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

Nat Commun. 2021 Jan 5;12(1):24. doi: 10.1038/s41467-020-19366-9.


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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anorexia Nervosa / blood
  • Anorexia Nervosa / ethnology
  • Anorexia Nervosa / genetics*
  • Anorexia Nervosa / physiopathology
  • Blood Glucose / metabolism*
  • Fasting / blood
  • Female
  • Gene Expression
  • Genetic Loci
  • Genome-Wide Association Study
  • Glucose Intolerance / blood
  • Glucose Intolerance / ethnology
  • Glucose Intolerance / genetics*
  • Glucose Intolerance / physiopathology
  • Humans
  • Insulin / blood*
  • Insulin Receptor Substrate Proteins / blood
  • Insulin Receptor Substrate Proteins / genetics*
  • Insulin Resistance / genetics*
  • Kruppel-Like Transcription Factors / blood
  • Kruppel-Like Transcription Factors / genetics*
  • Male
  • Middle Aged
  • Phenotype
  • Sex Characteristics
  • Sex Factors
  • Waist-Hip Ratio
  • Whites


  • Blood Glucose
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Kruppel-Like Transcription Factors
  • ZNF12 protein, human

Grant support