Cell-type-specific cis-eQTLs in pancreatic cell types identify novel risk genes for type 2 diabetes.

Type 2 diabetes (T2D) is a complex metabolic disorder strongly influenced by genetics. Most genetic studies, including expression quantitative trait loci (eQTL) analyses, use bulk pancreatic tissue, masking cell-specific mechanisms. Here, by integrating single-cell RNA sequencing, chromatin accessibility, and genome-wide association studies (GWAS) data, we systematically identified 328 pancreatic cell-type-specific cis-eQTLs associated with T2D. We pinpointed nine key genes (including STIL in beta and delta cells; ZSWIM5 in alpha, delta, and ductal cells; IL1RN, ANP32E, IPP, MLLT11, and SLC23A3 in delta cells; SNX4 in gamma cells; and RBMS1 in beta cells) whose SNPs overlapped with chromatin accessibility peaks. These genes highlight regulatory pathways in beta-cell dysfunction, metabolic stress responses, and disrupted pancreatic homeostasis. A public database, CTPeQTLs (https://ctpeqtls.netlify.app/), was developed to explore cis-eQTLs across diabetic and non-diabetic cohorts, revealing distinct regulatory patterns in both endocrine and exocrine cells, as well as disease-associated transcriptional dysregulation. Our findings uncover cell-specific genetic mechanisms in diabetes and provide potential therapeutic targets, supporting precision medicine strategies.