New genetic loci link adipose and insulin biology to body fat distribution

Dmitry Shungin, Thomas W Winkler, Damien C Croteau-Chonka, Teresa Ferreira, Adam E Locke, Reedik Mägi, Rona J Strawbridge, Tune H Pers, Krista Fischer, Anne E Justice, Tsegaselassie Workalemahu, Joseph M W Wu, Martin L Buchkovich, Nancy L Heard-Costa, Tamara S Roman, Alexander W Drong, Ci Song, Stefan Gustafsson, Felix R Day, Tonu EskoTove Fall, Zoltán Kutalik, Jian'an Luan, Joshua C Randall, André Scherag, Sailaja Vedantam, Andrew R Wood, Jin Chen, Rudolf Fehrmann, Juha Karjalainen, Bratati Kahali, Ching-Ti Liu, Ellen M Schmidt, Devin Absher, Najaf Amin, Denise Anderson, Marian Beekman, Jennifer L Bragg-Gresham, Steven Buyske, Ayse Demirkan, Georg B Ehret, Mary F Feitosa, Anuj Goel, Anne U Jackson, Toby Johnson, Marcus E Kleber, Kati Kristiansson, Alex S F Doney, Andrew D Morris, Colin N A Palmer, ADIPOGen Consortium

    Research output: Contribution to journalArticlepeer-review

    689 Citations (Scopus)

    Abstract

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

    Original languageEnglish
    Pages (from-to)187-196
    Number of pages10
    JournalNature
    Volume518
    Issue number7538
    DOIs
    Publication statusPublished - 12 Feb 2015

    Keywords

    • Adipocytes
    • Adipogenesis
    • Adipose Tissue
    • Age Factors
    • Body Fat Distribution
    • Body Mass Index
    • Continental Population Groups
    • Epigenesis, Genetic
    • Europe
    • Female
    • Genome, Human
    • Genome-Wide Association Study
    • Humans
    • Insulin
    • Insulin Resistance
    • Male
    • Models, Biological
    • Neovascularization, Physiologic
    • Obesity
    • Polymorphism, Single Nucleotide
    • Quantitative Trait Loci
    • Sex Characteristics
    • Transcription, Genetic
    • Waist-Hip Ratio

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