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. Lockes, Reedik Maegi, 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, Zoltan Kutalik, Jian'an Luan, Joshua C. Randall, Andre Scherag, Rudolf Fehrmann, Juha Karjalainen, Irene Mateo Leach, Jana V. Van Vliet-Ostaptchouk, Marcel Bruinenberg, Michael R. Erdos, Catharina A. Hartman, Hans L. Hillege, Ilja M. Nolte, Salome Scholtens, Albert Vernon Smith, Morris A. Swertz, Niek Verweij, Judith M. Vonk, Jing Hua Zhao, Harm-Jan Westra, Stephan J. L. Bakker, Ron T. Gansevoort, Meena Kumari, Albertine J. Oldehinkel, Brenda W. Penninx, Ronald P. Stolk, Harold Snieder, Pim van der Harst, Lude Franke, ADIPOGen Consortium, CARDIoGRAMplusC4d Consortium, CKDGen Consortium, GEFOS Consortium, GENIE Consortium, GLGC, ICBP, Int Endogene Consortium, Lifelines Cohort Study, MAGIC Investigators, MuTHER Consortium, PAGE Consortium, ReproGen Consortium

Research output: Contribution to journalArticleAcademicpeer-review

685 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

  • GENOME-WIDE ASSOCIATION
  • MESENCHYMAL STEM-CELLS
  • HUMAN HEIGHT
  • ADIPOGENIC DIFFERENTIATION
  • ABDOMINAL ADIPOSITY
  • SUSCEPTIBILITY LOCI
  • SEXUAL-DIMORPHISM
  • GLYCEMIC TRAITS
  • FALSE DISCOVERY
  • COMMON SNPS

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