UC San Diego

Adverse events during fetal pancreas development can result in insulin resistance, impaired glucose metabolism, and loss of beta cell function, leading to an increased risk of developing diabetes in adulthood. While current quantitative trait loci (QTL) datasets have been instrumental in characterizing genetic variants associated with diabetes, they only reflect molecular associations present in mature adult tissues. Furthermore, only a fraction of diabetes-associated loci colocalize with QTLs identified in adult whole pancreas and islet tissues. Given the important role of fetal development in adult diabetes predisposition, interrogating the molecular effects of genetic variation during this crucial period could provide valuable mechanistic insights into the etiology of obesity and diabetes. First, we conducted an eQTL analysis on 107 RNA-seq samples from iPSC-derived pancreatic progenitor cells (PPC) to map genetic loci associated with gene expression and isoform usage changes during early pancreas development. Colocalization with eQTLs from adult pancreatic tissues identified genetic variants that were either specifically active during early pancreas development, specifically active in the adult pancreatic stage, or shared across both stages but had stage-unique regulatory functions. Colocalization with genome-wide association studies (GWAS) loci revealed developmental-unique eQTLs with potential roles in glucose homeostasis or diabetes, including those associated with TPD52, CDC37L1-DT, MEG3, and CDH3. Second, we conducted chromatin accessibility QTL (caQTL) analysis using matched PPC ATAC-seq samples. We found that caQTL variants were enriched in distal regulatory regions, including CTCF-binding sites and PPC-specific super enhancer regions, and were enriched for motifs of transcription factors expressed in pancreatic progenitors. Colocalization of eQTLs, caQTLs, and GWAS signals identified putative regulatory mechanisms for TPD52 expression and its impact on fasting glucose levels, as well as KIT and its impact on body mass index. Together, this body of work provides a unique and powerful resource for interrogating the molecular effects of genetic variation during early pancreas development and their potential impact on adult complex pancreatic traits and disease.