Integrated Approaches to Identify miRNA Biomarkers Associated with Cognitive Dysfunction in Multiple Sclerosis Using Text Mining, Gene Expression, Pathways, and GWAS.

ABSTRACT

Multiple sclerosis (MS), a chronic autoimmune disorder, affects the central nervous system of many young adults. More than half of MS patients develop cognition problems. Although several genomic and transcriptomic studies are currently reported in MS cognitive impairment, a comprehensive repository dealing with all the experimental data is still underdeveloped. In this study, we combined text mining, gene regulation, pathway analysis, and genome-wide association studies (GWAS) to identify miRNA biomarkers to explore the cognitive dysfunction in MS, and to understand the genomic etiology of the disease. We first identified the dysregulated miRNAs associated with MS and cognitive dysfunction using PubTator (text mining), HMDD (experimental associations), miR2Disease, and PhenomiR database (differentially expressed miRNAs). Our results suggest that miRNAs such as hsa-mir-148b-3p, hsa-mir-7b-5p, and hsa-mir-7a-5p are commonly associated with MS and cognitive dysfunction. Next, we retrieved GWAS signals from GWAS Catalog, and analyzed the enrichment analysis of association signals in genes/miRNAs and their association networks. Then, we identified susceptible genetic loci, rs17119 (chromosome 6; p = 1 × 10-10), rs1843938 (chromosome 7; p = 1 × 10-10), and rs11637611 (chromosome 15; p = 1.00 × 10-15), associated with significant genetic risk. Lastly, we conducted a pathway analysis for the susceptible genetic variants and identified novel risk pathways. The ECM receptor signaling pathway (p = 3.98 × 10-8) and PI3K/Akt signaling pathway (p = 5.98 × 10-5) were found to be associated with differentially expressed miRNA biomarkers.