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Publication Information
Authors
Robertson Catherine C., Inshaw Jamie R. J., Onengut-Gumuscu Suna, Chen Wei-Min, Cruz David Flores Santa, Yang Hanzhi, Cutler Antony J., Crouch Daniel J. M., Farber Emily, Bridges S. Louis, Edberg Jeffrey C., Kimberly Robert P., Buckner Jane H., Deloukas Panos, Divers Jasmin, Dabelea Dana, Lawrence Jean M., Marcovina Santica, Shah Amy S., Greenbaum Carla J., Atkinson Mark A., Gregersen Peter K., Oksenberg Jorge R., Pociot Flemming, Rewers Marian J., Steck Andrea K., Dunger David B., Concannon Patrick, Concannon Patrick, Pociot Flemming, Rich Stephen S., Todd John A., Wicker Linda S., Concannon Patrick, Todd John A., Rich Stephen S.
Studies
Abstract
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 × 10-8) regions, including 36 novel. We define credible sets of T1D-associated variants and show 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 (caQTLs) and identify five regions where T1D risk variants colocalize with caQTLs. 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.