Disease-associated regulatory variation often displays plasticity or temporal-specificity in fetal pancreas

The role of genetic regulatory variation during fetal pancreas development is not well understood. We generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4,065 genes and 4,016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate endocrine and exocrine eQTLs identified in adult pancreatic tissues, which reveals 2,683 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1,139 eQTLs that exhibit regulatory plasticity across fetal-like and adult pancreas. Investigation of GWAS risk loci for pancreatic diseases shows that some putative causal regulatory variants are active in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity can exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.