. 2023 Apr;29(4-5):505-511.

doi: 10.1177/13524585221150736. Epub 2023 Feb 8.

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

Mary K Horton¹, Joan E Shim², Amelia Wallace³, Jennifer S Graves⁴, Gregory Aaen⁵, Benjamin Greenberg⁶, Soe Mar⁷, Yolanda Wheeler⁸, Bianca Weinstock-Guttman⁹, Amy Waldman¹⁰, Teri Schreiner¹¹, Moses Rodriguez¹², Jan-Mendelt Tillema¹², Tanuja Chitnis¹³, Lauren Krupp¹⁴, T Charles Casper¹⁵, Mary Rensel¹⁶, Janace Hart¹⁷, Hong L Quach¹, Diana L Quach¹, Catherine Schaefer¹⁸, Emmanuelle Waubant¹⁹, Lisa F Barcellos²⁰

Affiliations

¹ Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA/Center for Computational Biology, College of Engineering, University of California, Berkeley, CA, USA.
² Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA.
³ Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA/Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
⁴ Department of Neurosciences, School of Medicine, University of California, San Diego, CA, USA/Department of Neurology, University of California, San Francisco, CA, USA.
⁵ Pediatric MS Center, Loma Linda University Children's Hospital, San Bernardino, CA, USA.
⁶ Department of Neurology, University of Texas Southwestern, Dallas, TX, USA.
⁷ Pediatric-Onset Demyelinating Diseases and Autoimmune Encephalitis Center, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Alabama Center for Pediatric-Onset Demyelinating Disease, Children's Hospital of Alabama, Birmingham, AL, USA.
⁹ Pediatric Multiple Sclerosis Center, Jacobs Neurological Institute, SUNY Buffalo, NY, USA.
¹⁰ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Children's Hospital Colorado, University of Colorado, Denver, CO, USA.
¹² Mayo Clinic's Pediatric Multiple Sclerosis Center, Rochester, MN, USA.
¹³ Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, USA.
¹⁴ Lourie Center for Pediatric Multiple Sclerosis, Stony Brook Children's Hospital, Stony Brook, NY, USA.
¹⁵ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁶ Mellen Center, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Regional Pediatric MS Center, Neurology, University of California, San Francisco, CA, USA.
¹⁸ Kaiser Permanente Division of Research, Oakland, CA, USA.
¹⁹ Department of Neurology, University of California, San Francisco, CA, USA.
²⁰ Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA/Center for Computational Biology, College of Engineering, University of California, Berkeley, CA, USA/Kaiser Permanente Division of Research, Oakland, CA, USA.

PMID: 36755464
PMCID: PMC10149552
DOI: 10.1177/13524585221150736

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

Mary K Horton et al. Mult Scler. 2023 Apr.

. 2023 Apr;29(4-5):505-511.

doi: 10.1177/13524585221150736. Epub 2023 Feb 8.

Authors

Affiliations

¹ Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA/Center for Computational Biology, College of Engineering, University of California, Berkeley, CA, USA.
² Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA.
³ Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA/Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
⁴ Department of Neurosciences, School of Medicine, University of California, San Diego, CA, USA/Department of Neurology, University of California, San Francisco, CA, USA.
⁵ Pediatric MS Center, Loma Linda University Children's Hospital, San Bernardino, CA, USA.
⁶ Department of Neurology, University of Texas Southwestern, Dallas, TX, USA.
⁷ Pediatric-Onset Demyelinating Diseases and Autoimmune Encephalitis Center, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Alabama Center for Pediatric-Onset Demyelinating Disease, Children's Hospital of Alabama, Birmingham, AL, USA.
⁹ Pediatric Multiple Sclerosis Center, Jacobs Neurological Institute, SUNY Buffalo, NY, USA.
¹⁰ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Children's Hospital Colorado, University of Colorado, Denver, CO, USA.
¹² Mayo Clinic's Pediatric Multiple Sclerosis Center, Rochester, MN, USA.
¹³ Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, USA.
¹⁴ Lourie Center for Pediatric Multiple Sclerosis, Stony Brook Children's Hospital, Stony Brook, NY, USA.
¹⁵ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁶ Mellen Center, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Regional Pediatric MS Center, Neurology, University of California, San Francisco, CA, USA.
¹⁸ Kaiser Permanente Division of Research, Oakland, CA, USA.
¹⁹ Department of Neurology, University of California, San Francisco, CA, USA.
²⁰ Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA/Center for Computational Biology, College of Engineering, University of California, Berkeley, CA, USA/Kaiser Permanente Division of Research, Oakland, CA, USA.

PMID: 36755464
PMCID: PMC10149552
DOI: 10.1177/13524585221150736

Abstract

Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown.

Objective: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS.

Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk.

Results: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10^-3) and two MHC genes (BRD2, p = 5.89 × 10^-5 and AGER, p = 7.96 × 10^-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501.

Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Keywords: GWAS; Multiple sclerosis; POMS; pediatric-onset; rare variants.

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Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.K.H., J.E.S., A. Wallace, J.S.G., G.A., B.G., S.M., Y.W., A. Waldman, T.S., J.-M.T., T.C., M. Rensel., J.H., H.L.Q., D.L.Q., C.S., E.W., and L.F.B. declare no conflict of interest. B.W.-G. has participated in speaker’s bureaus, served as a consultant for, and/or received grant/research support from Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, and Horizon. B.W.-G. serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology. M. Rodriguez serves on the advisory board/panel for Serono, Biogen, Horizon, TG, Novartis, Falls Educational Foundation, Ohio NMSS, and IConquer MS. M. Rodriguez serves as a consultant for Biogen, Genentech, Improve Consulting, Kijia, Novartis, and BMS. M. Rodriguez receives grants/research support from Medimmune, Novartis, Biogen (MS Paths), Roche-Genentech, and CBF Foundation. M. Rodriguez serves on the Speaker’s Bureau for Genzyme, Biogen, and Multiple Sclerosis Association of America and is the owner of Brain Fresh and Brain Ops Group. T.C.C. has received research funding from Hoffmann-La Roche, Ltd. L.K. has received research or programmatic funding, or has received compensation for consulting, speaking, travel and meal allowances, or serving on dSMB committees from Biogen, Novartis, Eisai, Roche, Gerson Lehrman, Janssen, Medscape, NeuroLive, Peer View, WebMD, Bristol Myers Squibb, CME Outfitters, General Dynamics Information, At the Limits, Cambridge Medical Technologies, and Medergy Marketing. L.K. is also a non-compensated consultant and/or advisory board member with Novartis and Celgene. L.K. receives royalties for use of the Fatigue Severity Scale by various biopharmaceutical entities. B.G. has received consulting fees from Alexion, Novartis, EMD Serono, Horizon Therapeutics, Genentech/Roche, Signant, IQVIA, Sandoz, Genzyme, Immunovant, Cycle Pharma, and PRIME Education. B.G. has received grant funding from NIH, Anokion, Clene Nanomedicine, and Regeneron and serves as an unpaid member of the board of the Siegel Rare Neuroimmune Association. B.G. receives royalties from UpToDate.

Figures

**Figure 1.**
Two genes from SKAT-O analysis of rare and low-frequency variants within the MHC region were significantly associated with POMS. The line represents the Bonferroni significance cut-off (p = 0.05/52 MHC genes in the dataset). Genes were plotted at their starting location on the genome.

See this image and copyright information in PMC

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Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

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Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis

Authors

Affiliations

Abstract

Conflict of interest statement

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References

Publication types

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Substances

Grants and funding

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Full Text Sources

Medical

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