eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk

• Published in: Nature communications Vol. 14; no. 1; p. 6928
• Main Authors: Nguyen, Jennifer P., Arthur, Timothy D., Fujita, Kyohei, Salgado, Bianca M., Donovan, Margaret K. R., Matsui, Hiroko, Kim, Ji Hyun, D’Antonio-Chronowska, Agnieszka, D’Antonio, Matteo, Frazer, Kelly A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 45/100; 45/91; 49; 49/31; 631/208/191/2018; 631/208/200; 631/208/212/2019; 692/699/2743; Adult; Alternative splicing; Base Sequence; Cells (biology); Developmental stages; Diabetes; Diabetes mellitus; Diabetes Mellitus - genetics; Disease; Fetuses; Gene expression; Gene mapping; Genes; Genetic diversity; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Health risks; Humanities and Social Sciences; Humans; Isoforms; Mapping; multidisciplinary; Pancreas; Pancreatic diseases; Plastic properties; Plasticity; Polymorphism, Single Nucleotide; Progenitor cells; Quantitative Trait Loci - genetics; Risk; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42560-4

The impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4065 genes and 4016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only 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 likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages. Fetal development plays an important role in defining adult diabetes risk. Here, authors identified a genetic link between fetal pancreatic gene expression, obesity, and diabetes risk through eQTL mapping of iPSC-derived pancreatic progenitor cells.