Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Author:

Taylor Henry J.123ORCID,Hung Yu-Han4,Narisu Narisu1,Erdos Michael R.1,Kanke Matthew4,Yan Tingfen1,Grenko Caleb M.1,Swift Amy J.1,Bonnycastle Lori L.1,Sethupathy Praveen4,Collins Francis S.1ORCID,Taylor D. Leland1ORCID

Affiliation:

1. Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD 20892

2. British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0BB, UK

3. Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0BB, UK

4. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853

Abstract

Genetic studies have identified ≥240 loci associated with the risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterized the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans- acting genetic components and mapping cis -acting loci associated with miRNA expression [miRNA-expression quantitative trait loci (eQTLs)]. We found i) 84 heritable miRNAs, primarily regulated by trans -acting genetic effects, and ii) 5 miRNA-eQTLs. We also used several different strategies to identify T2D-associated miRNAs. First, we colocalized miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersected miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and found 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we performed differential expression analysis and identified 14 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

Funder

HHS | National Institutes of Health

American Diabetes Association

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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