The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

CHARGE Consortium; DIAGRAM Consortium; GLGC Consortium; Global-BPGen Consortium; ICBP Consortium; MAGIC Consortium; arcOGEN Consortium

doi:10.1371/journal.pgen.1005378

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

CHARGE Consortium
, DIAGRAM Consortium
, GLGC Consortium
, Global-BPGen Consortium
, ICBP Consortium
, MAGIC Consortium
, arcOGEN Consortium

Twin Research & Genetic Epidemiology

University of Regensburg
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, United States of America; Estonian Genome Center, Univeristy of Tartu, Tartu, Estonia; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Estonian Genome Center, Univeristy of Tartu, Tartu, Estonia; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
Lausanne University Hospital
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva, Switzerland; Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America; National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham, Massachusetts, United States of America.
University of Oxford
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom; Hammersmith Hospital, London, United Kingdom; Department of Genomics of Common Diseases, School of Public Health, Imperial College London, London, United Kingdom.
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America.
Boston University
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center A/S, Gentofte, Denmark; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
University of Western Australia
VA Maryland Health Care System, Baltimore, Maryland, United States of America; University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, United States of America.
University of California, Los Angeles
Universiy of Maryland School of Medicine, Department of Epidemiology & Public Health, Baltimore, Maryland, United States of America.
Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Pharmaceutical Sciences, University of Iceland, 107 Reykjavík, Iceland;
University of North Carolina at Chapel Hill
Washington University School of Medicine in St. Louis
University of Michigan
Uppsala University
Icahn School of Medicine at Mount Sinai
Estonian Biobank, Estonian Genome Center, University of Tartu, Tartu, Estonia.
University of Groningen
University of Texas Southwestern Medical Center
VU Amsterdam
HudsonAlpha Institute for Biotechnology
Skåne University Hospital
Imperial College London
LUMC Leiden University Medical Center
University of Washington
University of Lille
Montreal Heart Inst
Heidelberg University
Erasmus University Medical Center
University of Helsinki
King's College London

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

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Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Original language	English
Pages (from-to)	e1005378
Journal	PL o S Genetics
Volume	11
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1005378
Publication status	Published - 1 Oct 2015

Keywords

Adult
Age Factors
Aged
Body Mass Index
Body Size
Chromosome Mapping
European Continental Ancestry Group
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Sex Characteristics
Waist-Hip Ratio
Journal Article
Meta-Analysis

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The Influence of Age_WINKLER_Published1October2015_Publicdomain VoR CC0Final published version, 1.46 MBLicence: CC0

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Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study
Winkler, T. W., Justice, A. E., Graff, M., Barata, L., Feitosa, M. F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpeläinen, T. O., Lu, Y., Mägi, R., Mihailov, E., Pers, T. H., Rüeger, S., Teumer, A., Ehret, G. B., Ferreira, T., Heard-Costa, N. L. & Karjalainen, J. & 31 others, Lagou, V., Mahajan, A., Neinast, M. D., Prokopenko, I., Simino, J., Teslovich, T. M., Jansen, R., Westra, H.-J., White, C. C., Absher, D., Ahluwalia, T. S., Ahmad, S., Albrecht, E., Alves, A. C., Bragg-Gresham, J. L., de Craen, A. J. M., Bis, J. C., Lehne, B., Wilson, J. F., Wong, A., Zhao, J. H., Hysi, P. G., Kyriakou, T., Liu, Y.-P., Menni, C., Bennett, D. A., Bornstein, S. R., Chambers, J. C., James, A. L., Spector, T. D. & arcOGEN Consortium, Jun 2016, In: PL o S Genetics. 12, 6, p. e1006166
Research output: Contribution to journal › Article › peer-review

Open Access
14 Citations (Scopus)

Cite this

@article{21320a0144134ba4b6caff9cc1206bb0,

title = "The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study",

abstract = "Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to \textasciitilde{}2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5\%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.",

keywords = "Adult, Age Factors, Aged, Body Mass Index, Body Size, Chromosome Mapping, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Sex Characteristics, Waist-Hip Ratio, Journal Article, Meta-Analysis",

author = "Winkler, \{Thomas W.\} and Justice, \{Anne E.\} and Mariaelisa Graff and Llilda Barata and Feitosa, \{Mary F.\} and Su Chu and Jacek Czajkowski and T{\~o}nu Esko and Tove Fall and Kilpel{\"a}inen, \{Tuomas O.\} and Yingchang Lu and Reedik M{\"a}gi and Evelin Mihailov and Pers, \{Tune H.\} and Sina R{\"u}eger and Alexander Teumer and Ehret, \{Georg B.\} and Teresa Ferreira and Heard-Costa, \{Nancy L.\} and Juha Karjalainen and Vasiliki Lagou and Anubha Mahajan and Neinast, \{Michael D.\} and Inga Prokopenko and Jeannette Simino and Teslovich, \{Tanya M.\} and Rick Jansen and Harm-Jan Westra and White, \{Charles C.\} and Devin Absher and Ahluwalia, \{Tarunveer S.\} and Shafqat Ahmad and Eva Albrecht and Alves, \{Alexessander Couto\} and Bragg-Gresham, \{Jennifer L.\} and \{de Craen\}, \{Anton J. M.\} and Bis, \{Joshua C.\} and Am{\'e}lie Bonnefond and Gabrielle Boucher and Gemma Cadby and Yu-Ching Cheng and Chiang, \{Charleston W. K.\} and Graciela Delgado and Ayse Demirkan and Nicole Dueker and Niina Eklund and Gudny Eiriksdottir and Hysi, \{Pirro G.\} and Cristina Menni and Spector, \{Tim D.\} and \{CHARGE Consortium\} and \{DIAGRAM Consortium\} and \{GLGC Consortium\} and \{Global-BPGen Consortium\} and \{ICBP Consortium\} and \{MAGIC Consortium\} and \{arcOGEN Consortium\}",

year = "2015",

month = oct,

day = "1",

doi = "10.1371/journal.pgen.1005378",

language = "English",

volume = "11",

pages = "e1005378",

journal = "PL o S Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

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TY - JOUR

T1 - The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape

T2 - A Large-Scale Genome-Wide Interaction Study

AU - Winkler, Thomas W.

AU - Justice, Anne E.

AU - Graff, Mariaelisa

AU - Barata, Llilda

AU - Feitosa, Mary F.

AU - Chu, Su

AU - Czajkowski, Jacek

AU - Esko, Tõnu

AU - Fall, Tove

AU - Kilpeläinen, Tuomas O.

AU - Lu, Yingchang

AU - Mägi, Reedik

AU - Mihailov, Evelin

AU - Pers, Tune H.

AU - Rüeger, Sina

AU - Teumer, Alexander

AU - Ehret, Georg B.

AU - Ferreira, Teresa

AU - Heard-Costa, Nancy L.

AU - Karjalainen, Juha

AU - Lagou, Vasiliki

AU - Mahajan, Anubha

AU - Neinast, Michael D.

AU - Prokopenko, Inga

AU - Simino, Jeannette

AU - Teslovich, Tanya M.

AU - Jansen, Rick

AU - Westra, Harm-Jan

AU - White, Charles C.

AU - Absher, Devin

AU - Ahluwalia, Tarunveer S.

AU - Ahmad, Shafqat

AU - Albrecht, Eva

AU - Alves, Alexessander Couto

AU - Bragg-Gresham, Jennifer L.

AU - de Craen, Anton J. M.

AU - Bis, Joshua C.

AU - Bonnefond, Amélie

AU - Boucher, Gabrielle

AU - Cadby, Gemma

AU - Cheng, Yu-Ching

AU - Chiang, Charleston W. K.

AU - Delgado, Graciela

AU - Demirkan, Ayse

AU - Dueker, Nicole

AU - Eklund, Niina

AU - Eiriksdottir, Gudny

AU - Hysi, Pirro G.

AU - Menni, Cristina

AU - Spector, Tim D.

AU - CHARGE Consortium

AU - DIAGRAM Consortium

AU - GLGC Consortium

AU - Global-BPGen Consortium

AU - ICBP Consortium

AU - MAGIC Consortium

AU - arcOGEN Consortium

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

AB - Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

KW - Adult

KW - Age Factors

KW - Aged

KW - Body Mass Index

KW - Body Size

KW - Chromosome Mapping

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Sex Characteristics

KW - Waist-Hip Ratio

KW - Journal Article

KW - Meta-Analysis

U2 - 10.1371/journal.pgen.1005378

DO - 10.1371/journal.pgen.1005378

M3 - Article

C2 - 26426971

SN - 1553-7390

VL - 11

SP - e1005378

JO - PL o S Genetics

JF - PL o S Genetics

IS - 10

ER -

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Abstract

Keywords

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Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

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