The trans-ancestral genomic architecture of glycemic traits
Journal
Nature Genetics
Journal Volume
53
Journal Issue
6
Pages
840-860
Date Issued
2021
Author(s)
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. ? 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
SDGs
Other Subjects
glucose; hemoglobin A1c; insulin; glycosylated hemoglobin; adult; Africa south of the Sahara; African American; aged; ancestry group; Article; cohort analysis; East Asian; European; female; gene expression; gene frequency; gene linkage disequilibrium; gene locus; gene mapping; gene set analysis; genetic heterogeneity; genetic trait; genome-wide association study; genomics; glucose blood level; hemoglobin blood level; Hispanic; human; insulin blood level; major clinical study; male; meta analysis; non insulin dependent diabetes mellitus; pathophysiology; prevalence; risk factor; South Asian; allele; Caucasian; chromosomal mapping; gene expression profiling; genetic epigenesis; genetics; human genome; metabolism; multifactorial inheritance; quantitative trait; quantitative trait locus; Alleles; Blood Glucose; Epigenesis, Genetic; European Continental Ancestry Group; Gene Expression Profiling; Genome, Human; Genome-Wide Association Study; Glycated Hemoglobin A; Humans; Multifactorial Inheritance; Physical Chromosome Mapping; Quantitative Trait Loci; Quantitative Trait, Heritable
Publisher
Nature Research
Type
journal article