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

AUTHOR GROUP; 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:https://doi.org/10.1038/ng.3097

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

AUTHOR GROUP, 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. WatkinsH.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

1295 Citations (Scopus)

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 ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% 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/β-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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AUTHOR GROUP, 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., ... 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

@article{04acccd8c8a44bebbc3031642871da42,

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 ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% 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/β-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 = "{AUTHOR GROUP} and Wood, {Andrew R.} and Tonu Esko and Jian Yang and Sailaja Vedantam and Pers, {Tune H.} and Stefan Gustafsson and Chu, {Audrey Y.} and Karol Estrada and Jian'an Luan and Zolt{\'a}n Kutalik and Najaf Amin and Buchkovich, {Martin L.} and Croteau-Chonka, {Damien C.} and Day, {Felix R.} and Yanan Duan and Tove Fall and Rudolf Fehrmann and Teresa Ferreira and Jackson, {Anne U.} and Juha Karjalainen and Lo, {Ken Sin} and Locke, {Adam E.} and Reedik M{\"a}gi and Evelin Mihailov and Eleonora Porcu and Randall, {Joshua C.} and Andr{\'e} Scherag and Vinkhuyzen, {Anna A. E.} and Harm-Jan Westra and Winkler, {Thomas W.} and Tsegaselassie Workalemahu and Zhao, {Jing Hua} and Devin Absher and Eva Albrecht and Denise Anderson and Jeffrey Baron and Marian Beekman and Ayse Demirkan and Ehret, {Georg B.} and Bjarke Feenstra and Feitosa, {Mary F.} and Krista Fischer and Fraser, {Ross M.} and Anuj Goel and Jian Gong and Justice, {Anne E.} and Stavroula Kanoni and {van der Velde}, Nathalie and Hovingh, {G. Kees} and Kastelein, {John J. P.} 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 = "https://doi.org/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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AUTHOR GROUP, 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

TY - JOUR

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

AU - AUTHOR GROUP

AU - Wood, Andrew R.

AU - Esko, Tonu

AU - Yang, Jian

AU - Vedantam, Sailaja

AU - Pers, Tune H.

AU - Gustafsson, Stefan

AU - Chu, Audrey Y.

AU - Estrada, Karol

AU - Luan, Jian'an

AU - Kutalik, Zoltán

AU - Amin, Najaf

AU - Buchkovich, Martin L.

AU - Croteau-Chonka, Damien C.

AU - Day, Felix R.

AU - Duan, Yanan

AU - Fall, Tove

AU - Fehrmann, Rudolf

AU - Ferreira, Teresa

AU - Jackson, Anne U.

AU - Karjalainen, Juha

AU - Lo, Ken Sin

AU - Locke, Adam E.

AU - Mägi, Reedik

AU - Mihailov, Evelin

AU - Porcu, Eleonora

AU - Randall, Joshua C.

AU - Scherag, André

AU - Vinkhuyzen, Anna A. E.

AU - Westra, Harm-Jan

AU - Winkler, Thomas W.

AU - Workalemahu, Tsegaselassie

AU - Zhao, Jing Hua

AU - Absher, Devin

AU - Albrecht, Eva

AU - Anderson, Denise

AU - Baron, Jeffrey

AU - Beekman, Marian

AU - Demirkan, Ayse

AU - Ehret, Georg B.

AU - Feenstra, Bjarke

AU - Feitosa, Mary F.

AU - Fischer, Krista

AU - Fraser, Ross M.

AU - Goel, Anuj

AU - Gong, Jian

AU - Justice, Anne E.

AU - Kanoni, Stavroula

AU - van der Velde, Nathalie

AU - Hovingh, G. Kees

AU - Kastelein, John J. P.

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 ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% 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/β-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 ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% 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/β-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 - https://doi.org/10.1038/ng.3097

DO - https://doi.org/10.1038/ng.3097

M3 - Article

C2 - 25282103

SN - 1061-4036

VL - 46

SP - 1173

EP - 1186

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -