Genome-wide identification of circulating-miRNA expression quantitative trait loci reveals the role of several miRNAs in the regulation of cardiometabolic phenotypes. Issue 11 (31st January 2019)

• Record Type: Journal Article
• Authors: Nikpay, Majid; Beehler, Kaitlyn; Valsesia, Armand; Hager, Jorg; Harper, Mary-Ellen; Dent, Robert; McPherson, Ruth
• Is Part Of: Cardiovascular research. Volume 115:Issue 11(2019)
• Page Start: 1629
• Page End: 1645
• Publication Date: 2019-01-31
• Subjects: Circulating-miRNA -- RNA-Seq -- GWAS -- eQTL -- Biomarkers -- Cardiometabolic traits -- Multi-omic analysis; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvz030
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs) and to connect genetic risk to blood traits/biomarkers through the circulating miRNAs. Methods and results: Leveraging miRNA-Seq data and the 1000 Genomes imputed genotypes, we carried out genome-wide association analysis for SNPs that regulate the expression of circulating miRNAs in a sample of 710 unrelated subjects of European ancestry. Wherever possible, we used data from the Framingham and the Geuvadis studies to replicate our findings. We found at least one genome-wide significant ( P < 5e −8 ) miRNA-eQTL (mirQTL) for 143 circulating miRNAs. Overall each mirQTL explained a small portion (<1%) of variation in miRNA levels; however, we identified a few mirQTLs that explained 4% to 20% of variation in miRNA levels in plasma. Unlike trans -mirQTLs ( P = 0.7), cis -mirQTLs tend to be also associated with their counterpart mature miRNAs ( P < 0.0001), this suggests trans -mirQTLs exert their effect through processes that affect the stability of mature miRNAs; whereas, cis -mirQTLs mainly regulate the expression of primary-miRNAs. Next, we used the identified mirQTLs to investigate the links between circulating miRNAs with blood traits/biomarkers through Mendelian randomization analysis. We found miR-1908-5p plays an important role in regulating low-density lipoprotein (LDL), total cholesterol (TC), fasting glucose, HbA1c, and several lipid-metabolites in blood, whereas, miR-10b-5p mediates the trans -regulatory effect of the ABO locus on several blood proteins, coronary artery disease, and TC. Moreover, we demonstrated that a higher plasma level of miR-199a is causally associated with lower levels of LDL and TC. Finally, we found miR-143-3p and miR-145-5p are functionally related and mediate the effect of ZFPM2 on a number of its protein targets in blood including VEGFA, SERPINE1, and PDGFs . Conclusions: This study identifies SNPs that have a regulatory impact on circulating miRNAs, and underlines the role of several circulating miRNAs in mediating the effect of a number of GWAS loci on cardiometabolic phenotypes. Graphical Abstract: