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

Thomas W Winkler; Anne E Justice; Mariaelisa Graff; Llilda Barata; Mary F Feitosa; Su Chu; Jacek Czajkowski; Tõnu Esko; Tove Fall; Tuomas O Kilpeläinen; Yingchang Lu; Reedik Mägi; Evelin Mihailov; Tune H Pers; Sina Rüeger; Alexander Teumer; Georg B Ehret; Teresa Ferreira; Nancy L Heard-Costa; Juha Karjalainen; Vasiliki Lagou; Anubha Mahajan; Michael D Neinast; Inga Prokopenko; Jeannette Simino; Tanya M Teslovich; Rick Jansen; Harm-Jan Westra; Charles C White; Devin Absher; Tarun Veer Singh Ahluwalia; Shafqat Ahmad; Eva Albrecht; Alexessander Couto Alves; Jennifer L Bragg-Gresham; Anton J M de Craen; Joshua C Bis; Amélie Bonnefond; Gabrielle Boucher; Karina Banasik; Niels Grarup; Torben Hansen; Torben Jørgensen; Nikolaj T Krarup; Allan Linneberg; Rasmus Ribel-Madsen; Thomas H Sparsø; Mads Melbye; Oluf Pedersen; Thorkild I A Sørensen; CHARGE 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

Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha KarjalainenVasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarun Veer Singh Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Karina Banasik, Niels Grarup, Torben Hansen, Torben Jørgensen, Nikolaj T Krarup, Allan Linneberg, Rasmus Ribel-Madsen, Thomas H Sparsø, Mads Melbye, Oluf Pedersen, Thorkild I A Sørensen, CHARGE Consortium

158 Citations (Scopus)

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, WHR_adjBMI), 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 WHR_adjBMI, 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 WHR_adjBMI 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 WHR_adjBMI, 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 WHR_adjBMI. 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 WHR_adjBMI. 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
Article number	e1005378
Journal	P L o S Genetics
Volume	11
Issue number	10
Pages (from-to)	1-42
Number of pages	42
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1005378
Publication status	Published - 1 Oct 2015

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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., ... CHARGE Consortium (2015). The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. P L o S Genetics, 11(10), 1-42. Article e1005378. https://doi.org/10.1371/journal.pgen.1005378

Winkler, TW, Justice, AE, Graff, M, Barata, L, Feitosa, MF, Chu, S, Czajkowski, J, Esko, T, Fall, T, Kilpeläinen, TO, Lu, Y, Mägi, R, Mihailov, E, Pers, TH, Rüeger, S, Teumer, A, Ehret, GB, Ferreira, T, Heard-Costa, NL, Karjalainen, J, Lagou, V, Mahajan, A, Neinast, MD, Prokopenko, I, Simino, J, Teslovich, TM, Jansen, R, Westra, H-J, White, CC, Absher, D, Ahluwalia, TVS, Ahmad, S, Albrecht, E, Alves, AC, Bragg-Gresham, JL, de Craen, AJM, Bis, JC, Bonnefond, A, Boucher, G, Banasik, K , Grarup, N , Hansen, T, Jørgensen, T, Krarup, NT, Linneberg, A, Ribel-Madsen, R, Sparsø, TH, Melbye, M , Pedersen, O , Sørensen, TIA & CHARGE Consortium 2015, 'The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study', P L o S Genetics, vol. 11, no. 10, e1005378, pp. 1-42. https://doi.org/10.1371/journal.pgen.1005378

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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 ~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.",

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year = "2015",

month = oct,

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

language = "English",

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journal = "P L o S Genetics",

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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, Tarun Veer Singh

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 - Banasik, Karina

AU - Grarup, Niels

AU - Hansen, Torben

AU - Jørgensen, Torben

AU - Krarup, Nikolaj T

AU - Linneberg, Allan

AU - Ribel-Madsen, Rasmus

AU - Sparsø, Thomas H

AU - Melbye, Mads

AU - Pedersen, Oluf

AU - Sørensen, Thorkild I A

AU - CHARGE 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.

U2 - 10.1371/journal.pgen.1005378

DO - 10.1371/journal.pgen.1005378

M3 - Journal article

C2 - 26426971

SN - 1553-7390

VL - 11

SP - 1

EP - 42

JO - P L o S Genetics

JF - P L o S Genetics

IS - 10

M1 - e1005378

ER -

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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