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 unexpected 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 causal role for the exocrine pancreas in T1D pathogenesis and highlight the power of combining large-scale GWAS and single cell epigenomics to provide novel insight into the cellular origins of complex disease.

中文翻译：

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大规模遗传关联和单细胞可及的染色质图谱确定了1型糖尿病风险的细胞类型特异性机制

将复杂疾病的全基因组关联研究（GWAS）转换为机械的见解，需要全面了解风险变异对疾病相关细胞类型的影响。为了揭示1型糖尿病（T1D）风险的细胞类型特异性机制，我们结合了遗传关联图谱和单细胞表观基因组学。我们在489679个样本中执行了迄今为止最大的T1D GWAS，这些样本被归类为59.2M变异，其中鉴定了74个新的关联信号，包括几个大的罕见稀有变异。总共141个信号的精细映射极大地提高了因果变量可信集的分辨率，这些因果变量可信集主要映射到非编码序列。为了注释T1D风险变异的特定于细胞类型的调控机制，我们绘制了448个 使用snATAC-seq 131,554个核，可检测胰腺和外周血单核细胞类型中的142个候选顺式调控元件（cCRE）。T1D风险变体富含CD4 + T细胞中活跃的cCRE，以及多种意外细胞类型，包括胰腺外分泌腺泡和导管细胞。映射到外分泌特异性cCRE的多个信号上的高概率T1D风险变体，包括CEL，GP2和CFTR附近的新基因座。在CFTR位点，可能的因果变异体rs7795896映射在调节CFTR的导管特异性远端cCRE中，而风险等位基因降低了导管细胞中转录因子结合，增强子活性和CFTR表达。