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

Citation

Winkler, Thomas W.; Justice, Anne E.; Graff, Mariaelisa; Barata, Llilda P.; Feitosa, Mary F.; Chu, Su; Czajkowski, Jacek; Esko, Tonu; Fall, Tove; & Kilpelainen, Tuomas O., et al. (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. PMCID: PMC4591371

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, 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.

URL

http://dx.doi.org/10.1371/journal.pgen.1005378

Reference Type

Journal Article

Year Published

2015

Journal Title

PLOS Genetics

Series Title

TW Winkler et al. PLoS Genet 12 (6), e1006166. 2016. PMID 27355579.

Author(s)

Winkler, Thomas W.
Justice, Anne E.
Graff, Mariaelisa
Barata, Llilda P.
Feitosa, Mary F.
Chu, Su
Czajkowski, Jacek
Esko, Tonu
Fall, Tove
Kilpelainen, Tuomas O.
Lu, Yingchang
Magi, Reedik
Mihailov, Evelin
Pers, Tune H.
Rueger, Sina
Teumer, Alexander
Ehret, Georg B.
Ferreira, Teresa
Heard-Costa, Nancy L.
Karjalainen, Juha
Lagou, Vasiliki
Mahajan, Anubha
Neinast, Michael D.
Prokopenko, Inga
Simino, Jeannette
Teslovich, Tanya M.
Jansen, Rick
Westra, Harm-Jan
White, Charles C.
Absher, Devin M.
Ahluwalia, Tarunveer S.
Ahmad, Shafqat
Albrecht, Eva
Alves, Alexessander Couto
Bragg-Gresham, Jennifer L.
de Craen, Antonius J. M.
Bis, Joshua C.
Bonnefond, Amelie
Boucher, Gabrielle
Cadby, Gemma
Cheng, Yu-Ching
Chiang, Charleston W. K.
Delgado, Graciela E.
Demirkan, Ayse
Dueker, Nicole
Eklund, Niina
Eiriksdottir, Gudny
Eriksson, Joel
Feenstra, Bjarke
Fischer, Krista
Frau, Francesca
Galesloot, Tessel E.
Geller, Frank
Goel, Anuj
Gorski, Mathias
Grammer, Tanja B.
Gustafsson, Stefan
Haitjema, Saskia
Hottenga, Jouke-Jan
Huffman, Jennifer E.
Jackson, Anne U.
Jacobs, Kevin B.
Johansson, Asa
Kaakinen, Marika
Kleber, Marcus E.
Lahti, Jari
Leach, Irene Mateo
Lehne, Benjamin
Liu, Youfang
Lo, Ken Sin
Lorentzon, Mattias
Luan, Jian'an
Madden, Pamela A. F.
Mangino, Massimo
McKnight, Barbara
Medina-Gomez, Carolina
Monda, Keri L.
Montasser, May E.
Muller, Gabriele
Muller-Nurasyid, Martina
Nolte, Ilja M.
Panoutsopoulou, Kalliope
Pascoe, Laura
Paternoster, Lavinia
Rayner, Nigel W.
Renström, Frida
Rizzi, Federica
Rose, Lynda M.
Ryan, Kathy A.
Salo, Perttu
Sanna, Serena
Scharnagl, Hubert
Shi, Jianxin
Smith, Albert V.
Southam, Lorraine
Stancakova, Alena
Steinthorsdottir, Valgerdur
Strawbridge, Rona J.
Sung, Yun J.
Tachmazidou, Ioanna
Tanaka, Toshiko
Thorleifsson, Gudmar
Trompet, Stella
Pervjakova, Natalia
Tyrer, Jonathan P.
Vandenput, Liesbeth
van der Laan, Sander W.
van der Velde, Nathalie
van Setten, Jessica
van Vliet-Ostaptchouk, Jana V.
Verweij, Niek
Vlachopoulou, Efthymia
Waite, Lindsay L.
Wang, Sophie R.
Wang, Zhaoming
Wild, Sarah H.
Willenborg, Christina
Wilson, James F.
Wong, Andrew
Yang, Jian
Yengo, Loic
Yerges-Armstrong, Laura M.
Yu, Lei
Zhang, Weihua
Zhao, Jing Hua
Andersson, Ehm Astrid
Bakker, Stephan J. L.
Baldassarre, Damiano
Banasik, Karina
Barcella, Matteo
Barlassina, Cristina
Bellis, Claire
Benaglio, Paola
Blangero, John
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Bonnet, Fabrice
Bonnycastle, Lori L.
Boyd, Heather A.
Bruinenberg, Marcel
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Campbell, Harry
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Claudi-Boehm, Simone
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de Geus, Eco J. C.
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Dimitriou, Maria
Duan, Jubao
Enroth, Stefan
Eury, Elodie
Farmaki, Aliki-Eleni
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Friedrich, Nele
Gejman, Pablo V.
Gigante, Bruna
Glorioso, Nicola
Go, Alan S.
Gottesman, Omri
Grassler, Jurgen
Grallert, Harald
Grarup, Niels
Gu, Yu-Mei
Broer, Linda
Ham, Annelies C.
Hansen, Torben
Harris, Tamara B.
Hartman, Catharina A.
Hassinen, Maija
Hastie, Nicholas D.
Hattersley, Andrew T.
Heath, Andrew C.
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Hernandez, Dena
Hillege, Hans L.
Holmen, Oddgeir L.
Hovingh, G. Kees
Hui, Jennie
Husemoen, Lise L.
Hutri-Kahonen, Nina
Hysi, Pirro G.
Illig, Thomas
De Jager, Philip L.
Jalilzadeh, Shapour
Jorgensen, Torben
Jukema, J. Wouter
Juonala, Markus
Kanoni, Stavroula
Karaleftheri, Maria
Khaw, Kay-Tee
Kinnunen, Leena
Kittner, Steven J.
Koenig, Wolfgang
Kolcic, Ivana
Kovacs, Peter
Krarup, Nikolaj T.
Kratzer, Wolfgang
Kruger, Janine
Kuh, Diana
Kumari, Meena
Kyriakou, Theodosios
Langenberg, Claudia
Lannfelt, Lars
Lanzani, Chiara
Lotay, Vaneet
Launer, Lenore J.
Leander, Karin
Lindstrom, Jaana
Linneberg, Allan
Liu, Yan-Ping
Lobbens, Stephane
Luben, Robert
Lyssenko, Valeriya
Mannisto, Satu
Magnusson, Patrik K. E.
McArdle, Wendy L.
Menni, Cristina
Merger, Sigrun
Milani, Lili
Montgomery, Grant W.
Morris, Andrew P.
Narisu, Narisu
Nelis, Mari
Ong, Ken K.
Palotie, Aarno
Perusse, Louis
Pichler, Irene
Pilia, Maria G.
Pouta, Anneli
Rheinberger, Myriam
Ribel-Madsen, Rasmus
Richards, Marcus
Rice, Kenneth M.
Rice, Treva K.
Rivolta, Carlo
Salomaa, Veikko
Sanders, Alan R.
Sarzynski, Mark A.
Scholtens, Salome
Scott, Robert A.
Scott, William R.
Sebert, Sylvain
Sengupta, Sebanti
Sennblad, Bengt
Seufferlein, Thomas
Silveira, Angela
Slagboom, P. Eline
Smit, Jan H.
Sparso, Thomas H.
Stirrups, Kathleen E.
Stolk, Ronald P.
Stringham, Heather M.
Swertz, Morris A.
Swift, Amy J.
Syvanen, Ann-Christine
Tan, Sian-Tsung
Thorand, Barbara
Tonjes, Anke
Tremblay, Angelo
Tsafantakis, Emmanouil
van der Most, Peter J.
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Vohl, Marie-Claude
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de Bakker, Paul I. W.
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Boehm, Bernhard O.
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de Faire, Ulf
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Franks, Paul W.
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Hayward, Caroline
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Knekt, Paul
Koistinen, Heikki A.
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Koskinen, Seppo
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Maerz, Winfried
Martin, Nicholas G.
Laakso, Markku
Lakka, Timo A.
Lehtimaki, Terho
Lettre, Guillaume
Levinson, Douglas F.
Lind, Lars
Lokki, Marja-Liisa
Mantyselka, Pekka
Melbye, Mads
Metspalu, Andres
Mitchell, Braxton D.
Moll, Frans L.
Murray, Jeffrey C.
Musk, Arthur W.
Nieminen, Markku S.
Njolstad, Inger
Ohlsson, Claes
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Oostra, Ben A.
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Pasterkamp, Gerard
Pedersen, Nancy L.
Pedersen, Oluf
Penninx, Brenda W. J. H. W.
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Peters, Annette
Polasek, Ozren
Pramstaller, Peter P.
Psaty, Bruce M.
Qi, Lu
Quertermous, Thomas
Raitakari, Olli T.
Rankinen, Tuomo
Rauramaa, Rainer
Ridker, Paul M.
Rioux, John D.
Rivadeneira, Fernando
Rotter, Jerome I.
Rudan, Igor
den Ruijter, Hester M.
Saltevo, Juha
Sattar, Naveed
Schunkert, Heribert
Schwarz, Peter E. H.
Shuldiner, Alan R.
Sinisalo, Juha
Snieder, Harold
Sorensen, Thorkild I. A.
Spector, Timothy D.
Staessen, Jan A.
Stefania, Bandinelli
Thorsteinsdottir, Unnur
Stumvoll, Michael
Tardif, Jean-Claude
Tremoli, Elena
Tuomilehto, Jaakko
Uitterlinden, Andre G.
Uusitupa, Matti
Verbeek, Andre L. M.
Vermeulen, Sita H.
Viikari, Jorma S.
Vitart, Veronique
Volzke, Henry
Vollenweider, Peter
Waeber, Gerard
Walker, Mark
Wallaschofski, Henri
Wareham, Nicholas J.
Watkins, Hugh
Zeggini, Eleftheria
CHARGE Consortium,
DIAGRAM Consortium,
GLGC Consortium,
Global-BPGen Consortium,
ICBP Consortium,
MAGIC Consortium,
Chakravarti, Aravinda
Clegg, Deborah J.
Cupples, L. Adrienne
Gordon-Larsen, Penny
Jaquish, Cashell E.
Rao, Dabeeru C.
Abecasis, Gonçalo R.
Assimes, Themistocles L.
Barroso, Ines
Berndt, Sonja I.
Boehnke, Michael
Deloukas, Panos
Fox, Caroline S.
Groop, Leif C.
Hunter, David J.
Ingelsson, Erik
Kaplan, Robert C.
McCarthy, Mark I.
Mohlke, Karen L.
O'Connell, Jeffrey R.
Schlessinger, David
Strachan, David P.
Stefansson, Kari
van Duijn, Cornelia M.
Hirschhorn, Joel N.
Lindgren, Cecilia M.
Heid, Iris M.
North, Kari E.
Borecki, Ingrid B.
Kutalik, Zoltan
Loos, Ruth J. F.

PMCID

PMC4591371

ORCiD

Gordon-Larsen - 0000-0001-5322-4188
Graff - 0000-0001-6380-1735