Hartman Institute for Therapeutic Organ Regeneration

Functional interrogation of twenty type 2 diabetes-associated genes using isogenic hESC-derived β-like cells.

TitleFunctional interrogation of twenty type 2 diabetes-associated genes using isogenic hESC-derived β-like cells.
Publication TypeJournal Article
Year of Publication2023
AuthorsXue D, Narisu N, D Taylor L, Zhang M, Grenko C, Taylor HJ, Yan T, Tang X, Sinha N, Zhu J, J Vandana J, Chong AChi Nok, Lee A, Mansell EC, Swift AJ, Erdos MR, Zhou T, Bonnycastle LL, Zhong A, Chen S, Collins FS
JournalbioRxiv
Date Published2023 May 08
Abstract

<p>Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival. We performed RNA-seq and ATAC-seq on hESC-β cells from each knockout line. Analyses of T2D GWAS signals overlapping with HNF4A-dependent ATAC peaks identified a specific SNP as a likely causal variant. In addition, we performed integrative association analyses and identified four genes ( and ) associated with insulin production, and two genes ( and ) associated with sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental hESC line, to identify a single likely functional variant at each of 23 T2D GWAS signals.</p>

DOI10.1101/2023.05.07.539774
Alternate JournalbioRxiv
PubMed ID37214922
PubMed Central IDPMC10197532

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
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