Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
Genome-wide Association Study
Genetic Association
Epigenomics
Genetic architecture
Genetic genealogy
Cell type
DOI:
10.1038/s41586-024-07019-6
Publication Date:
2024-02-19T17:02:21Z
AUTHORS (374)
ABSTRACT
Abstract Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms are often specific to cell type 3,4 . Here, characterize the genetic contribution these across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases T2D. We identify 1,289 independent signals at significance ( P < 5 × 10 −8 ) map 611 loci, which 145 loci are, our knowledge, previously unreported. define eight non-overlapping clusters T2D characterized by distinct profiles cardiometabolic trait associations. These differentially enriched for cell-type-specific regions open chromatin, pancreatic islets, adipocytes, endothelial cells enteroendocrine cells. build cluster-specific partitioned polygenic scores in further 279,552 ancestry, 30,288 T2D, test their with T2D-related vascular outcomes. Cluster-specific associated coronary artery disease, peripheral end-stage diabetic nephropathy highlighting importance obesity-related development Our findings show value integrating multi-ancestry single-cell epigenomics disentangle aetiological heterogeneity drives progression This might offer route optimize global access genetically informed care.
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