Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis.
Henry J TaylorYu-Han HungNarisu NarisuMichael R ErdosMatthew KankeTingfen YanCaleb M GrenkoAmy J SwiftLori L BonnycastlePraveen SethupathyFrancis S CollinsD Leland TaylorPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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.
Keyphrases
- genome wide
- poor prognosis
- type diabetes
- long non coding rna
- dna methylation
- cell proliferation
- endothelial cells
- copy number
- blood glucose
- glycemic control
- binding protein
- cardiovascular disease
- high resolution
- metabolic syndrome
- machine learning
- skeletal muscle
- insulin resistance
- gene expression
- pluripotent stem cells
- induced pluripotent stem cells
- single molecule
- deep learning
- big data
- functional connectivity