RT Journal Article
SR Electronic
T1 Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.19.158071
DO 10.1101/2020.06.19.158071
A1 C.C. Robertson
A1 J.R.J. Inshaw
A1 S. Onengut-Gumuscu
A1 W.M. Chen
A1 D. Flores Santa Cruz
A1 H. Yang
A1 A.J. Cutler
A1 D.J.M. Crouch
A1 E. Farber
A1 S.L. Bridges, Jr.
A1 J.C. Edberg
A1 R.P. Kimberly
A1 J.H. Buckner
A1 P. Deloukas
A1 J. Divers
A1 D. Dabelea
A1 J.M. Lawrence
A1 S. Marcovina
A1 A.S. Shah
A1 C.J. Greenbaum
A1 M.A. Atkinson
A1 P.K. Gregersen
A1 J.R. Oksenberg
A1 F. Pociot
A1 M.J. Rewers
A1 A.K. Steck
A1 D.B. Dunger
A1 Type 1 Diabetes Genetics Consortium
A1 L.S. Wicker
A1 P. Concannon
A1 J.A. Todd
A1 S.S. Rich
YR 2020
UL http://biorxiv.org/content/early/2020/06/20/2020.06.19.158071.abstract
AB We report the largest and most ancestrally diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 152 regions associated to false discovery rate < 0.01, including 36 regions associated to genome-wide significance for the first time. Credible sets of disease-associated variants are specifically enriched in immune cell accessible chromatin, particularly in CD4+ effector T cells. Colocalization with chromatin accessibility quantitative trait loci (QTL) in CD4+ T cells identified five regions where differences in T1D risk and chromatin accessibility are potentially driven by the same causal variant. Allele-specific chromatin accessibility further refined the set of putative causal variants with functional relevance in CD4+ T cells and integration of whole blood expression QTLs identified candidate T1D genes, providing high-yield targets for mechanistic follow-up. We highlight rs72938038 in BACH2 as a candidate causal T1D variant, where the T1D risk allele leads to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritise 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, including proposed genetic regulatory mechanisms of T1D-associated variants and genetic support for therapeutic targets for immune intervention.Competing Interest StatementThe authors have declared no competing interest.