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, André Scherag, Sailaja 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, Heinz 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 Adrianus 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 Gordon 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, 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 KrjutÅ¡kov, 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, Andrew David Morris, Colin N. A. Palmer, Raimund Erbel, Susanne Moebus, Markus Maria 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. Böhm, 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, Kari E. North, Cecilia M. Lindgren, Lu Qi, Ruth J. F. Loos, Iris M. Heid, Joel N. Hirschhorn, Mark I. McCarthy, Gonçalo R. Abecasis, Kari Stefansson, David P. Strachan, David Schlessinger, Jeffrey R. O'Connell, Cornelia M. van Duijn

  • Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference 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 significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.

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Author: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, André Scherag, Sailaja 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, Heinz 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 Adrianus 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 Gordon 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, 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 KrjutÅ¡kov, 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, Andrew David Morris, Colin N. A. Palmer, Raimund Erbel, Susanne Moebus, Markus Maria 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. Böhm, 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, Kari E. North, Cecilia M. Lindgren, Lu Qi, Ruth J. F. Loos, Iris M. Heid, Joel N. Hirschhorn, Mark I. McCarthy, Gonçalo R. Abecasis, Kari Stefansson, David P. Strachan, David Schlessinger, Jeffrey R. O'Connell, Cornelia M. van Duijn
URN:urn:nbn:de:hebis:30:3-301058
DOI:https://doi.org/10.1371/journal.pgen.1003500
ISSN:1553-7404
ISSN:1553-7390
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/23754948
Parent Title (English):PLoS Genetics
Publisher:Public Library of Science
Place of publication:San Francisco, Calif.
Document Type:Article
Language:English
Date of Publication (online):2013/06/06
Date of first Publication:2013/06/06
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Creating Corporation:DIAGRAM Consortium
Contributing Corporation:MAGIC Investigators
Release Date:2013/06/20
Volume:9
Issue:(6):e1003500
Page Number:19
Note:
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
HeBIS-PPN:34739762X
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0