miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS

On behalf of the US Network of Pediatric MS Centers

Research output: Contribution to journalArticle

Abstract

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 microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA 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 miRNA 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 miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR−SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes. Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling. Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

Original languageEnglish (US)
JournalAnnals of Clinical and Translational Neurology
DOIs
StatePublished - Jan 1 2019

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Genome-Wide Association Study
MicroRNAs
Multiple Sclerosis
Pediatrics
Genes
Single Nucleotide Polymorphism
Biomarkers
Small Untranslated RNA
Gene Regulatory Networks
Epigenomics
Software
Binding Sites

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

Cite this

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS. / On behalf of the US Network of Pediatric MS Centers.

In: Annals of Clinical and Translational Neurology, 01.01.2019.

Research output: Contribution to journalArticle

@article{36626bc58ea0496b992141c92e7cbef4,
title = "miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS",
abstract = "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 microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA 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 miRNA 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 miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR−SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes. Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling. Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.",
author = "{On behalf of the US Network of Pediatric MS Centers} and Brooke Rhead and Xiaorong Shao and Graves, {Jennifer S.} and Tanuja Chitnis and Waldman, {Amy T.} and Timothy Lotze and Teri Schreiner and Anita Belman and Lauren Krupp and Benjamin Greenberg and Bianca Weinstock–Guttman and Gregory Aaen and Tillema, {Jan M.} and Moses Rodriguez and Janace Hart and Stacy Caillier and Jayne Ness and Yolanda Harris and Jennifer Rubin and Candee, {Meghan S.} and Mark Gorman and Leslie Benson and Soe Mar and Ilana Kahn and John Rose and Casper, {T. Charles} and Hong Quach and Diana Quach and Catherine Schaefer and Emmanuelle Waubant and Barcellos, {Lisa F.}",
year = "2019",
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T1 - miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS

AU - On behalf of the US Network of Pediatric MS Centers

AU - Rhead, Brooke

AU - Shao, Xiaorong

AU - Graves, Jennifer S.

AU - Chitnis, Tanuja

AU - Waldman, Amy T.

AU - Lotze, Timothy

AU - Schreiner, Teri

AU - Belman, Anita

AU - Krupp, Lauren

AU - Greenberg, Benjamin

AU - Weinstock–Guttman, Bianca

AU - Aaen, Gregory

AU - Tillema, Jan M.

AU - Rodriguez, Moses

AU - Hart, Janace

AU - Caillier, Stacy

AU - Ness, Jayne

AU - Harris, Yolanda

AU - Rubin, Jennifer

AU - Candee, Meghan S.

AU - Gorman, Mark

AU - Benson, Leslie

AU - Mar, Soe

AU - Kahn, Ilana

AU - Rose, John

AU - Casper, T. Charles

AU - Quach, Hong

AU - Quach, Diana

AU - Schaefer, Catherine

AU - Waubant, Emmanuelle

AU - Barcellos, Lisa F.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA 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 miRNA 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 miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR−SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes. Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling. Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

AB - 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 microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA 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 miRNA 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 miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR−SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes. Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling. Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

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DO - 10.1002/acn3.786

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