TY - JOUR
T1 - miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS
AU - 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 M.
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.
N1 - Funding Information:
This work was supported in part by the NIH NINDS: 1R01NS071463 (PI: Waubant), R01NS049510 (PI: Barcellos), F31NS096885 (PI: Rhead); NIH NIEHS: R01ES017080 (PI: Barcellos), NIH NIAID: R01AI076544 (PI: Barcellos), the National MS Society HC 0165 (PI: Casper), and Race to Erase MS (PI: Waubant).
Funding Information:
E. Waubant is site PI for a Novartis and Roche trial. She has volunteered on an advisory board for a Novartis trial. She is a nonremunerated advisor for clinical trial design to Novartis, Biogen-IDEC, Sanofi, Genentech, Serono, and Celgene. She has funding from the NMSS, PCORI, and the Race to Erase MS. She is the section editor for Annals of Clinical and Translational Neurology, and co-Chief editor for MS And Related Disorders. A. Waldman reports grants from NIH (NINDS) NS071463 and from NMSS during the conduct of the study, as well as funds for investigator-initiated study from Ionis Pharmaceuticals and Biogen Idec and grants from United Leukodystrophy Foundation outside the submitted work. She is a consultant for Optum and has received royalties from UpToDate. B. Greenberg has received grant funding from Chugai, Medimmune, Medday, National Institutes of Health (NIH), NMSS, Guthy Jackson Charitable Foundation, and Transverse Myelitis Association. He has received consulting fees from Novartis, EMD Serono, Celgene, and Alexion. L. Benson reports BG12 clinical trial support from Biogen, grants from Boston Children’s Hospital Office of Faculty Development, travel funds from National MS Society, and personal fees from National Vaccine Compensation Program outside the submitted work. T.C. Casper reports grants from National MS Society. J. Graves reports speaking honoraria from Novartis outside the submitted work. B. Weinstock-Guttman reports grants and personal fees from Biogen, EMD Serono, Novartis, and Genentech, and personal fees from Mallinckrodt outside the submitted work.
Funding Information:
The authors thank Jorge Oksenberg for assisting with processing and DNA extraction of patient and control samples, Hans Christian von Buedingen for assisting with cell sorting for the miRNA analysis, and Shelly Roalstad for assisting with data collection. This work was supported in part by the NIH NINDS: 1R01NS071463 (PI: Waubant), R01NS049510 (PI: Barcellos), F31NS096885 (PI: Rhead); NIH NIEHS: R01ES017080 (PI: Barcellos), NIH NIAID: R01AI076544 (PI: Barcellos), the National MS Society HC 0165 (PI: Casper), and Race to Erase MS (PI: Waubant).
Publisher Copyright:
© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2019/6/1
Y1 - 2019/6/1
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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U2 - 10.1002/acn3.786
DO - 10.1002/acn3.786
M3 - Article
C2 - 31211169
AN - SCOPUS:85066028926
VL - 6
SP - 1053
EP - 1061
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
IS - 6
ER -