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

Jennifer P. Nguyen, Timothy D. Arthur, Kyohei Fujita, Bianca M. Salgado, Margaret K.R. Donovan, iPSCORE Consortium, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, View ORCID ProfileMatteo D’Antonio, Kelly A. Frazer
doi: https://doi.org/10.1101/2021.03.17.435846
Jennifer P. Nguyen
1Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USA
2Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA, 92093, USA
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Timothy D. Arthur
2Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA, 92093, USA
3Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA
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Kyohei Fujita
4Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA
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Bianca M. Salgado
4Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA
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Margaret K.R. Donovan
1Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USA
2Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA, 92093, USA
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Hiroko Matsui
4Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA
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Agnieszka D’Antonio-Chronowska
6Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92093, USA
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  • For correspondence: adc055@health.ucsd.edu madantonio@health.ucsd.edu kafrazer@health.ucsd.edu
Matteo D’Antonio
2Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA, 92093, USA
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  • ORCID record for Matteo D’Antonio
  • For correspondence: adc055@health.ucsd.edu madantonio@health.ucsd.edu kafrazer@health.ucsd.edu
Kelly A. Frazer
4Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA
6Department of Pediatrics, University of California, San Diego, La Jolla, CA, 92093, USA
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  • For correspondence: adc055@health.ucsd.edu madantonio@health.ucsd.edu kafrazer@health.ucsd.edu
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Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵5 A full list of Consortium members and their affiliations appears at the end of the manuscript

  • We updated the manuscript.

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152610

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 23, 2023.
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Disease-associated regulatory variation often displays plasticity or temporal-specificity in fetal pancreas
Jennifer P. Nguyen, Timothy D. Arthur, Kyohei Fujita, Bianca M. Salgado, Margaret K.R. Donovan, iPSCORE Consortium, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Matteo D’Antonio, Kelly A. Frazer
bioRxiv 2021.03.17.435846; doi: https://doi.org/10.1101/2021.03.17.435846
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Disease-associated regulatory variation often displays plasticity or temporal-specificity in fetal pancreas
Jennifer P. Nguyen, Timothy D. Arthur, Kyohei Fujita, Bianca M. Salgado, Margaret K.R. Donovan, iPSCORE Consortium, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Matteo D’Antonio, Kelly A. Frazer
bioRxiv 2021.03.17.435846; doi: https://doi.org/10.1101/2021.03.17.435846

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