Genetic risk factors for pediatric-onset multiple sclerosis

Author:

Gianfrancesco Milena A1,Stridh Pernilla2,Shao Xiaorong1,Rhead Brooke3,Graves Jennifer S4,Chitnis Tanuja5,Waldman Amy6,Lotze Timothy7,Schreiner Teri8,Belman Anita9,Greenberg Benjamin10,Weinstock–Guttman Bianca11,Aaen Gregory12,Tillema Jan M13,Hart Janace14,Caillier Stacy14,Ness Jayne15,Harris Yolanda15,Rubin Jennifer16,Candee Meghan17,Krupp Lauren9,Gorman Mark18,Benson Leslie18,Rodriguez Moses13,Mar Soe19,Kahn Ilana20,Rose John21,Roalstad Shelly22,Casper T Charles22,Shen Ling23,Quach Hong1,Quach Diana1,Hillert Jan24,Hedstrom Anna24,Olsson Tomas2,Kockum Ingrid2,Alfredsson Lars25,Schaefer Catherine26,Barcellos Lisa F27,Waubant Emmanuelle4,

Affiliation:

1. Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA

2. Department of Clinical Neuroscience and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

3. Computational Biology Graduate Group, University of California, Berkeley, Berkeley, CA, USA

4. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

5. Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, USA

6. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

7. Blue Bird Circle Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX, USA

8. Children’s Hospital Colorado, University of Colorado, Denver, CO, USA

9. The Lourie Center for Pediatric MS, Stony Brook Children’s Hospital, Stony Brook, NY, USA

10. Department of Neurology & Neurotherapeutics, University of Texas Southwestern, Dallas, TX, USA

11. Pediatric Multiple Sclerosis Center, Jacobs Neurological Institute, SUNY Buffalo, Buffalo, NY, USA

12. Pediatric MS Center, Loma Linda University Children’s Hospital, Loma Linda, CA, USA

13. Pediatric MS Center, Mayo Clinic, Rochester, MN, USA

14. Department of Neurology and Regional Pediatric MS Center, University of California, San Francisco, San Francisco, CA, USA

15. Center for Pediatric Onset Demyelinating Disease, University of Alabama and Children’s Hospital of Alabama, Birmingham, AL, USA

16. Division of Neurology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

17. University of Utah and Primary Children’s Hospital, Salt Lake City, UT, USA

18. Boston Children’s Hospital, Boston, MA, USA

19. Pediatric–onset Demyelinating Diseases and Autoimmune Encephalitis Center, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, USA

20. Children’s National Medical Center, Washington, DC, USA

21. Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA

22. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

23. Division of Research, Kaiser Permanente, Oakland, CA, USA

24. Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden

25. Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden/Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden

26. Division of Research, Kaiser Permanente, Oakland, CA, USA/Research Program on Genes, Environment and Health, Kaiser Permanente, Oakland, CA

27. Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA/Computational Biology Graduate Group, University of California, Berkeley, Berkeley, CA, USA; Division of Research, Kaiser Permanente, Oakland, CA, USA

Abstract

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10−16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10−16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Funder

National Institute of Neurological Disorders and Stroke

National Multiple Sclerosis Society

National Institute of Allergy and Infectious Diseases

National Institute of Environmental Health Sciences

Publisher

SAGE Publications

Subject

Neurology (clinical),Neurology

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