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

Authors: Joshua C. Randall, Thomas W. Winkler, Zoltán Kutalik, Sonja I. Berndt, Anne 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, André Scherag, Sailaja Vedantam, Andrew R. Wood, Liming Liang, Valgerður Steinthórsdóttir, Guðmar Þorleifsson, Emmanouil T. Dermitzakis, Antigone S. Dimas, Fredrik Karpe, Josine L. Min, George Nicholson, Deborah J. Clegg, Thomas N. Person, Jon P. Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, Amélie Bonnefond, Philippe Froguel, MAGIC Investigators, Jouke‐Jan Hottenga, Inga Prokopenko, Lindsay L. Waite, Tamara B. Harris, Albert V. Smith, Alan R. Shuldiner, Wendy L. McArdle, Mark J. Caulfield, Patricia B. Munroe, Henrik Grönberg, Yii-Der Ida Chen, Li Guo, J. Beckmann, Toby Johnson, Unnur Þorsteinsdóttir, Maris Teder‐Laving, Kay‐Tee Khaw, Nicholas J. Wareham, Wei 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 W.J.H. Penninx, Anna-Liisa Hartikainen, Marjo‐Riitta Järvelin, Ulf Gyllensten, Dorret I. Boomsma, Harry Campbell, James F. Wilson, Stephen J. Chanock, Martin Farrall, Anuj Goel, Carolina Medina‐Gómez, Fernando Rivadeneira, Karol Estrada, André G. Uitterlinden, Albert Hofman, M. Carola Zillikens, Martin den Heijer, Lambertus A. Kiemeney, Andrea Maschio, Per Hall, Jonathan P. Tyrer, Alexander Teumer, Henry Völzke, Péter Kovács, Anke Tönjes, Massimo Mangino, Tim D. Spector, Caroline Hayward, Igor Rudan, Alistair S. Hall, Nilesh J. Samani, Antony Attwood, Jennifer G. Sambrook, Joseph Hung, Lyle J. Palmer, Marja‐Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki V. 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 T. Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John Beilby, Jennie Hui, Jennifer Jolley, Hendrik B. Sager, Stefan R. Bornstein, Peter 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 KrjutÅ¡kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian’an Luan, Ken K. Ong, Peter S. Chines, Sirkka Keinänen‐Kiukaanniemi, Timo Saaristo, Sarah Edkins, Paul W. Franks, Göran Hallmans, Dmitry Shungin, Andrew David 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 Köenig, 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, J. W. G. Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf dé Fairé, 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 D. Hingorani, Mika Kivimäki, Meena Kumari, Themistocles L. Assimes, Inês Barroso, Michael Boehnke, Ingrid B. Borecki, Panos Deloukas, Caroline S. Fox, Timothy M. Frayling, Leif C. Groop, Talin Haritunians, David J. Hunter, Erik Ingelsson, Robert C. Kaplan, Karen L. Mohlke, Jeffrey R. O’Connell, David Schlessinger, David P. Strachan, Kāri Stefánsson, 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 - PLoS Genetics 2013 cited by 459

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.