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

Abstract

Genetic studies have identified ≥240 loci associated with 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, representing the largest sequencing-based analysis of miRNA expression in human islets to date. We characterize 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-eQTLs). We find (i) 81 heritable miRNAs, primarily regulated by trans-acting genetic effects, and (ii) 5 miRNA-eQTLs. We also use several different strategies to identify T2D-associated miRNAs. First, we colocalize 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 intersect miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and find 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we perform differential expression analysis and identify 13 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.

Identification and functional validation of human islet microRNAs associated with donor trait

“…We ( Figure 2C ) and others [40] found miR-214-3p associated with donor sex in human islets. The long non-coding RNA X-inactivation specific transcript (XIST, required for inducing X-chromosome inactivation in females) has been shown to interact with miR-214-3p [41].…”

The ChickenGTEx pilot analysis: a reference of regulatory variants across 28 chicken tissues

“…We have demonstrated that different molecular phenotypes of the same genes were likely to be controlled by distinct genomic loci through distinct regulatory mechanisms, indicating the importance of integrating omics data corresponding to multi-layer biologically-important molecular phenotypes (e.g., epigenetic mark activity and microRNA expression (74)) in future studies. This is consistent with findings in humans that most of the sQTL and 3a'QTL were distinct from eQTL (75,76).…”