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The trans-ancestral genomic architecture of glycemic traits

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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.

Original languageEnglish
JournalNature Genetics
Issue number6
Pages (from-to)840-860
Number of pages21
Publication statusPublished - Jun 2021

    Research areas

  • Alleles, Blood Glucose/genetics, Epigenesis, Genetic, European Continental Ancestry Group/genetics, 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

ID: 67442756