Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Joshua C. Randall, Thomas W. Winkler, Zoltán Kutalik, Sonja I. Berndt, Anne U. Jackson, Keri L. Monda, Tuomas O. Kilpeläinen, Tõnu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F. Feitosa, Damien C. Croteau-Chonka, Felix R. Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E. Locke, Iain Mathieson, Andre ScheragSailaja Vedantam, Andrew R. Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T. Dermitzakis, Antigone S. Dimas, Fredrik Karpe, Josine L. Min, George Nicholson, Deborah J. Clegg, Thomas Person, Jon P. Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, Amélie Bonnefond, Philippe Froguel, Jouke Jan Hottenga, Inga Prokopenko, Lindsay L. Waite, Tamara B. Harris, Albert Vernon Smith, Alan R. Shuldiner, Wendy L. McArdle, Mark J. Caulfield, Patricia B. Munroe, Henrik Grönberg, Yii Der Ida Chen, Guo Li, Jacques S. Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay Tee Khaw, Nicholas J. Wareham, Jing Hua Zhao, Najaf Amin, Ben A. Oostra, Aldi T. Kraja, Michael A. Province, L. Adrienne Cupples, Nancy L. Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S. Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H. Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A. Hicks, Åsa Johansson, Peter P. Pramstaller, Sekar Kathiresan, Elizabeth K. Speliotes, Brenda Penninx, Anna Liisa Hartikainen, Marjo Riitta Jarvelin, Ulf Gyllensten, Dorret I. Boomsma, Harry Campbell, James F. Wilson, Stephen J. Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G. Uitterlinden, Albert Hofman, M. Carola Zillikens, Martin den Heijer, Lambertus A. Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D. Spector, Caroline Hayward, Igor Rudan, Alistair S. Hall, Nilesh J. Samani, Antony Paul Attwood, Jennifer G. Sambrook, Joseph Hung, Lyle J. Palmer, Marja Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G. Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M. Nolte, Harold Snieder, Melanie M. van der Klauw, Jana V. van Vliet-Ostaptchouk, Pablo V. Gejman, Jianxin Shi, Kevin B. Jacobs, Zhaoming Wang, Stephan J.L. Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G. Martin, Sarah E. Medland, Grant W. Montgomery, Jian Yang, Daniel I. Chasman, Paul M. Ridker, Lynda M. Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G. Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P. Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R. Bornstein, Peter E.H. Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J. Swift, Matti Uusitupa, Mustafa Atalay, Timo A. Lakka, Rainer Rauramaa, Jennifer L. Bolton, Gerry Fowkes, Ross M. Fraser, Jackie F. Price, Krista Fischer, Kaarel KrjutÅkov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K. Ong, Peter S. Chines, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Sarah Edkins, Paul W. Franks, Göran Hallmans, Dmitry Shungin, Andrewvid da Morris, Colin N.A. Palmer, Raimund Erbel, Susanne Moebus, Markus M. Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E. Humphries, Rona J. Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O. Boehm, Marcus E. Kleber, Winfried März, Bernhard R. Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W.G. Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K.E. Magnusson, Nancy L. Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L. Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Themistocles L. Assimes, Inês Barroso, Michael Boehnke, Ingrid B. Borecki, Panos Deloukas, Caroline S. Fox, Timothy Frayling, Leif C. Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L. Mohlke, Jeffrey R. O'Connell, David Schlessinger, David P. Strachan, Kari Stefansson, Cornelia M. van Duijn, Gonçalo R. Abecasis, Mark I. McCarthy, Joel N. Hirschhorn, Lu Qi, Ruth J.F. Loos, Cecilia M. Lindgren, Kari E. North, Iris M. Heid

Research output: Contribution to journalArticle

204 Scopus citations

Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10-8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Original languageEnglish (US)
Article numbere1003500
JournalPLoS genetics
Volume9
Issue number6
DOIs
StatePublished - Jun 2013

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Randall, J. C., Winkler, T. W., Kutalik, Z., Berndt, S. I., Jackson, A. U., Monda, K. L., Kilpeläinen, T. O., Esko, T., Mägi, R., Li, S., Workalemahu, T., Feitosa, M. F., Croteau-Chonka, D. C., Day, F. R., Fall, T., Ferreira, T., Gustafsson, S., Locke, A. E., Mathieson, I., ... Heid, I. M. (2013). Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits. PLoS genetics, 9(6), [e1003500]. https://doi.org/10.1371/journal.pgen.1003500