Trust / United Kingdom R01 HL059367 / HL / NHLBI NIH HHS / United States MC_U127561128 / / Medical Research Council / United Kingdom DA12854 / DA / NIDA NIH HHS / United States R01-MH63706 / MH / NIMH NIH HHS / United States R01-MH59565 / MH / NIMH NIH HHS / United States N01-HC75150 / HC / NHLBI NIH HHS / United States K23 DK080145-01 / DK / NIDDK NIH HHS / United States N01 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/ United States 076113 / / Wellcome Trust / United Kingdom P30 DK063491 / DK / NIDDK NIH HHS / United States R01 MH059571 / MH / NIMH NIH HHS / United States U01-MH79470 / MH / NIMH NIH HHS / United States R01 MH059565 / MH / NIMH NIH HHS / United States / / Intramural NIH HHS / United States U01 GM074518-05 / GM / NIGMS NIH HHS / United States R01 HL086694-02 / HL / NHLBI NIH HHS / United States 079771 / / Wellcome Trust / United Kingdom R01 MH081800-01 / MH / NIMH NIH HHS / United States HL71981 / HL / NHLBI NIH HHS / United States 263-MA-410953 / / PHS HHS / United States P30 DK072488 / DK / NIDDK NIH HHS / United States R01-DK068336 / DK / NIDDK NIH HHS / United States R01 CA050385-20 / CA / NCI NIH HHS / United States / / Cancer Research UK / United Kingdom Z01-HG000024 / HG / NHGRI NIH HHS / United States R01 DK058845-11 / DK / NIDDK NIH HHS / United States R01 DK068336-01 / DK / NIDDK NIH HHS / United States R01-DK073490 / DK / NIDDK NIH HHS / United States U01 MH079470-03 / MH 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United Kingdom R01 CA047988 / CA / NCI NIH HHS / United States RC2 HG005581-02 / RC / CCR NIH HHS / United States R01 HL043851-10 / HL / NHLBI NIH HHS / United States R01-HL087700 / HL / NHLBI NIH HHS / United States M01 RR000425 / RR / NCRR NIH HHS / United States N01AG12109 / AG / NIA NIH HHS / United States DK062370 / DK / NIDDK NIH HHS / United States HG005214 / HG / NHGRI NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States N01-HC85085 / HC / NHLBI NIH HHS / United States R01 DK089256 / DK / NIDDK NIH HHS / United States U19 HL069757 / HL / NHLBI NIH HHS / United States N01-HC85080 / HC / NHLBI NIH HHS / United States K08-AR055688 / AR / NIAMS NIH HHS / United States T32-HG00040 / HG / NHGRI NIH HHS / United States R01 AA013321-05 / AA / NIAAA NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States R01 CA067262-14 / CA / NCI NIH HHS / United States R01 HL087641-01 / HL / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States R01 CA104021-02 / CA / NCI NIH HHS / United States R01 MH059566 / MH / NIMH NIH HHS / United States PG/02/128/14470 / / British Heart Foundation / United Kingdom R01 HG002651-05 / HG / NHGRI NIH HHS / United States R01-MH059160 / MH / NIMH NIH HHS / United States 068545/Z/02 / / Wellcome Trust / United Kingdom R01-HL087679 / HL / NHLBI NIH HHS / United States N01-HC85084 / HC / NHLBI NIH HHS / United States R01 CA049449 / CA / NCI NIH HHS / United States U01 HG005214-02 / HG / NHGRI NIH HHS / United States CA50385 / CA / NCI NIH HHS / United States HG005581 / HG / NHGRI NIH HHS / United States K08 AR055688-04 / AR / NIAMS NIH HHS / United States R01 DK073490-01 / DK / NIDDK NIH HHS / United States RL1 MH083268 / MH / NIMH NIH HHS / United States R01 MH059588 / MH / NIMH NIH HHS / United States U01-CA098233 / CA / NCI NIH HHS / United States Z01 HG000024 / HG / NHGRI NIH HHS / United States P01 CA087969-12 / CA / NCI NIH HHS / United States R01-MH79469 / MH / NIMH NIH HHS / United 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Medical Research Council / United Kingdom R01 HL087700 / HL / NHLBI NIH HHS / United States 077016/Z/05/Z / / Wellcome Trust / United Kingdom Z01 AG007380 / AG / NIA NIH HHS / United States G0600331(77796) / / Medical Research Council / United Kingdom G0000934 / / Medical Research Council / United Kingdom U01-HL72515 / HL / NHLBI NIH HHS / United States R01 AG031890 / AG / NIA NIH HHS / United States U01 HL069757 / HL / NHLBI NIH HHS / United States U01 HG004399 / HG / NHGRI NIH HHS / United States U01 GM074518 / GM / NIGMS NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States RC2 HG005581-02 / HG / NHGRI NIH HHS / United States U54 RR020278 / RR / NCRR NIH HHS / United States 081682 / / Wellcome Trust / United Kingdom AA13326 / AA / NIAAA NIH HHS / United States K23-DK080145 / DK / NIDDK NIH HHS / United States DK46200 / DK / NIDDK NIH HHS / United States N01-HC35129 / HC / NHLBI NIH HHS / United States U01 HL069757-10 / HL / NHLBI NIH HHS / United States CA65725 / 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