Defining the role of common variation in the genomic and biological architecture of adult human height

A.R. Wood; T. Esko; J. Yang; S. Vedantam; T.H. Pers; S. Gustafsson; A.Y. Chu; K. Estrada; J. Luan; Z. Kutalik; N. Amin; M.L. Buchkovich; D.C. Croteau-Chonka; F.R. Day; Y. Duan; T. Fall; R.S. Fehrmann; T. Ferreira; A.U. Jackson; J. Karjalainen; K.S. Lo; A.E. Locke; R. Mägi; E. Mihailov; E. Porcu; J.C. Randall; A. Scherag; A.A.E. Vinkhuyzen; H.J. Westra; T.W. Winkler; T. Workalemahu; J.H. Zhao; D. Absher; E. Albrecht; D. Anderson; J. Baron; M. Beekman; A. Demirkan; G.B. Ehret; B. Feenstra; M.F. Feitosa; K. Fischer; R.M. Fraser; A. Goel; J. Gong; A.E. Justice; S. Kanoni; M.E. Kleber; K. Kristiansson; U. Lim; Q. Helmer; D.I. Boomsma; D. Saleheen; D. Schlessinger; P.E. Slagboom; H. Snieder; T.D. Spector; K. Strauch; M. Stumvoll; J. Tuomilehto; M. Uusitupa; P. van der Harst; H. Völzke; M. Walker; N.J. Wareham; H. Watkins; H.E. Wichmann; J.F. Wilson; P. Zanen; P. Deloukas; I.M. Heid; C.M. Lindgren; K.L. Mohlke; E.K. Speliotes; U. Thorsteinsdottir; I. Barroso; C.S. Fox; K.E. North; D.P. Strachan; J.S. Beckmann; S.I. Berndt; M. Boehnke; I.B. Borecki; M.I. McCarthy; A. Metspalu; J.H. Smit; S. Pilz; N.M. van Schoor; K. Stefansson; A.G. Uitterlinden; C.M. van Duijn; L. Franke; C.J. Willer; A.L. Price; G. Lettre; R.J.F. Loos; M.N. Weedon; E. Ingelsson; J.R. O'Connell; G.R. Abecasis; D.I. Chasman; M.E. Goddard; P.M. Visscher; J.N. Hirschhorn; T.M. Frayling

doi:10.1038/ng.3097

Defining the role of common variation in the genomic and biological architecture of adult human height

A.R. Wood, T. Esko, J. Yang, S. Vedantam, T.H. Pers, S. Gustafsson, A.Y. Chu, K. Estrada, J. Luan, Z. Kutalik, N. Amin, M.L. Buchkovich, D.C. Croteau-Chonka, F.R. Day, Y. Duan, T. Fall, R.S. Fehrmann, T. Ferreira, A.U. Jackson, J. KarjalainenK.S. Lo, A.E. Locke, R. Mägi, E. Mihailov, E. Porcu, J.C. Randall, A. Scherag, A.A.E. Vinkhuyzen, H.J. Westra, T.W. Winkler, T. Workalemahu, J.H. Zhao, D. Absher, E. Albrecht, D. Anderson, J. Baron, M. Beekman, A. Demirkan, G.B. Ehret, B. Feenstra, M.F. Feitosa, K. Fischer, R.M. Fraser, A. Goel, J. Gong, A.E. Justice, S. Kanoni, M.E. Kleber, K. Kristiansson, U. Lim, Q. Helmer, D.I. Boomsma, D. Saleheen, D. Schlessinger, P.E. Slagboom, H. Snieder, T.D. Spector, K. Strauch, M. Stumvoll, J. Tuomilehto, M. Uusitupa, P. van der Harst, H. Völzke, M. Walker, N.J. Wareham, H. Watkins, H.E. Wichmann, J.F. Wilson, P. Zanen, P. Deloukas, I.M. Heid, C.M. Lindgren, K.L. Mohlke, E.K. Speliotes, U. Thorsteinsdottir, I. Barroso, C.S. Fox, K.E. North, D.P. Strachan, J.S. Beckmann, S.I. Berndt, M. Boehnke, I.B. Borecki, M.I. McCarthy, A. Metspalu, J.H. Smit, S. Pilz, N.M. van Schoor, K. Stefansson, A.G. Uitterlinden, C.M. van Duijn, L. Franke, C.J. Willer, A.L. Price, G. Lettre, R.J.F. Loos, M.N. Weedon, E. Ingelsson, J.R. O'Connell, G.R. Abecasis, D.I. Chasman, M.E. Goddard, P.M. Visscher, J.N. Hirschhorn, T.M. Frayling

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were 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/I 2-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.

Original language	English
Pages (from-to)	1173-1186
Number of pages	14
Journal	Nature Genetics
Volume	46
Issue number	11
DOIs	https://doi.org/10.1038/ng.3097
Publication status	Published - 2014

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Wood, A. R., Esko, T., Yang, J., Vedantam, S., Pers, T. H., Gustafsson, S., Chu, A. Y., Estrada, K., Luan, J., Kutalik, Z., Amin, N., Buchkovich, M. L., Croteau-Chonka, D. C., Day, F. R., Duan, Y., Fall, T., Fehrmann, R. S., Ferreira, T., Jackson, A. U., ... Frayling, T. M. (2014). Defining the role of common variation in the genomic and biological architecture of adult human height. Nature Genetics, 46(11), 1173-1186. https://doi.org/10.1038/ng.3097

Wood, A.R. ; Esko, T. ; Yang, J. ; Vedantam, S. ; Pers, T.H. ; Gustafsson, S. ; Chu, A.Y. ; Estrada, K. ; Luan, J. ; Kutalik, Z. ; Amin, N. ; Buchkovich, M.L. ; Croteau-Chonka, D.C. ; Day, F.R. ; Duan, Y. ; Fall, T. ; Fehrmann, R.S. ; Ferreira, T. ; Jackson, A.U. ; Karjalainen, J. ; Lo, K.S. ; Locke, A.E. ; Mägi, R. ; Mihailov, E. ; Porcu, E. ; Randall, J.C. ; Scherag, A. ; Vinkhuyzen, A.A.E. ; Westra, H.J. ; Winkler, T.W. ; Workalemahu, T. ; Zhao, J.H. ; Absher, D. ; Albrecht, E. ; Anderson, D. ; Baron, J. ; Beekman, M. ; Demirkan, A. ; Ehret, G.B. ; Feenstra, B. ; Feitosa, M.F. ; Fischer, K. ; Fraser, R.M. ; Goel, A. ; Gong, J. ; Justice, A.E. ; Kanoni, S. ; Kleber, M.E. ; Kristiansson, K. ; Lim, U. ; Helmer, Q. ; Boomsma, D.I. ; Saleheen, D. ; Schlessinger, D. ; Slagboom, P.E. ; Snieder, H. ; Spector, T.D. ; Strauch, K. ; Stumvoll, M. ; Tuomilehto, J. ; Uusitupa, M. ; van der Harst, P. ; Völzke, H. ; Walker, M. ; Wareham, N.J. ; Watkins, H. ; Wichmann, H.E. ; Wilson, J.F. ; Zanen, P. ; Deloukas, P. ; Heid, I.M. ; Lindgren, C.M. ; Mohlke, K.L. ; Speliotes, E.K. ; Thorsteinsdottir, U. ; Barroso, I. ; Fox, C.S. ; North, K.E. ; Strachan, D.P. ; Beckmann, J.S. ; Berndt, S.I. ; Boehnke, M. ; Borecki, I.B. ; McCarthy, M.I. ; Metspalu, A. ; Smit, J.H. ; Pilz, S. ; van Schoor, N.M. ; Stefansson, K. ; Uitterlinden, A.G. ; van Duijn, C.M. ; Franke, L. ; Willer, C.J. ; Price, A.L. ; Lettre, G. ; Loos, R.J.F. ; Weedon, M.N. ; Ingelsson, E. ; O'Connell, J.R. ; Abecasis, G.R. ; Chasman, D.I. ; Goddard, M.E. ; Visscher, P.M. ; Hirschhorn, J.N. ; Frayling, T.M. / Defining the role of common variation in the genomic and biological architecture of adult human height. In: Nature Genetics. 2014 ; Vol. 46, No. 11. pp. 1173-1186.

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title = "Defining the role of common variation in the genomic and biological architecture of adult human height",

abstract = "Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were 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/I 2-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.",

author = "A.R. Wood and T. Esko and J. Yang and S. Vedantam and T.H. Pers and S. Gustafsson and A.Y. Chu and K. Estrada and J. Luan and Z. Kutalik and N. Amin and M.L. Buchkovich and D.C. Croteau-Chonka and F.R. Day and Y. Duan and T. Fall and R.S. Fehrmann and T. Ferreira and A.U. Jackson and J. Karjalainen and K.S. Lo and A.E. Locke and R. M{\"a}gi and E. Mihailov and E. Porcu and J.C. Randall and A. Scherag and A.A.E. Vinkhuyzen and H.J. Westra and T.W. Winkler and T. Workalemahu and J.H. Zhao and D. Absher and E. Albrecht and D. Anderson and J. Baron and M. Beekman and A. Demirkan and G.B. Ehret and B. Feenstra and M.F. Feitosa and K. Fischer and R.M. Fraser and A. Goel and J. Gong and A.E. Justice and S. Kanoni and M.E. Kleber and K. Kristiansson and U. Lim and Q. Helmer and D.I. Boomsma and D. Saleheen and D. Schlessinger and P.E. Slagboom and H. Snieder and T.D. Spector and K. Strauch and M. Stumvoll and J. Tuomilehto and M. Uusitupa and {van der Harst}, P. and H. V{\"o}lzke and M. Walker and N.J. Wareham and H. Watkins and H.E. Wichmann and J.F. Wilson and P. Zanen and P. Deloukas and I.M. Heid and C.M. Lindgren and K.L. Mohlke and E.K. Speliotes and U. Thorsteinsdottir and I. Barroso and C.S. Fox and K.E. North and D.P. Strachan and J.S. Beckmann and S.I. Berndt and M. Boehnke and I.B. Borecki and M.I. McCarthy and A. Metspalu and J.H. Smit and S. Pilz and {van Schoor}, N.M. and K. Stefansson and A.G. Uitterlinden and {van Duijn}, C.M. and L. Franke and C.J. Willer and A.L. Price and G. Lettre and R.J.F. Loos and M.N. Weedon and E. Ingelsson and J.R. O'Connell and G.R. Abecasis and D.I. Chasman and M.E. Goddard and P.M. Visscher and J.N. Hirschhorn and T.M. Frayling",

year = "2014",

doi = "10.1038/ng.3097",

language = "English",

volume = "46",

pages = "1173--1186",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

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Wood, AR, Esko, T, Yang, J, Vedantam, S, Pers, TH, Gustafsson, S, Chu, AY, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, ML, Croteau-Chonka, DC, Day, FR, Duan, Y, Fall, T, Fehrmann, RS, Ferreira, T, Jackson, AU, Karjalainen, J, Lo, KS, Locke, AE, Mägi, R, Mihailov, E, Porcu, E, Randall, JC, Scherag, A, Vinkhuyzen, AAE, Westra, HJ, Winkler, TW, Workalemahu, T, Zhao, JH, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, GB, Feenstra, B, Feitosa, MF, Fischer, K, Fraser, RM, Goel, A, Gong, J, Justice, AE, Kanoni, S, Kleber, ME, Kristiansson, K, Lim, U, Helmer, Q, Boomsma, DI, Saleheen, D, Schlessinger, D, Slagboom, PE, Snieder, H, Spector, TD, Strauch, K, Stumvoll, M, Tuomilehto, J, Uusitupa, M, van der Harst, P, Völzke, H, Walker, M, Wareham, NJ, Watkins, H, Wichmann, HE, Wilson, JF, Zanen, P, Deloukas, P, Heid, IM, Lindgren, CM, Mohlke, KL, Speliotes, EK, Thorsteinsdottir, U, Barroso, I, Fox, CS, North, KE, Strachan, DP, Beckmann, JS, Berndt, SI, Boehnke, M, Borecki, IB, McCarthy, MI, Metspalu, A, Smit, JH, Pilz, S, van Schoor, NM, Stefansson, K, Uitterlinden, AG, van Duijn, CM, Franke, L, Willer, CJ, Price, AL, Lettre, G, Loos, RJF, Weedon, MN, Ingelsson, E, O'Connell, JR, Abecasis, GR, Chasman, DI, Goddard, ME, Visscher, PM, Hirschhorn, JN & Frayling, TM 2014, 'Defining the role of common variation in the genomic and biological architecture of adult human height', Nature Genetics, vol. 46, no. 11, pp. 1173-1186. https://doi.org/10.1038/ng.3097

Defining the role of common variation in the genomic and biological architecture of adult human height. / Wood, A.R.; Esko, T.; Yang, J.; Vedantam, S.; Pers, T.H.; Gustafsson, S.; Chu, A.Y.; Estrada, K.; Luan, J.; Kutalik, Z.; Amin, N.; Buchkovich, M.L.; Croteau-Chonka, D.C.; Day, F.R.; Duan, Y.; Fall, T.; Fehrmann, R.S.; Ferreira, T.; Jackson, A.U.; Karjalainen, J.; Lo, K.S.; Locke, A.E.; Mägi, R.; Mihailov, E.; Porcu, E.; Randall, J.C.; Scherag, A.; Vinkhuyzen, A.A.E.; Westra, H.J.; Winkler, T.W.; Workalemahu, T.; Zhao, J.H.; Absher, D.; Albrecht, E.; Anderson, D.; Baron, J.; Beekman, M.; Demirkan, A.; Ehret, G.B.; Feenstra, B.; Feitosa, M.F.; Fischer, K.; Fraser, R.M.; Goel, A.; Gong, J.; Justice, A.E.; Kanoni, S.; Kleber, M.E.; Kristiansson, K.; Lim, U.; Helmer, Q.; Boomsma, D.I.; Saleheen, D.; Schlessinger, D.; Slagboom, P.E.; Snieder, H.; Spector, T.D.; Strauch, K.; Stumvoll, M.; Tuomilehto, J.; Uusitupa, M.; van der Harst, P.; Völzke, H.; Walker, M.; Wareham, N.J.; Watkins, H.; Wichmann, H.E.; Wilson, J.F.; Zanen, P.; Deloukas, P.; Heid, I.M.; Lindgren, C.M.; Mohlke, K.L.; Speliotes, E.K.; Thorsteinsdottir, U.; Barroso, I.; Fox, C.S.; North, K.E.; Strachan, D.P.; Beckmann, J.S.; Berndt, S.I.; Boehnke, M.; Borecki, I.B.; McCarthy, M.I.; Metspalu, A.; Smit, J.H.; Pilz, S.; van Schoor, N.M.; Stefansson, K.; Uitterlinden, A.G.; van Duijn, C.M.; Franke, L.; Willer, C.J.; Price, A.L.; Lettre, G.; Loos, R.J.F.; Weedon, M.N.; Ingelsson, E.; O'Connell, J.R.; Abecasis, G.R.; Chasman, D.I.; Goddard, M.E.; Visscher, P.M.; Hirschhorn, J.N.; Frayling, T.M.

In: Nature Genetics, Vol. 46, No. 11, 2014, p. 1173-1186.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Defining the role of common variation in the genomic and biological architecture of adult human height

AU - Wood, A.R.

AU - Esko, T.

AU - Yang, J.

AU - Vedantam, S.

AU - Pers, T.H.

AU - Gustafsson, S.

AU - Chu, A.Y.

AU - Estrada, K.

AU - Luan, J.

AU - Kutalik, Z.

AU - Amin, N.

AU - Buchkovich, M.L.

AU - Croteau-Chonka, D.C.

AU - Day, F.R.

AU - Duan, Y.

AU - Fall, T.

AU - Fehrmann, R.S.

AU - Ferreira, T.

AU - Jackson, A.U.

AU - Karjalainen, J.

AU - Lo, K.S.

AU - Locke, A.E.

AU - Mägi, R.

AU - Mihailov, E.

AU - Porcu, E.

AU - Randall, J.C.

AU - Scherag, A.

AU - Vinkhuyzen, A.A.E.

AU - Westra, H.J.

AU - Winkler, T.W.

AU - Workalemahu, T.

AU - Zhao, J.H.

AU - Absher, D.

AU - Albrecht, E.

AU - Anderson, D.

AU - Baron, J.

AU - Beekman, M.

AU - Demirkan, A.

AU - Ehret, G.B.

AU - Feenstra, B.

AU - Feitosa, M.F.

AU - Fischer, K.

AU - Fraser, R.M.

AU - Goel, A.

AU - Gong, J.

AU - Justice, A.E.

AU - Kanoni, S.

AU - Kleber, M.E.

AU - Kristiansson, K.

AU - Lim, U.

AU - Helmer, Q.

AU - Boomsma, D.I.

AU - Saleheen, D.

AU - Schlessinger, D.

AU - Slagboom, P.E.

AU - Snieder, H.

AU - Spector, T.D.

AU - Strauch, K.

AU - Stumvoll, M.

AU - Tuomilehto, J.

AU - Uusitupa, M.

AU - van der Harst, P.

AU - Völzke, H.

AU - Walker, M.

AU - Wareham, N.J.

AU - Watkins, H.

AU - Wichmann, H.E.

AU - Wilson, J.F.

AU - Zanen, P.

AU - Deloukas, P.

AU - Heid, I.M.

AU - Lindgren, C.M.

AU - Mohlke, K.L.

AU - Speliotes, E.K.

AU - Thorsteinsdottir, U.

AU - Barroso, I.

AU - Fox, C.S.

AU - North, K.E.

AU - Strachan, D.P.

AU - Beckmann, J.S.

AU - Berndt, S.I.

AU - Boehnke, M.

AU - Borecki, I.B.

AU - McCarthy, M.I.

AU - Metspalu, A.

AU - Smit, J.H.

AU - Pilz, S.

AU - van Schoor, N.M.

AU - Stefansson, K.

AU - Uitterlinden, A.G.

AU - van Duijn, C.M.

AU - Franke, L.

AU - Willer, C.J.

AU - Price, A.L.

AU - Lettre, G.

AU - Loos, R.J.F.

AU - Weedon, M.N.

AU - Ingelsson, E.

AU - O'Connell, J.R.

AU - Abecasis, G.R.

AU - Chasman, D.I.

AU - Goddard, M.E.

AU - Visscher, P.M.

AU - Hirschhorn, J.N.

AU - Frayling, T.M.

PY - 2014

Y1 - 2014

N2 - Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were 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/I 2-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.

AB - Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were 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/I 2-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.

U2 - 10.1038/ng.3097

DO - 10.1038/ng.3097

M3 - Article

VL - 46

SP - 1173

EP - 1186

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 11

ER -

Defining the role of common variation in the genomic and biological architecture of adult human height

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