Open Accessmi RNA contributions to pediatric‐onset multiple sclerosis inferred from GWAS
Author(s) -
Rhead Brooke,
Shao Xiaorong,
Graves Jennifer S.,
Chitnis Tanuja,
Waldman Amy T.,
Lotze Timothy,
Schreiner Teri,
Belman Anita,
Krupp Lauren,
Greenberg Benjamin M.,
Weinstock–Guttman Bianca,
Aaen Gregory,
Tillema Jan M.,
Rodriguez Moses,
Hart Janace,
Caillier Stacy,
Ness Jayne,
Harris Yolanda,
Rubin Jennifer,
Candee Meghan S.,
Gorman Mark,
Benson Leslie,
Mar Soe,
Kahn Ilana,
Rose John,
Casper T. Charles,
Quach Hong,
Quach Diana,
Schaefer Catherine,
Waubant Emmanuelle,
Barcellos Lisa F.
Publication year - 2019
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.786
Subject(s) - microrna , genome wide association study , epigenetics , single nucleotide polymorphism , gene , multiple sclerosis , genetics , biomarker , pathogenesis , medicine , biology , bioinformatics , immunology , genotype
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.