Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk

Joshua Chiou, Ryan J Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Paola Benaglio, Serina Huang, Katha Korgaonkar, Sandra Heller, Alexander Kleger, Sebastian Preissl, David U Gorkin, Maike Sander, Kyle J Gaulton.
Nature. 2021-05-19;594(7863):398-402.
Abstract
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.
Datasets
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