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

Elect Med Records & Genom eMERGE C; MIGen Consortium; PAGE Consortium; LifeLines Cohort Study; Andrew R. Wood; Tonu Esko; Jian Yang; Sailaja Vedantam; Tune H. Pers; Stefan Gustafsson; Audrey Y. Chun; Karol Estrada; Jian'an Luan; Zoltan Kutalik; Najaf Amin; Martin L. Buchkovich; Damien C. Croteau-Chonka; Felix R. Day; Yanan Duan; Tove Fall; Rudolf Fehrmann; Teresa Ferreira; Anne U. Jackson; Juha Karjalainen; Ken Sin Lo; Adam E. Locke; Reedik Maegi; Evelin Mihailov; Eleonora Porcu; Joshua C. Randall; Andre Scherag; Anna A. E. Vinkhuyzen; Harm-Jan Westra; Thomas W. Winkler; Tsegaselassie Workalemahu; Jing Hua Zhao; Devin Absher; Eva Albrecht; Denise Anderson; Jeffrey Baron; Marian Beekman; Ayse Demirkan; Ross M. Fraser; Jennifer L. Bolton; Caroline Hayward; Stela McLachlan; Alan F. Wright; Harry Campbell; Andrew D. Morris; Jackie F. Price; Igor Rudan; Mark Walker; James F. Wilson; Peter M. Visscher

doi:10.1038/ng.3097

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

Elect Med Records & Genom eMERGE C, MIGen Consortium, PAGE Consortium, LifeLines Cohort Study, Andrew R. Wood, Tonu Esko, Jian Yang, Sailaja Vedantam, Tune H. Pers, Stefan Gustafsson, Audrey Y. Chun, Karol Estrada, Jian'an Luan, Zoltan Kutalik, Najaf Amin, Martin L. Buchkovich, Damien C. Croteau-Chonka, Felix R. Day, Yanan Duan, Tove FallRudolf Fehrmann, Teresa Ferreira, Anne U. Jackson, Juha Karjalainen, Ken Sin Lo, Adam E. Locke, Reedik Maegi, Evelin Mihailov, Eleonora Porcu, Joshua C. Randall, Andre Scherag, Anna A. E. Vinkhuyzen, Harm-Jan Westra, Thomas W. Winkler, Tsegaselassie Workalemahu, Jing Hua Zhao, Devin Absher, Eva Albrecht, Denise Anderson, Jeffrey Baron, Marian Beekman, Ayse Demirkan, Ross M. Fraser, Jennifer L. Bolton, Caroline Hayward, Stela McLachlan, Alan F. Wright, Harry Campbell, Andrew D. Morris, Jackie F. Price, Igor Rudan, Mark Walker, James F. Wilson, Peter M. Visscher^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 similar to 2,000, similar to 3,700 and similar to 9,500 SNPs explained similar to 21%, similar to 24% and similar to 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/beta-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 - 5 Oct 2014

Keywords / Materials (for Non-textual outputs)

GENETIC-VARIATION
COMPLEX TRAITS
HERITABILITY
MUTATIONS
SNPS

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10.1038/ng.3097

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Elect Med Records & Genom eMERGE C, MIGen Consortium, PAGE Consortium, LifeLines Cohort Study, Wood, A. R., Esko, T., Yang, J., Vedantam, S., Pers, T. H., Gustafsson, S., Chun, A. Y., Estrada, K., Luan, J., Kutalik, Z., Amin, N., Buchkovich, M. L., Croteau-Chonka, D. C., Day, F. R., Duan, Y., ... Visscher, P. 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

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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 similar to 2,000, similar to 3,700 and similar to 9,500 SNPs explained similar to 21%, similar to 24% and similar to 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/beta-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.",

keywords = "GENETIC-VARIATION, COMPLEX TRAITS, HERITABILITY, MUTATIONS, SNPS",

author = "{Elect Med Records & Genom eMERGE C} and {MIGen Consortium} and {PAGE Consortium} and {LifeLines Cohort Study} and Wood, {Andrew R.} and Tonu Esko and Jian Yang and Sailaja Vedantam and Pers, {Tune H.} and Stefan Gustafsson and Chun, {Audrey Y.} and Karol Estrada and Jian'an Luan and Zoltan 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 Maegi and Evelin Mihailov and Eleonora Porcu and Randall, {Joshua C.} and Andre 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 Fraser, {Ross M.} and Bolton, {Jennifer L.} and Caroline Hayward and Stela McLachlan and Wright, {Alan F.} and Harry Campbell and Morris, {Andrew D.} and Price, {Jackie F.} and Igor Rudan and Mark Walker and Wilson, {James F.} and Visscher, {Peter M.}",

year = "2014",

month = oct,

day = "5",

doi = "10.1038/ng.3097",

language = "English",

volume = "46",

pages = "1173--1186",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

}

Elect Med Records & Genom eMERGE C, MIGen Consortium, PAGE Consortium, LifeLines Cohort Study, Wood, AR, Esko, T, Yang, J, Vedantam, S, Pers, TH, Gustafsson, S, Chun, AY, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, ML, Croteau-Chonka, DC, Day, FR, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, AU, Karjalainen, J, Lo, KS, Locke, AE, Maegi, R, Mihailov, E, Porcu, E, Randall, JC, Scherag, A, Vinkhuyzen, AAE, Westra, H-J, Winkler, TW, Workalemahu, T, Zhao, JH, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Fraser, RM, Bolton, JL, Hayward, C, McLachlan, S, Wright, AF, Campbell, H , Morris, AD , Price, JF , Rudan, I, Walker, M, Wilson, JF & Visscher, PM 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 - Elect Med Records & Genom eMERGE C

AU - MIGen Consortium

AU - PAGE Consortium

AU - LifeLines Cohort Study

AU - Wood, Andrew R.

AU - Esko, Tonu

AU - Yang, Jian

AU - Vedantam, Sailaja

AU - Pers, Tune H.

AU - Gustafsson, Stefan

AU - Chun, Audrey Y.

AU - Estrada, Karol

AU - Luan, Jian'an

AU - Kutalik, Zoltan

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 - Maegi, Reedik

AU - Mihailov, Evelin

AU - Porcu, Eleonora

AU - Randall, Joshua C.

AU - Scherag, Andre

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 - Fraser, Ross M.

AU - Bolton, Jennifer L.

AU - Hayward, Caroline

AU - McLachlan, Stela

AU - Wright, Alan F.

AU - Campbell, Harry

AU - Morris, Andrew D.

AU - Price, Jackie F.

AU - Rudan, Igor

AU - Walker, Mark

AU - Wilson, James F.

AU - Visscher, Peter M.

PY - 2014/10/5

Y1 - 2014/10/5

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 similar to 2,000, similar to 3,700 and similar to 9,500 SNPs explained similar to 21%, similar to 24% and similar to 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/beta-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 similar to 2,000, similar to 3,700 and similar to 9,500 SNPs explained similar to 21%, similar to 24% and similar to 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/beta-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.

KW - GENETIC-VARIATION

KW - COMPLEX TRAITS

KW - HERITABILITY

KW - MUTATIONS

KW - SNPS

U2 - 10.1038/ng.3097

DO - 10.1038/ng.3097

M3 - Article

SN - 1061-4036

VL - 46

SP - 1173

EP - 1186

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

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Keywords / Materials (for Non-textual outputs)

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