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, Tarunveer S. Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L. Bragg-Gresham, Anton J. M. de Craen, Joshua C. Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W. K. Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E. Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B. Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E. Huffman, Anne U. Jackson, Kevin B. Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E. Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A. F. Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L. Monda, May E. Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M. Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W. Rayner, Frida Renström, Federica Rizzi, Lynda M. Rose, Kathy A. Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J. Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P. Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V. van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L. Waite, Sophie R. Wang, Zhaoming Wang, Sarah H. Wild, Christina Willenborg, James F. Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M. Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A. Andersson, Stephan J. L. Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L. Bonnycastle, Heather A. Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S. Chines, Simone Claudi-Boehm, John Cole, Francis S. Collins, Eco J. C. de Geus, Lisette C. P. G. M. de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G. Forouhi, Nele Friedrich, Pablo V. Gejman, Bruna Gigante, Nicola Glorioso, Alan S. Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C. Ham, Torben Hansen, Tamara B. Harris, Catharina A. Hartman, Maija Hassinen, Nicholas Hastie, Andrew T. Hattersley, Andrew C. Heath, Anjali K. Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L. Husemoen, Nina Hutri-Kähönen, Pirro G. Hysi, Thomas Illig, Philip L. De Jager, Shapour Jalilzadeh, Torben Jørgensen, J. Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J. Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T. Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J. Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K. Magnusson, Wendy L. McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W. Montgomery, Andrew P. Morris, Narisu Narisu, Mari Nelis, Ken K. Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G. Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M. Rice, Treva K. Rice, Carlo Rivolta, Veikko Salomaa, Alan R. Sanders, Mark A. Sarzynski, Salome Scholtens, Robert A. Scott, William R. Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P. Eline Slagboom, Jan H. Smit, Thomas H. Sparsø, Kathleen Stirrups, Ronald P. Stolk, Heather M. Stringham, Morris A Swertz, Amy J. Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J. van der Most, Uwe Völker, Marie-Claude Vohl, Judith M. Vonk, Melanie Waldenberger, Ryan W. Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F. Wright, M. Carola Zillikens, Suzanne C. van Dijk, Natasja M. van Schoor, Folkert W. Asselbergs, Paul I. W. de Bakker, Jacques S. Beckmann, John Beilby, David A. Bennett, Richard N. Bergman, Sven Bergmann, Carsten A. Böger, Bernhard O. Boehm, Eric Boerwinkle, Dorret I. Boomsma, Stefan R. Bornstein, Erwin P. Bottinger, Claude Bouchard, John C. Chambers, Stephen J. Chanock, Daniel I. Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G. Eriksson, Denis A. Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W. Franks, Philippe Froguel, Ron T. Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V. Huikuri, Kristian Hveem, Alan L. James, Joanne M. Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A. L. M. Kiemeney, Mika Kivimaki, Paul B. Knekt, Heikki A. Koistinen, Jaspal S. Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F. Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D. Mitchell, Frans L. Moll, Jeffrey C. Murray, Arthur W. Musk, Markku S. Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J. Oldehinkel, Ben A. Oostra, Lyle J Palmer, James S. Pankow, Gerard Pasterkamp, Nancy L. Pedersen, Oluf Pedersen, Brenda W. Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P. Pramstaller, Bruce M. Psaty, Lu Qi, Thomas Quertermous, Olli T. Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M. Ridker, John D. Rioux, Fernando Rivadeneira, Jerome I. Rotter, Igor Rudan, Hester M. den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E. H. Schwarz, Alan R. Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I. A. Sørensen, Tim D. Spector, Jan A. Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G. Uitterlinden, Matti Uusitupa, André L. M. Verbeek, Sita H. Vermeulen, Jorma S. Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J. Wareham, Hugh Watkins, Eleftheria Zeggini, Aravinda Chakravarti, Deborah J. Clegg, L. Adrienne Cupples, Penny Gordon-Larsen, Cashell E. Jaquish, D. C. Rao, Goncalo R. Abecasis, Themistocles L. Assimes, Inês Barroso, Sonja I. Berndt, Michael Boehnke, Panos Deloukas, Caroline S. Fox, Leif C. Groop, David J. Hunter, Erik Ingelsson, Robert C. Kaplan, Mark I. McCarthy, Karen L. Mohlke, Jeffrey R. O'Connell, David Schlessinger, David P. Strachan, Kari Stefansson, Cornelia M. van Duijn, Joel N. Hirschhorn, Cecilia M. Lindgren, Iris M. Heid, Kari E. North, Ingrid B. Borecki, Zoltán Kutalik, Ruth J. F. Loos

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.