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Objective  Onset of multiple sclerosis ( MS ) occurs in childhood for approximately 5% of cases (pediatric  MS , or ped‐ MS ). Epigenetic influences are strongly implicated in  MS  pathogenesis in adults, including the contribution from micro RNA s (mi RNA s), small noncoding  RNA s that affect gene expression by binding target gene  mRNA s. Few studies have specifically examined mi RNA s in ped‐ MS , but individuals developing  MS  at an early age may carry a relatively high burden of genetic risk factors, and mi RNA  dysregulation may therefore play a larger role in the development of ped‐ MS  than in adult‐onset  MS . This study aimed to look for evidence of mi RNA  involvement in ped‐ MS  pathogenesis.    Methods   GWAS  results from 486 ped‐ MS  cases and 1362 controls from the U.S. Pediatric  MS  Network and Kaiser Permanente Northern California membership were investigated for mi RNA ‐specific signals. First, enrichment of mi RNA ‐target gene network signals was evaluated using  MIGWAS  software. Second,  SNP s in mi RNA  genes and in target gene binding sites (miR− SNP s) were tested for association with ped‐ MS , and pathway analysis was performed on associated target genes.    Results   MIGWAS  analysis showed that mi RNA ‐target gene signals were enriched in  GWAS  ( P  = 0.038) and identified 39 candidate biomarker mi RNA ‐target gene pairs, including immune and neuronal signaling genes. The miR‐ SNP  analysis implicated dysregulation of mi RNA  binding to target genes in five pathways, mainly involved in immune signaling.    Interpretation  Evidence from  GWAS  suggests that mi RNA s play a role in ped‐ MS  pathogenesis by affecting immune signaling and other pathways. Candidate biomarker mi RNA ‐target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

mi RNA contributions to pediatric‐onset multiple sclerosis inferred from GWAS