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

TW Winkler, AE Justice, M Graff, L Barata, MF Feitosa, S Chu, J Czajkowski, T Esko, T Fall, TO Kilpelainen, YC Lu, R Magi, E Mihailov, TH Pers, S Rueger, A Teumer, GB Ehret, T Ferreira, NL Heard-Costa, J KarjalainenV Lagou, A Mahajan, MD Neinast, I Prokopenko, J Simino, TM Teslovich, R Jansen, HJ Westra, CC White, D Absher, TS Ahluwalia, Shahzad Ahmad, E Albrecht, AC Alves, JL Bragg-Gresham, AJM de Craen, JC Bis, A Bonnefond, G Boucher, G Cadby, YC Cheng, CWK Chiang, G Delgado, Ayse Demirkan, N Dueker, N Eklund, G Eiriksdottir, J Eriksson, B Feenstra, K (Kirsten) Fischer, F Frau, TE Galesloot, F Geller, A Goel, M Gorski, TB Grammer, S Gustafsson, S Haitjema, JJ (Jouke Jan) Hottenga, JE Huffman, AU Jackson, KB Jacobs, A Johansson, M Kaakinen, ME Kleber, J Lahti, IM Leach, B Lehne, YF Liu, KS Lo, M Lorentzon, J Luan, PAF Madden, M Mangino, B McKnight, Maria Medina Gomez, KL Monda, ME Montasser, G Muller, M Muller-Nurasyid, IM (Ilja) Nolte, K Panoutsopoulou, L Pascoe, L Paternoster, NW Rayner, F Renstrom, F Rizzi, LM Rose, KA Ryan, P Salo, S Sanna, H Scharnagl, JX Shi, AV Smith, L Southam, A Stancakova, V Steinthorsdottir, RJ Strawbridge, YJ Sung, I Tachmazidou, T Tanaka, G Thorleifsson, S Trompet, N Pervjakova, JP Tyrer, L Vandenput, Sander Laan, Nathalie van der Velde, J van Setten, JV van Vliet-Ostaptchouk, N (Niek) Verweij, E Vlachopoulou, LL Waite, SR Wang, ZM Wang, SH Wild, C Willenborg, JF Wilson, A Wong, Jiaqi Yang, L Yengo, LM Yerges-Armstrong, L Yu, WH Zhang, JH Zhao, EA Andersson, SJL Bakker, D Baldassarre, K Banasik, M Barcella, C Barlassina, C Bellis, P Benaglio, J Blangero, M Bluher, F Bonnet, LL Bonnycastle, HA Boyd, M Bruinenberg, AS Buchman, H Campbell, YDI Chen, PS Chines, S Claudi-Boehm, J Cole, FS Collins, EJC de Geus, LCPGM (Lisette) de Groot, M Dimitriou, J Duan, S Enroth, E Eury, AE Farmaki, NG Forouhi, N Friedrich, PV Gejman, B Gigante, N Glorioso, AS Go, O Gottesman, J Grassler, H Grallert, N Grarup, YM Gu, Linda Broer, Annelies Ham, T Hansen, TB Harris, CA Hartman, M Hassinen, N Hastie, AT Hattersley, AC Heath, AK Henders, D Hernandez, H Hillege, O Holmen, KG Hovingh, J Hui, LL Husemoen, N Hutri-Kahonen, PG Hysi, T Illig, PL De Jager, S Jalilzadeh, T Jorgensen, JW Jukema, M Juonala, S Kanoni, M Karaleftheri, KT Khaw, L Kinnunen, SJ Kittner, W Koenig, I Kolcic, P Kovacs, NT Krarup, W Kratzer, J Kruger, D Kuh, M Kumari, T Kyriakou, C Langenberg, L Lannfelt, C Lanzani, V Lotay, LJ (Lenore) Launer, K Leander, J Lindstrom, A Linneberg, YP Liu, S Lobbens, R Luben, V Lyssenko, S Mannisto, PK Magnusson, WL McArdle, C Menni, S Merger, L Milani, GW Montgomery, AP Morris, N Narisu, M Nelis, KK Ong, A Palotie, L Perusse, I Pichler, MG Pilia, A Pouta, M Rheinberger, R Ribel-Madsen, M Richards, KM Rice, TK Rice, C Rivolta, V Salomaa, AR Sanders, MA Sarzynski, s Scholtens, RA Scott, WR Scott, S Sebert, S Sengupta, B Sennblad, T Seufferlein, A Silveira, PE (Eline) Slagboom, JH Smit, TH Sparso, K Stirrups, RP (Ronald) Stolk, HM Stringham, MA Swertz, AJ Swift, AC Syvanen, ST Tan, B Thorand, A Tonjes, A Tremblay, E Tsafantakis, PJ van der Most, U Volker, MC Vohl, JM Vonk, M Waldenberger, RW Walker, R Wennauer, E Widen, G Willemsen, T Wilsgaard, AF Wright, M.C. Zillikens, Suzanne Boon - van Dijk, NM Schoor, FW Asselbergs, PIW de Bakker, JS Beckmann, J Beilby, DA Bennett, RN Bergman, S Bergmann, CA Boger, BO Boehm, E Boerwinkle, DI Boomsma, SR Bornstein, EP Bottinger, C Bouchard, JC Chambers, SJ Chanock, DI Chasman, F Cucca, D Cusi, G Dedoussis, J Erdmann, JG Eriksson, DA Evans, U de Faire, M Farrall, L Ferrucci, I Ford, L Franke, PW Franks, P Froguel, RT Gansevoort, C Gieger, H Gronberg, V Gudnason, U Gyllensten, P Hall, A Hamsten, P van der Harst, C Hayward, M Heliovaara, C Hengstenberg, AA Hicks, A Hingorani, Bert Hofman, F Hu, HV Huikuri, K Hveem, AL James, JM Jordan, A Jula, M Kahonen, E Kajantie, S Kathiresan, LALM Kiemeney, M Kivimaki, PB Knekt, HA Koistinen, JS Kooner, S Koskinen, J Kuusisto, W Maerz, NG Martin, M Laakso, TA Lakka, T Lehtimaki, G Lettre, DF Levinson, L Lind, ML Lokki, P Mantyselka, M Melbye, A Metspalu, BD Mitchell, FL Moll, JC Murray, AW Musk, MS Nieminen, I Njolstad, C Ohlsson, AJ (A.) Oldehinkel, Ben Oostra, LJ Palmer, JS Pankow, G Pasterkamp, NL Pedersen, O Pedersen, BW Penninx, M Perola, A Peters, O Polasek, PP Pramstaller, BM Psaty, L Qi, T Quertermous, OT Raitakari, T Rankinen, R Rauramaa, PM Ridker, JD Rioux, Fernando Rivadeneira, JI Rotter, I Rudan, HM den Ruijter, J Saltevo, N Sattar, H Schunkert, PEH Schwarz, AR Shuldiner, J Sinisalo, H Snieder, TIA Sorensen, TD Spector, JA Staessen, B Stefania, U Thorsteinsdottir, M Stumvoll, JC Tardif, E Tremoli, J Tuomilehto, André Uitterlinden, M Uusitupa, ALM Verbeek, SH Vermeulen, JS Viikari, V Vitart, H Volzke, P Vollenweider, G Waeber, M Walker, H Wallaschofski, NJ Wareham, H Watkins, E Zeggini, A Chakravarti, DJ Clegg, LA Cupples, P Gordon-Larsen, CE Jaquish, DC Rao, GR Abecasis, TL Assimes, I Barroso, SI Berndt, M Boehnke, P Deloukas, CS Fox, LC Groop, DJ Hunter, E Ingelsson, RC Kaplan, MI McCarthy, KL Mohlke, JR O'Connell, D Schlessinger, DP Strachan, K Stefansson, Cornelia Duijn, JN Hirschhorn, CM Lindgren, IM Heid, KE North, IB Borecki, Z Kutalik, RJF Loos

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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 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.
Original languageUndefined/Unknown
JournalPLoS Genetics (online)
Volume11
Issue number10
DOIs
Publication statusPublished - 2015

Research programs

  • EMC NIHES-01-64-02
  • EMC OR-01-39-08

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