Allele-specific vitamin D receptor binding is associated with pediatric-onset multiple sclerosis

Defne Yilmaz¹, Cameron Adams¹, Mary K Horton¹, Jennifer S Graves², Carla Francisco³, Alice Edwards³, Hong Quach¹, Diana Quach¹, Gregory Aaen⁴, Timothy Lotze⁵, Soe Mar⁶, Jayne Ness⁷, Yolanda Wheeler⁷, Mark P Gorman⁸, Leslie Benson⁸, Bianca Weinstock-Guttman⁹, Amy Waldman¹⁰, Teri Schreiner¹¹, Jan-Mendelt Tillema¹², Tanuja Chitnis¹³, John Rose¹⁴, T Charles Casper¹⁵, Mary Rensel¹⁶, Emmanuelle Waubant³, Lisa F Barcellos¹; Network of Pediatric Multiple Sclerosis Centers

Affiliations

¹ Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA; Center for Computational Biology, College of Computing, Data Science and Society, University of California, Berkeley, CA, USA.
² Department of Neurosciences, School of Medicine, University of California, San Diego, CA, USA.
³ Department of Neurology, University of California, San Francisco, CA, USA.
⁴ Pediatric MS Center, Loma Linda University Children's Hospital, Loma Linda, CA, USA.
⁵ Texas Children's Hospital, Houston, TX, USA.
⁶ Pediatric-onset Demyelinating Diseases and Autoimmune Encephalitis Center, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
⁷ UAB Center for Pediatric Onset Demyelinating Disease, Children's of Alabama, Birmingham, AL, USA.
⁸ Department of Neurology, Boston Children's Hospital, Boston, MA, 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 Departments of Neurology and Pediatrics, University of Colorado, Aurora, CO, USA.
¹² Mayo Clinic's Pediatric Multiple Sclerosis Center, Rochester, MN, USA.
¹³ Mass General Brigham Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, USA.
¹⁴ Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁵ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁶ Mellen Center, Cleveland Clinic, OH, USA.

PMID: 40438528
PMCID: PMC12117238
DOI: 10.1177/20552173251335625

Allele-specific vitamin D receptor binding is associated with pediatric-onset multiple sclerosis

Defne Yilmaz et al. Mult Scler J Exp Transl Clin. 2025.

. 2025 May 27;11(2):20552173251335625.

doi: 10.1177/20552173251335625. eCollection 2025 Apr-Jun.

Authors

Affiliations

¹ Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA; Center for Computational Biology, College of Computing, Data Science and Society, University of California, Berkeley, CA, USA.
² Department of Neurosciences, School of Medicine, University of California, San Diego, CA, USA.
³ Department of Neurology, University of California, San Francisco, CA, USA.
⁴ Pediatric MS Center, Loma Linda University Children's Hospital, Loma Linda, CA, USA.
⁵ Texas Children's Hospital, Houston, TX, USA.
⁶ Pediatric-onset Demyelinating Diseases and Autoimmune Encephalitis Center, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA.
⁷ UAB Center for Pediatric Onset Demyelinating Disease, Children's of Alabama, Birmingham, AL, USA.
⁸ Department of Neurology, Boston Children's Hospital, Boston, MA, 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 Departments of Neurology and Pediatrics, University of Colorado, Aurora, CO, USA.
¹² Mayo Clinic's Pediatric Multiple Sclerosis Center, Rochester, MN, USA.
¹³ Mass General Brigham Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, USA.
¹⁴ Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁵ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁶ Mellen Center, Cleveland Clinic, OH, USA.

PMID: 40438528
PMCID: PMC12117238
DOI: 10.1177/20552173251335625

Abstract

Background and objectives: The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs).

Methods: Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in 725 cases and 592 controls of European ancestry from the US Network of Pediatric MS Centers. Associations between each VDR-BV and pedMS were estimated using logistic regression adjusting for the first three genome-wide principal components. A significant interaction between a VDR-BV and 25(OH)D GIV provided evidence for a causal association unbiased by pleiotropy.

Results: One VDR-BV, rs2531804, previously associated with adult-onset MS, was also significantly associated with pedMS after multiple testing correction.

Discussion: This study is the first to use VDR-BVs from previous MR studies to demonstrate causal differences in VDR binding at a locus contributing to pedMS susceptibility.

Keywords: Mendelian randomization; Pediatric multiple sclerosis; genetic epidemiology; multiple sclerosis pathogenesis; statistical genetics.

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Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

**Figure 1.**
Vitamin D metabolism and receptor binding pathway in human body. Figure created using BioRender.

**Figure 2.**
(A, B) Results from meta-analyses of association between 25(OH)D genetic instrumental variables (GIV_25(OH)D) and adult MS (KPNC, UKB, GSA, Human Omni from Adams et al.) and pedMS. τ²= estimate of between study heterogeneity; I²= proportion of variance due to heterogeneity; and p = p-value for Cochran's Q test of heterogeneity. (A) GIV_25(OH)D calculated using independent GWAS variants from Jiang et al. 2019 and its association with adult and pedMS; (B) GIV_25(OH)D calculated using independent GWAS variants from Revez et al. 2020 and its association with adult and pedMS. (C) Results from meta-analyses of GIV_VDR for rs2531804 and its association with adult MS (KPNC, UKB, GSA, Human Omni from Adams et al.) and pedMS.

See this image and copyright information in PMC

References

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Allele-specific vitamin D receptor binding is associated with pediatric-onset multiple sclerosis

Affiliations

Allele-specific vitamin D receptor binding is associated with pediatric-onset multiple sclerosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources