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, DIAGRAM Consortium, Amélie Bonnefond, Philippe Froguel, MAGIC Investigators, 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, Andrew David Morris, Colin N. A. Palmer

    Research output: Contribution to journalArticle

    204 Citations (Scopus)

    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
    Pages (from-to)e1003500
    JournalPLoS Genetics
    Volume9
    Issue number6
    DOIs
    Publication statusPublished - Jun 2013

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  • Cite this

    Randall, J. C., Winkler, T. W., Kutalik, Z., Berndt, S. I., Jackson, A. U., Monda, K. L., Kilpeläinen, T. O., Esko, T., Mägi, R., Li, S., Workalemahu, T., Feitosa, M. F., Croteau-Chonka, D. C., Day, F. R., Fall, T., Ferreira, T., Gustafsson, S., Locke, A. E., Mathieson, I., ... Palmer, C. N. A. (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. https://doi.org/10.1371/journal.pgen.1003500