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

Winkler, Thomas W. and Justice, Anne E. and Graff, Mariaelisa and Barata, Llilda and Feitosa, Mary F. and Chu, Su and Czajkowski, Jacek and Esko, Tõnu and Fall, Tove and Kilpeläinen, Tuomas O. and Lu, Yingchang and Mägi, Reedik and Mihailov, Evelin and Pers, Tune H. and Rüeger, Sina and Teumer, Alexander and Ehret, Georg B. and Ferreira, Teresa and Heard-Costa, Nancy L. and Karjalainen, Juha and Lagou, Vasiliki and Mahajan, Anubha and Neinast, Michael D. and Prokopenko, Inga and Simino, Jeannette and Teslovich, Tanya M. and Jansen, Rick and Westra, Harm-Jan and White, Charles C. and Absher, Devin and Ahluwalia, Tarunveer S. and Ahmad, Shafqat and Albrecht, Eva and Alves, Alexessander Couto and Bragg-Gresham, Jennifer L. and de Craen, Anton J. M. and Bis, Joshua C. and Bonnefond, Amélie and Boucher, Gabrielle and Cadby, Gemma and Cheng, Yu-Ching and Chiang, Charleston W. K. and Delgado, Graciela and Demirkan, Ayse and Dueker, Nicole and Eklund, Niina and Eiriksdottir, Gudny and Eriksson, Joel and Feenstra, Bjarke and Fischer, Krista and Frau, Francesca and Galesloot, Tessel E. and Geller, Frank and Goel, Anuj and Gorski, Mathias and Grammer, Tanja B. and Gustafsson, Stefan and Haitjema, Saskia and Hottenga, Jouke-Jan and Huffman, Jennifer E. and Jackson, Anne U. and Jacobs, Kevin B. and Johansson, Åsa and Kaakinen, Marika and Kleber, Marcus E. and Lahti, Jari and Mateo Leach, Irene and Lehne, Benjamin and Liu, Youfang and Lo, Ken Sin and Lorentzon, Mattias and Luan, Jian'an and Madden, Pamela A. F. and Mangino, Massimo and McKnight, Barbara and Medina-Gomez, Carolina and Monda, Keri L. and Montasser, May E. and Müller, Gabriele and Müller-Nurasyid, Martina and Nolte, Ilja M. and Panoutsopoulou, Kalliope and Pascoe, Laura and Paternoster, Lavinia and Rayner, Nigel W. and Renström, Frida and Rizzi, Federica and Rose, Lynda M. and Ryan, Kathy A. and Salo, Perttu and Sanna, Serena and Scharnagl, Hubert and Shi, Jianxin and Smith, Albert Vernon and Southam, Lorraine and Stančáková, Alena and Steinthorsdottir, Valgerdur and Strawbridge, Rona J. and Sung, Yun Ju and Tachmazidou, Ioanna and Tanaka, Toshiko and Thorleifsson, Gudmar and Trompet, Stella and Pervjakova, Natalia and Tyrer, Jonathan P. and Vandenput, Liesbeth and van der Laan, Sander W. and van der Velde, Nathalie and van Setten, Jessica and van Vliet-Ostaptchouk, Jana V. and Verweij, Niek and Vlachopoulou, Efthymia and Waite, Lindsay L. and Wang, Sophie R. and Wang, Zhaoming and Wild, Sarah H. and Willenborg, Christina and Wilson, James F. and Wong, Andrew and Yang, Jian and Yengo, Loïc and Yerges-Armstrong, Laura M. and Yu, Lei and Zhang, Weihua and Zhao, Jing Hua and Andersson, Ehm A. and Bakker, Stephan J. L. and Baldassarre, Damiano and Banasik, Karina and Barcella, Matteo and Barlassina, Cristina and Bellis, Claire and Benaglio, Paola and Blangero, John and Blüher, Matthias and Bonnet, Fabrice and Bonnycastle, Lori L. and Boyd, Heather A. and Bruinenberg, Marcel and Buchman, Aron S. and Campbell, Harry and Chen, Yii-Der Ida and Chines, Peter S. and Claudi-Boehm, Simone and Cole, John and Collins, Francis S. and de Geus, Eco J. C. and de Groot, Lisette C. P. G. M. and Dimitriou, Maria and Duan, Jubao and Enroth, Stefan and Eury, Elodie and Farmaki, Aliki-Eleni and Forouhi, Nita G. and Friedrich, Nele and Gejman, Pablo V. and Gigante, Bruna and Glorioso, Nicola and Go, Alan S. and Gottesman, Omri and Gräßler, Jürgen and Grallert, Harald and Grarup, Niels and Gu, Yu-Mei and Broer, Linda and Ham, Annelies C. and Hansen, Torben and Harris, Tamara B. and Hartman, Catharina A. and Hassinen, Maija and Hastie, Nicholas and Hattersley, Andrew T. and Heath, Andrew C. and Henders, Anjali K. and Hernandez, Dena and Hillege, Hans and Holmen, Oddgeir and Hovingh, Kees G. and Hui, Jennie and Husemoen, Lise L. and Hutri-Kähönen, Nina and Hysi, Pirro G. and Illig, Thomas and De Jager, Philip L. and Jalilzadeh, Shapour and Jørgensen, Torben and Jukema, J. Wouter and Juonala, Markus and Kanoni, Stavroula and Karaleftheri, Maria and Khaw, Kay Tee and Kinnunen, Leena and Kittner, Steven J. and Koenig, Wolfgang and Kolcic, Ivana and Kovacs, Peter and Krarup, Nikolaj T. and Kratzer, Wolfgang and Krüger, Janine and Kuh, Diana and Kumari, Meena and Kyriakou, Theodosios and Langenberg, Claudia and Lannfelt, Lars and Lanzani, Chiara and Lotay, Vaneet and Launer, Lenore J. and Leander, Karin and Lindström, Jaana and Linneberg, Allan and Liu, Yan-Ping and Lobbens, Stéphane and Luben, Robert and Lyssenko, Valeriya and Männistö, Satu and Magnusson, Patrik K. and McArdle, Wendy L. and Menni, Cristina and Merger, Sigrun and Milani, Lili and Montgomery, Grant W. and Morris, Andrew P. and Narisu, Narisu and Nelis, Mari and Ong, Ken K. and Palotie, Aarno and Pérusse, Louis and Pichler, Irene and Pilia, Maria G. and Pouta, Anneli and Rheinberger, Myriam and Ribel-Madsen, Rasmus and Richards, Marcus and Rice, Kenneth M. and Rice, Treva K. and Rivolta, Carlo and Salomaa, Veikko and Sanders, Alan R. and Sarzynski, Mark A. and Scholtens, Salome and Scott, Robert A. and Scott, William R. and Sebert, Sylvain and Sengupta, Sebanti and Sennblad, Bengt and Seufferlein, Thomas and Silveira, Angela and Slagboom, P. Eline and Smit, Jan H. and Sparsø, Thomas H. and Stirrups, Kathleen and Stolk, Ronald P. and Stringham, Heather M. and Swertz, Morris A. and Swift, Amy J. and Syvänen, Ann-Christine and Tan, Sian-Tsung and Thorand, Barbara and Tönjes, Anke and Tremblay, Angelo and Tsafantakis, Emmanouil and van der Most, Peter J. and Völker, Uwe and Vohl, Marie-Claude and Vonk, Judith M. and Waldenberger, Melanie and Walker, Ryan W. and Wennauer, Roman and Widén, Elisabeth and Willemsen, Gonneke and Wilsgaard, Tom and Wright, Alan F. and Zillikens, M. Carola and van Dijk, Suzanne C. and van Schoor, Natasja M. and Asselbergs, Folkert W. and de Bakker, Paul I. W. and Beckmann, Jacques S. and Beilby, John and Bennett, David A. and Bergman, Richard N. and Bergmann, Sven and Böger, Carsten A. and Boehm, Bernhard O. and Boerwinkle, Eric and Boomsma, Dorret I. and Bornstein, Stefan R. and Bottinger, Erwin P. and Bouchard, Claude and Chambers, John C. and Chanock, Stephen J. and Chasman, Daniel I. and Cucca, Francesco and Cusi, Daniele and Dedoussis, George and Erdmann, Jeanette and Eriksson, Johan G. and Evans, Denis A. and de Faire, Ulf and Farrall, Martin and Ferrucci, Luigi and Ford, Ian and Franke, Lude and Franks, Paul W. and Froguel, Philippe and Gansevoort, Ron T. and Gieger, Christian and Grönberg, Henrik and Gudnason, Vilmundur and Gyllensten, Ulf and Hall, Per and Hamsten, Anders and van der Harst, Pim and Hayward, Caroline and Heliövaara, Markku and Hengstenberg, Christian and Hicks, Andrew A. and Hingorani, Aroon and Hofman, Albert and Hu, Frank and Huikuri, Heikki V. and Hveem, Kristian and James, Alan L. and Jordan, Joanne M. and Jula, Antti and Kähönen, Mika and Kajantie, Eero and Kathiresan, Sekar and Kiemeney, Lambertus A. L. M. and Kivimaki, Mika and Knekt, Paul B. and Koistinen, Heikki A. and Kooner, Jaspal S. and Koskinen, Seppo and Kuusisto, Johanna and Maerz, Winfried and Martin, Nicholas G. and Laakso, Markku and Lakka, Timo A. and Lehtimäki, Terho and Lettre, Guillaume and Levinson, Douglas F. and Lind, Lars and Lokki, Marja-Liisa and Mäntyselkä, Pekka and Melbye, Mads and Metspalu, Andres and Mitchell, Braxton D. and Moll, Frans L. and Murray, Jeffrey C. and Musk, Arthur W. and Nieminen, Markku S. and Njølstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J. and Oostra, Ben A. and Palmer, Lyle J. and Pankow, James S. and Pasterkamp, Gerard and Pedersen, Nancy L. and Pedersen, Oluf and Penninx, Brenda W. and Perola, Markus and Peters, Annette and Polašek, Ozren and Pramstaller, Peter P. and Psaty, Bruce M. and Qi, Lu and Quertermous, Thomas and Raitakari, Olli T. and Rankinen, Tuomo and Rauramaa, Rainer and Ridker, Paul M. and Rioux, John D. and Rivadeneira, Fernando and Rotter, Jerome I. and Rudan, Igor and den Ruijter, Hester M. and Saltevo, Juha and Sattar, Naveed and Schunkert, Heribert and Schwarz, Peter E. H. and Shuldiner, Alan R. and Sinisalo, Juha and Snieder, Harold and Sørensen, Thorkild I. A. and Spector, Tim D. and Staessen, Jan A. and Stefania, Bandinelli and Thorsteinsdottir, Unnur and Stumvoll, Michael and Tardif, Jean-Claude and Tremoli, Elena and Tuomilehto, Jaakko and Uitterlinden, André G. and Uusitupa, Matti and Verbeek, André L. M. and Vermeulen, Sita H. and Viikari, Jorma S. and Vitart, Veronique and Völzke, Henry and Vollenweider, Peter and Waeber, Gérard and Walker, Mark and Wallaschofski, Henri and Wareham, Nicholas J. and Watkins, Hugh and Zeggini, Eleftheria and Charge Consortium, and Diagram Consortium, and Glgc Consortium, and Global-BPGen Consortium, and Icbp Consortium, and Magic Consortium, and Chakravarti, Aravinda and Clegg, Deborah J. and Cupples, L. Adrienne and Gordon-Larsen, Penny and Jaquish, Cashell E. and Rao, D. C. and Abecasis, Goncalo R. and Assimes, Themistocles L. and Barroso, Inês and Berndt, Sonja I. and Boehnke, Michael and Deloukas, Panos and Fox, Caroline S. and Groop, Leif C. and Hunter, David J. and Ingelsson, Erik and Kaplan, Robert C. and McCarthy, Mark I. and Mohlke, Karen L. and O'Connell, Jeffrey R. and Schlessinger, David and Strachan, David P. and Stefansson, Kari and van Duijn, Cornelia M. and Hirschhorn, Joel N. and Lindgren, Cecilia M. and Heid, Iris M. and North, Kari E. and Borecki, Ingrid B. and Kutalik, Zoltán and Loos, Ruth J. F.. (2015) The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS Genetics, 11 (10). e1005378.

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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 ~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.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Public Library of Science
ISSN:1553-7390
e-ISSN:1553-7404
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:03 Mar 2021 11:32
Deposited On:03 Mar 2021 11:32

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