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Fine-mapping, trans-ancestral, and genomic analyses identify causal variants, cells, genes, and drug targets for type 1 diabetes
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7 2021
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Source: Nat Genet. 53(7):962-971
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Alternative Title:Nat Genet
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Description:We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10|) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4| effector T cells. Using chromatin-accessibility profiling of CD4| T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
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Pubmed ID:34127860
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Pubmed Central ID:PMC8273124
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Volume:53
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Issue:7
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