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, Albert Vernon Smith, Jing Hua Zhao, Brenda Penninx, Ilja M Nolte, Harold Snieder, Melanie M Van der Klauw, Jana V Van Vliet-Ostaptchouk, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Meena Kumari, DIAGRAM Consortium

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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
Article number1003500
Number of pages19
JournalPLoS genetics
Volume9
Issue number6
DOIs
Publication statusPublished - Jun-2013

Keywords

  • BODY-MASS INDEX
  • WAIST-HIP RATIO
  • FAT DISTRIBUTION
  • ENZYME-ACTIVITIES
  • ADULT HEIGHT
  • PPAR-GAMMA
  • RISK
  • VARIANTS
  • METAANALYSIS
  • OBESITY

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