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

Jennifer P. Nguyen, Timothy D. Arthur, Kyohei Fujita, Bianca M. Salgado, Margaret K. R. Donovan, Hiroko Matsui, Ji Hyun Kim, Agnieszka D’Antonio-Chronowska, Matteo D’Antonio and Kelly A. Frazer ()
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Jennifer P. Nguyen: University of California, San Diego
Timothy D. Arthur: University of California, San Diego
Kyohei Fujita: University of California, San Diego
Bianca M. Salgado: University of California San Diego, 9500 Gilman Dr
Margaret K. R. Donovan: University of California, San Diego
Hiroko Matsui: University of California San Diego, 9500 Gilman Dr
Ji Hyun Kim: Dongguk University Ilsan Hospital
Agnieszka D’Antonio-Chronowska: University of California, San Diego
Matteo D’Antonio: University of California, San Diego
Kelly A. Frazer: University of California, San Diego

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42560-4

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