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

Author:

Horton Mary K1ORCID,Shim Joan E2,Wallace Amelia3ORCID,Graves Jennifer S4ORCID,Aaen Gregory5,Greenberg Benjamin6ORCID,Mar Soe7,Wheeler Yolanda8,Weinstock-Guttman Bianca9ORCID,Waldman Amy10,Schreiner Teri11ORCID,Rodriguez Moses12,Tillema Jan-Mendelt12,Chitnis Tanuja13ORCID,Krupp Lauren14,Casper T Charles15,Rensel Mary16ORCID,Hart Janace17,Quach Hong L1,Quach Diana L1,Schaefer Catherine18,Waubant Emmanuelle19,Barcellos Lisa F20

Affiliation:

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.

Funder

Wayne and Gladys Valley Foundation

Robert Wood Johnson Foundation

National Multiple Sclerosis Society

Division of Intramural Research, National Institute of Allergy and Infectious Diseases

Ellison Medical Foundation

National Institute of Environmental Health Sciences

National Institute of Neurological Disorders and Stroke

Publisher

SAGE Publications

Subject

Neurology (clinical),Neurology

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