The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
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 TS., Ahmad S., Albrecht E., Alves AC., Bragg-Gresham JL., de Craen AJM., Bis JC., Bonnefond A., Boucher G., Cadby G., Cheng Y-C., Chiang CWK., Delgado G., Demirkan A., Dueker N., Eklund N., Eiriksdottir G., Eriksson J., Feenstra B., Fischer K., Frau F., Galesloot TE., Geller F., Goel A., Gorski M., Grammer TB., Gustafsson S., Haitjema S., Hottenga J-J., Huffman JE., Jackson AU., Jacobs KB., Johansson Å., Kaakinen M., Kleber ME., Lahti J., Mateo Leach I., Lehne B., Liu Y., Lo KS., Lorentzon M., Luan J., Madden PAF., Mangino M., McKnight B., Medina-Gomez C., Monda KL., Montasser ME., Müller G., Müller-Nurasyid M., Nolte IM., Panoutsopoulou K., Pascoe L., Paternoster L., Rayner NW., Renström F., Rizzi F., Rose LM., Ryan KA., Salo P., Sanna S., Scharnagl H., Shi J., Smith AV., Southam L., Stančáková A., Steinthorsdottir V., Strawbridge RJ., Sung YJ., Tachmazidou I., Tanaka T., Thorleifsson G., Trompet S., Pervjakova N., Tyrer JP., Vandenput L., van der Laan SW., van der Velde N., van Setten J., van Vliet-Ostaptchouk JV., Verweij N., Vlachopoulou E., Waite LL., Wang SR., Wang Z., Wild SH., Willenborg C., Wilson JF., Wong A., Yang J., Yengo L., Yerges-Armstrong LM., Yu L., Zhang W., Zhao JH., Andersson EA., Bakker SJL., Baldassarre D., Banasik K., Barcella M., Barlassina C., Bellis C., Benaglio P., Blangero J., Blüher M., Bonnet F., Bonnycastle LL., Boyd HA., Bruinenberg M., Buchman AS., Campbell H., Chen Y-DI., Chines PS., Claudi-Boehm S., Cole J., Collins FS., de Geus EJC., de Groot LCPGM., Dimitriou M., Duan J., Enroth S., Eury E., Farmaki A-E., Forouhi NG., Friedrich N., Gejman PV., Gigante B., Glorioso N., Go AS., Gottesman O., Gräßler J., Grallert H., Grarup N., Gu Y-M., Broer L., Ham AC., Hansen T., Harris TB., Hartman CA., Hassinen M., Hastie N., Hattersley AT., Heath AC., Henders AK., Hernandez D., Hillege H., Holmen O., Hovingh KG., Hui J., Husemoen LL., Hutri-Kähönen N., Hysi PG., Illig T., De Jager PL., Jalilzadeh S., Jørgensen T., Jukema JW., Juonala M., Kanoni S., Karaleftheri M., Khaw KT., Kinnunen L., Kittner SJ., Koenig W., Kolcic I., Kovacs P., Krarup NT., Kratzer W., Krüger J., Kuh D., Kumari M., Kyriakou T., Langenberg C., Lannfelt L., Lanzani C., Lotay V., Launer LJ., Leander K., Lindström J., Linneberg A., Liu Y-P., Lobbens S., Luben R., Lyssenko V., Männistö S., Magnusson PK., McArdle WL., Menni C., Merger S., Milani L., Montgomery GW., Morris AP., Narisu N., Nelis M., Ong KK., Palotie A., Pérusse L., Pichler I., Pilia MG., Pouta A., Rheinberger M., Ribel-Madsen R., Richards M., Rice KM., Rice TK., Rivolta C., Salomaa V., Sanders AR., Sarzynski MA., Scholtens S., Scott RA., Scott WR., Sebert S., Sengupta S., Sennblad B., Seufferlein T., Silveira A., Slagboom PE., Smit JH., Sparsø TH., Stirrups K., Stolk RP., Stringham HM., Swertz MA., Swift AJ., Syvänen A-C., Tan S-T., Thorand B., Tönjes A., Tremblay A., Tsafantakis E., van der Most PJ., Völker U., Vohl M-C., Vonk JM., Waldenberger M., Walker RW., Wennauer R., Widén E., Willemsen G., Wilsgaard T., Wright AF., Zillikens MC., van Dijk SC., van Schoor NM., Asselbergs FW., de Bakker PIW., Beckmann JS., Beilby J., Bennett DA., Bergman RN., Bergmann S., Böger CA., Boehm BO., Boerwinkle E., Boomsma DI., Bornstein SR., Bottinger EP., Bouchard C., Chambers JC., Chanock SJ., Chasman DI., Cucca F., Cusi D., Dedoussis G., Erdmann J., Eriksson JG., Evans DA., de Faire U., Farrall M., Ferrucci L., Ford I., Franke L., Franks PW., Froguel P., Gansevoort RT., Gieger C., Grönberg H., Gudnason V., Gyllensten U., Hall P., Hamsten A., van der Harst P., Hayward C., Heliövaara M., Hengstenberg C., Hicks AA., Hingorani A., Hofman A., Hu F., Huikuri HV., Hveem K., James AL., Jordan JM., Jula A., Kähönen M., Kajantie E., Kathiresan S., Kiemeney LALM., Kivimaki M., Knekt PB., Koistinen HA., Kooner JS., Koskinen S., Kuusisto J., Maerz W., Martin NG., Laakso M., Lakka TA., Lehtimäki T., Lettre G., Levinson DF., Lind L., Lokki M-L., Mäntyselkä P., Melbye M., Metspalu A., Mitchell BD., Moll FL., Murray JC., Musk AW., Nieminen MS., Njølstad I., Ohlsson C., Oldehinkel AJ., Oostra BA., Palmer LJ., Pankow JS., Pasterkamp G., Pedersen NL., Pedersen O., Penninx BW., Perola M., Peters A., Polašek O., Pramstaller PP., Psaty BM., Qi L., Quertermous T., Raitakari OT., Rankinen T., Rauramaa R., Ridker PM., Rioux JD., Rivadeneira F., Rotter JI., Rudan I., den Ruijter HM., Saltevo J., Sattar N., Schunkert H., Schwarz PEH., Shuldiner AR., Sinisalo J., Snieder H., Sørensen TIA., Spector TD., Staessen JA., Stefania B., Thorsteinsdottir U., Stumvoll M., Tardif J-C., Tremoli E., Tuomilehto J., Uitterlinden AG., Uusitupa M., Verbeek ALM., Vermeulen SH., Viikari JS., Vitart V., Völzke H., Vollenweider P., Waeber G., Walker M., Wallaschofski H., Wareham NJ., Watkins H., Zeggini E., CHARGE Consortium None., DIAGRAM Consortium None., GLGC Consortium None., Global-BPGen Consortium None., ICBP Consortium None., MAGIC Consortium None., Chakravarti A., Clegg DJ., Cupples LA., Gordon-Larsen P., Jaquish CE., Rao DC., Abecasis GR., Assimes TL., Barroso I., Berndt SI., Boehnke M., Deloukas P., Fox CS., Groop LC., Hunter DJ., Ingelsson E., Kaplan RC., McCarthy MI., Mohlke KL., O'Connell JR., Schlessinger D., Strachan DP., Stefansson K., van Duijn CM., Hirschhorn JN., Lindgren CM., Heid IM., North KE., Borecki IB., Kutalik Z., Loos RJF.
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.