The trans-ancestral genomic architecture of glycemic traits

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Nat Genet 53 (6) 840-860 [2021-06-00; online 2021-05-31]

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.

NGI Uppsala (SNP&SEQ Technology Platform)

National Genomics Infrastructure

QC bibliography QC xrefs

PubMed 34059833

DOI 10.1038/s41588-021-00852-9

Crossref 10.1038/s41588-021-00852-9

pii: 10.1038/s41588-021-00852-9
pmc: PMC7610958
mid: EMS120610