The trans-ancestral genomic architecture of glycemic traits

LifeLines Cohort Study, The Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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 x 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.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Original languageEnglish
Pages (from-to)840-860
Number of pages41
JournalNature Genetics
Volume53
Issue number6
Early online date31 May 2021
DOIs
Publication statusPublished - Jun 2021

Keywords

  • WIDE ASSOCIATION
  • INSULIN-RESISTANCE
  • GENE-EXPRESSION
  • DISEASE RISK
  • VARIANTS
  • GLUCOSE
  • LOCI
  • METAANALYSIS
  • MECHANISMS
  • HEMOGLOBIN

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