Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits

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

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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.
Faculties and Departments:09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB) > Research Group Rivolta IOB
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Public Library of Science
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Apr 2023 03:10
Deposited On:10 Mar 2021 14:37

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