Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk
- Translating genome-wide association studies (GWAS) of complex disease into mechanistic insight requires a comprehensive understanding of risk variant effects on disease-relevant cell types. To uncover cell type-specific mechanisms of type 1 diabetes (T1D) risk, we combined genetic association mapping and single cell epigenomics. We performed the largest to-date GWAS of T1D in 489,679 samples imputed into 59.2M variants, which identified 74 novel association signals including several large-effect rare variants. Fine-mapping of 141 total signals substantially improved resolution of causal variant credible sets, which primarily mapped to non-coding sequence. To annotate cell type-specific regulatory mechanisms of T1D risk variants, we mapped 448,142 candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types using snATAC-seq of 131,554 nuclei. T1D risk variants were enriched in cCREs active in CD4+ T cells as well as several additional cell types including pancreatic exocrine acinar and ductal cells. High-probability T1D risk variants at multiple signals mapped to exocrine-specific cCREs including novel loci near CEL, GP2 and CFTR. At the CFTR locus, the likely causal variant rs7795896 mapped in a ductal-specific distal cCRE which regulated CFTR and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of combining large-scale GWAS and single cell epigenomics to provide insight into the cellular origins of complex disease.
- DSR498EST, DSR154TPS, DSR438WOP, DSR346BYL, DSR442HUB, DSR707UPV, DSR049FNX, DSR031KHQ, DSR692GIQ, DSR518CVA, DSR816KMT, DSR343BJL, DSR043PPI, DSR644USU, DSR247GCT, DSR294OVU, DSR467IUK, DSR862VRJ, DSR069AHP, DSR223BJV, DSR197KBT, DSR234HXR, DSR928RQE, DSR780YWW, DSR579LZJ, DSR550HPP, DSR185GHH, DSR018TPI, DSR179DUH, DSR478ONG, DSR213MXZ, DSR489SMI, DSR878UFU, DSR134FCG, DSR828VFT, DSR325RMY, DSR805RPA, DSR097XAH, DSR260WKD, DSR850IVU, DSR591ZJC, DSR247PPG, DSR821QOK, DSR521RYC, DSR705YZV, DSR630CDR, DSR457TFN, DSR397SUR, DSR158NKH, DSR961ZKL, DSR946TIV, DSR305VNP, DSR056HMW, DSR998IGH, DSR746SVT, DSR131NAF, DSR166ECC, DSR345BXM, DSR212PJX, DSR430JXD, DSR268KVC, DSR392JWG, DSR519OVI, DSR813PSH, DSR104LZJ, DSR059MDJ, DSR738GNU, DSR499CQG, DSR092ALL, DSR078DAN, DSR831GCV, DSR056DWK, DSR047LET