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

被引：279

作者：

Winkler, Thomas W. ^{[1
]}

Justice, Anne E. ^{[2
]}

Graff, Mariaelisa ^{[2
]}

Barata, Llilda ^{[3
]}

Feitosa, Mary F. ^{[3
]}

Chu, Su ^{[4
]}

Czajkowski, Jacek ^{[3
]}

Esko, Tonu ^{[5
,6
,7
,8
,9
,10
,11
]}

Fall, Tove ^{[12
,13
]}

Kilpelainen, Tuomas O. ^{[14
,15
]}

Lu, Yingchang ^{[16
,17
]}

Magi, Reedik ^{[10
,18
]}

Mihailov, Evelin ^{[10
]}

Pers, Tune H. ^{[7
,8
,9
,11
,19
]}

Rueeger, Sina ^{[20
,21
]}

Teumer, Alexander ^{[22
,23
]}

Ehret, Georg B. ^{[24
,25
]}

Ferreira, Teresa ^{[18
]}

Heard-Costa, Nancy L. ^{[26
,27
]}

Karjalainen, Juha ^{[28
]}

Lagou, Vasiliki ^{[18
,29
]}

Mahajan, Anubha ^{[18
]}

Neinast, Michael D. ^{[30
]}

Prokopenko, Inga ^{[18
,29
,31
,32
]}

Simino, Jeannette ^{[33
]}

Teslovich, Tanya M. ^{[4
]}

Jansen, Rick ^{[34
,35
]}

Westra, Harm-Jan ^{[36
,37
,38
,39
,40
]}

White, Charles C. ^{[41
]}

Absher, Devin ^{[42
]}

Ahluwalia, Tarunveer S. ^{[14
,43
,44
]}

Ahmad, Shafqat ^{[45
]}

Albrecht, Eva ^{[46
]}

Alves, Alexessander Couto ^{[47
]}

Bragg-Gresham, Jennifer L. ^{[4
]}

de Craen, Anton J. M. ^{[48
]}

Bis, Joshua C. ^{[49
,50
]}

Bonnefond, Amelie ^{[51
,52
,53
]}

Boucher, Gabrielle ^{[54
]}

Cadby, Gemma ^{[55
]}

Cheng, Yu-Ching ^{[56
,57
]}

Chiang, Charleston W. K. ^{[58
]}

Delgado, Graciela ^{[59
]}

Demirkan, Ayse ^{[60
]}

Dueker, Nicole ^{[61
]}

Eklund, Niina ^{[62
,63
,64
]}

Eiriksdottir, Gudny ^{[65
]}

Eriksson, Joel ^{[66
]}

Feenstra, Bjarke ^{[67
]}

Fischer, Krista ^{[10
]}

机构：

[1] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany

[2] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[3] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[4] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[5] MIT, Broad Inst, Cambridge, MA 02139 USA

[6] Harvard Univ, Cambridge, MA 02138 USA

[7] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA

[8] Boston Childrens Hosp, Div Genet, Boston, MA USA

[9] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA

[10] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[11] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[12] Uppsala Univ, Sci Life Lab, Uppsala, Sweden

[13] Uppsala Univ, Dept Med Sci Mol Epidemiol, Uppsala, Sweden

[14] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark

[15] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[16] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[17] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA

[18] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[19] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA

[20] Swiss Inst Bioinformat, Lausanne, Switzerland

[21] Univ Hosp Lausanne CHUV, Inst Social & Prevent Med, Lausanne, Switzerland

[22] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[23] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[24] Univ Hosp Geneva, Dept Specialties Internal Med, Geneva, Switzerland

[25] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA

[26] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA

[27] NHLBI, Framingham Heart Study, Framingham, MA USA

[28] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[29] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[30] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[31] Hammersmith Hosp, London, England

[32] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England

[33] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA

[34] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands

[35] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands

[36] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[37] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[38] Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA

[39] Harvard Univ, Sch Med, Boston, MA 02115 USA

[40] Partners Ctr Personalized Genet Med, Boston, MA USA

[41] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA

[42] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[43] Steno Diabet Ctr A S, Gentofte, Denmark

[44] Univ Copenhagen, Herlev & Gentofte Hosp, COPSAC, Copenhagen, Denmark

[45] Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden

[46] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[47] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC Hlth Protect Agcy HPA Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England

[48] Leiden Univ Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands

[49] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[50] Univ Washington, Dept Med, Seattle, WA 98195 USA

来源：

PLOS GENETICS | 2015年 / 11卷 / 10期

基金：

欧洲研究理事会; 美国国家卫生研究院; 英国惠康基金; 英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 美国食品与农业研究所; 新加坡国家研究基金会; 瑞士国家科学基金会; 瑞典研究理事会; 俄罗斯基础研究基金会; 芬兰科学院; 澳大利亚研究理事会;

关键词：

SELF-REPORTED HEIGHT; FAT DISTRIBUTION; MASS INDEX; NATURAL MENOPAUSE; WEIGHT-GAIN; COMMON SNPS; LIFE-COURSE; LOCI; OBESITY; METAANALYSIS;

D O I：

10.1371/journal.pgen.1005378

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 similar 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 providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

引用

页码：1 / 42

页数：42

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