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

Authors:
Dr Zoltán Kutalik, PhD
Dr Zoltán Kutalik, PhD
Institute of Social and Preventive Medicine, CHUV
Assistant Professor
Biostatistics
Lausanne, Vaud | Switzerland
Dr. Najaf Amin, PhD
Dr. Najaf Amin, PhD
Erasmus University Medical Center
Rotterdam | Netherlands
Joshua C Randall Thomas W Winkler 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 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 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 Asa 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 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 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

PLoS Genet 2013 Jun 6;9(6):e1003500. Epub 2013 Jun 6.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.

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.

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http://dx.doi.org/10.1371/journal.pgen.1003500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674993PMC
June 2013
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