Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Research output: Contribution to journalArticle

Abstract

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. © 2021, The Author(s).

Details

Authors
  • Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)
  • Vasiliki Lagou
  • Ulrika Krus
  • Leif Groop
  • Tiinamaija Tuomi
  • Valeriya Lyssenko
  • Inga Prokopenko
Organisations
External organisations
  • University of Oxford
  • Catholic University of Leuven
  • Skåne University Hospital
  • Institute of Biochemistry and Genetics, Ufa Scientific Center RAS
  • Imperial College London
  • Wellcome Trust Centre for Human Genetics
  • University of Surrey
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
  • Medical Genetics
Original languageEnglish
Article number24
JournalNature Communications
Volume12
Issue number1
Publication statusPublished - 2021
Publication categoryResearch
Peer-reviewedYes