The trans-ancestral genomic architecture of glycemic traits

Nat Genet. 2021 Jun;53(6):840-860. doi: 10.1038/s41588-021-00852-9. Epub 2021 May 31.

Abstract

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

Publication types

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

MeSH terms

  • Alleles
  • Blood Glucose / genetics*
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Genome, Human
  • Genome-Wide Association Study
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Multifactorial Inheritance / genetics
  • Physical Chromosome Mapping
  • Quantitative Trait Loci / genetics
  • Quantitative Trait, Heritable*
  • Whites / genetics*

Substances

  • Blood Glucose
  • Glycated Hemoglobin A

Grant support