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

Mary K Horton; Joan E Shim; Amelia Wallace; Jennifer S Graves; Gregory Aaen; Benjamin Greenberg; Soe Mar; Yolanda Wheeler; Bianca Weinstock-Guttman; Amy Waldman; Teri Schreiner; Moses Rodriguez; Jan-Mendelt Tillema; Tanuja Chitnis; Lauren Krupp; T Charles Casper; Mary Rensel; Janace Hart; Hong L Quach; Diana L Quach; Catherine Schaefer; Emmanuelle Waubant; Lisa F Barcellos

doi:10.1177/13524585221150736

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

Mult Scler. 2023 Apr;29(4-5):505-511. doi: 10.1177/13524585221150736. Epub 2023 Feb 8.

Authors

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Child
Genetic Predisposition to Disease
Genotype
HLA-DRB1 Chains / genetics
Humans
Multiple Sclerosis* / genetics

Substances

HLA-DRB1 Chains

Abstract

Publication types

MeSH terms

Substances

Grants and funding