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

Andrew R Wood; Tonu Esko; Jian Yang; Sailaja Vedantam; Tune H Pers; Stefan Gustafsson; Audrey Y Chu; Karol Estrada; Jian'an Luan; Zoltán 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 Mägi; Evelin Mihailov; Eleonora Porcu; Joshua C Randall; André 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; Georg B Ehret; Bjarke Feenstra; Mary F Feitosa; Krista Fischer; Ross M Fraser; Anuj Goel; Jian Gong; Anne E Justice; Stavroula Kanoni; Aaron Isaacs; Andrew Wong; Kevin B Jacobs; Electronic Medical Records and Genomics (eMERGE) Consortium; Peter M. Visscher; Joel N. Hirschhorn; Timothy M Frayling

doi:10.1038/ng.3097

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

Andrew R Wood, Tonu Esko, Jian Yang, Sailaja Vedantam, Tune H Pers, Stefan Gustafsson, Audrey Y Chu, Karol Estrada, Jian'an Luan, Zoltán 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 KarjalainenKen Sin Lo, Adam E Locke, Reedik Mägi, Evelin Mihailov, Eleonora Porcu, Joshua C Randall, André 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, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Ross M Fraser, Anuj Goel, Jian Gong, Anne E Justice, Stavroula Kanoni, Aaron Isaacs, Andrew Wong, Kevin B Jacobs, Electronic Medical Records and Genomics (eMERGE) Consortium, Peter M. Visscher^*, Joel N. Hirschhorn^*, Timothy M Frayling^*

^*Corresponding author for this work

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 ∼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)	1173-86
Number of pages	14
Journal	Nature Genetics
Volume	46
Issue number	11
DOIs	https://doi.org/10.1038/ng.3097
Publication status	Published - Nov 2014
Externally published	Yes

Keywords

Adult
Analysis of Variance
Body Height/genetics
European Continental Ancestry Group/genetics
Genetic Variation/genetics
Genetics, Population
Genome-Wide Association Study/methods
Humans
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide/genetics

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Cite this

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., 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), 1173-86. 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 ∼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. ",

keywords = "Adult, Analysis of Variance, Body Height/genetics, European Continental Ancestry Group/genetics, Genetic Variation/genetics, Genetics, Population, Genome-Wide Association Study/methods, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide/genetics",

author = "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 Aaron Isaacs and Andrew Wong and Jacobs, {Kevin B} and {Electronic Medical Records and Genomics (eMERGE) Consortium} and Visscher, {Peter M.} and Hirschhorn, {Joel N.} and Frayling, {Timothy M}",

year = "2014",

month = nov,

doi = "10.1038/ng.3097",

language = "English",

volume = "46",

pages = "1173--86",

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, R, Ferreira, T, Jackson, AU, Karjalainen, J, Lo, KS, Locke, AE, Mägi, 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, Ehret, GB, Feenstra, B, Feitosa, MF, Fischer, K, Fraser, RM, Goel, A, Gong, J, Justice, AE, Kanoni, S, Isaacs, A, Wong, A, Jacobs, KB, Electronic Medical Records and Genomics (eMERGE) Consortium, 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. 1173-86. 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 - 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 - Isaacs, Aaron

AU - Wong, Andrew

AU - Jacobs, Kevin B

AU - Electronic Medical Records and Genomics (eMERGE) Consortium

AU - Visscher, Peter M.

AU - Hirschhorn, Joel N.

AU - Frayling, Timothy M

PY - 2014/11

Y1 - 2014/11

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.

KW - Adult

KW - Analysis of Variance

KW - Body Height/genetics

KW - European Continental Ancestry Group/genetics

KW - Genetic Variation/genetics

KW - Genetics, Population

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Oligonucleotide Array Sequence Analysis

KW - Polymorphism, Single Nucleotide/genetics

U2 - 10.1038/ng.3097

DO - 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 -