eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
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Published:2023-10-30
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Nguyen Jennifer P., Arthur Timothy D., Fujita Kyohei, Salgado Bianca M., Donovan Margaret K. R., Aguiar Lana Ribeiro, Arias Angelo D., Benaglio Paola, Berggren W. Travis, Belmonte Juan Carlos Izpisua, Borja Victor, Cook Megan, DeBoever Christopher, Diffenderfer Kenneth E., Farnam KathyJean, Garcia Melvin, Harismendy Olivier, Henson Benjamin A., Jakubosky David, Jepsen Kristen, Li He, Nariai Naoki, O’Connor Daniel T., Okubo Jonathan, Panopoulos Athanasia D., Rao Fengwen, Reyna Joaquin, Silva Nayara, Smith Erin N., Sohmer Josh, Yost Shawn, Young Greenwald William. W., Matsui Hiroko, Kim Ji HyunORCID, D’Antonio-Chronowska Agnieszka, D’Antonio Matteo, Frazer Kelly A.ORCID,
Abstract
AbstractThe 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.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference118 articles.
1. DiscovEHR Collaboration, CHARGE. et al. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature 570, 71–76 (2019). . 2. Chen, J. et al. The trans-ancestral genomic architecture of glycemic traits. Nat. Genet 53, 840–860 (2021). 3. Chiou, J. et al. Interpreting type 1 diabetes risk with genetics and single-cell epigenomics. Nature 594, 398–402 (2021). 4. Mahajan, A. et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet. 50, 1505–1513 (2018). 5. Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011).
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