When Genes Meet Multiple Sclerosis: What Vitamin D Really Does Change
For years, vitamin D has been treated as a kind of “sunshine shield” against multiple sclerosis (MS): low blood levels of 25-hydroxyvitamin D [25(OH)D] are associated with a higher risk of developing MS and with more active disease in people who already have it. But observational studies are messy—people with lower vitamin D might differ in many other ways (diet, outdoor activity, disability, socioeconomic status) that also affect outcomes. The study by Vasileiou et al. asked a sharper question: if your genetics predispose you to lower vitamin D, does that translate into worse MS once the disease has already started? In other words, does the “vitamin D genetic lottery” influence MS progression, not just MS risk?
Turning the Vitamin D Genome into a Scorecard
To get at that question, the authors used a polygenic risk score (PGS) for 25(OH)D—a single number summarizing the combined impact of many common genetic variants that each nudge vitamin D levels up or down. They built this PGS from very large genome-wide association studies (up to 485,762 individuals) that mapped which variants are reliably associated with circulating 25(OH)D, using stringent significance thresholds and linkage disequilibrium clumping to avoid redundancy. Crucially, this PGS acts as a genetically anchored proxy for long-term vitamin D status, largely independent of sun exposure, diet, or supplementation. The primary PGS came from a body mass index–adjusted GWAS (to leverage the largest sample size), with additional scores and thresholds used in sensitivity analyses.
Who Was Studied and What Was Measured?
The team pooled 1,924 people with MS of European ancestry from three well-characterized cohorts: the CombiRx randomized trial (n = 575), the Johns Hopkins MS Center cohort (n = 1,152), and the Winnipeg immune-mediated inflammatory diseases (IMID) cohort (n = 197). These participants represented mostly relapsing–remitting MS, with a wide spectrum of ages and disease durations. The investigators linked each person’s vitamin D PGS to a rich set of outcomes: clinical disability (Expanded Disability Status Scale, EDSS), functional performance (timed 25-foot walk, nine-hole peg test, PASAT-3), relapse rates, MRI-based measures (brain parenchymal fraction, gray and white matter fractions, T2 lesion volume, new lesion accrual), and retinal ganglion cell inner plexiform layer (GCIPL) thickness from optical coherence tomography as a sensitive biomarker of neurodegeneration.
First Check: Does the Vitamin D PGS Actually Track Vitamin D?
Before asking whether vitamin D genetics affect MS course, the authors needed to confirm that their PGS actually correlates with real-world 25(OH)D levels. In a subset of 935 Johns Hopkins participants with clinically measured vitamin D, they showed that each standard deviation increase in the PGS was associated with a 3.08% higher circulating 25(OH)D level (95% CI 1.77%–4.42%), explaining about 2.24% of the variance in vitamin D. They also excluded people with very high levels (≥70 ng/mL) to minimize distortion from heavy supplementation. This confirms that the PGS is a valid, though modest, genetic proxy for vitamin D levels in people with MS—strong enough to test for medium or larger effects on disease outcomes.
The Core Result: No Evidence That Lower Genetic Vitamin D Worsens MS
Despite the genetic–vitamin D link, the main finding was strikingly null. Across cohorts and models, higher vitamin D PGS did not associate with fewer relapses, slower EDSS worsening, or better performance on walking and hand function tests. Similarly, there was no consistent association with MRI metrics: not with the rate of new lesion formation, not with T2 lesion volume growth, and not with whole brain, gray matter, or white matter atrophy. Even GCIPL thinning—an especially sensitive measure of global neurodegeneration—showed no meaningful difference across PGS quartiles. Results were stable whether the PGS was treated as a continuous variable or grouped into quartiles, in models with extensive adjustment (age, sex, ancestry, disease duration, prior relapses, disease-modifying therapy, medications affecting vitamin D), and when pooling cohorts via random-effects meta-analysis.
Stress-Testing the Finding: Sensitivity Analyses and Mendelian Randomization
Recognizing the risk of false negatives, the authors stress-tested their results in several ways. They repeated analyses using an unadjusted vitamin D PGS, relaxed the p-value threshold for SNP inclusion (5 × 10⁻⁵) to capture more genetic signal, and obtained broadly similar null findings. They also applied Mendelian randomization (using individual vitamin D variants as instruments) to test for causal effects of 25(OH)D on relapse risk and new lesion formation; again, no clear associations emerged, and analyses of pleiotropy and heterogeneity did not point to strong hidden biases. As a final check, in the Johns Hopkins subset they modeled measured serum 25(OH)D against new lesion rate over five years and still did not see an association (rate ratio ~1.04 per SD increase). Together, these converging negative results argue that—within established MS—modulating vitamin D levels, at least within typical ranges, may not meaningfully change inflammatory or neurodegenerative trajectories.
Reconciling Risk, Progression, and the Role of Vitamin D in MS
The key conceptual takeaway is that vitamin D may be very important for developing MS but much less influential once MS is established. Prior Mendelian randomization work strongly supports low genetically determined 25(OH)D as a causal risk factor for MS onset; this study shows that the same type of genetic instrument does not predict subsequent disease course. Methodological caveats remain: the PGS explains only a small portion of vitamin D variability; the cohorts are limited to European ancestry; supplementation data and medication use may be imperfectly captured; and PGS-based approaches average vitamin D exposure across the life course, potentially missing critical windows earlier in life. Still, in the context of large, negative randomized controlled trials of high-dose vitamin D in MS, these findings reinforce the view that vitamin D supplementation is unlikely to be a disease-modifying lever for people who already have MS, even if raising vitamin D for bone health or general wellness remains reasonable.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Vasileiou, E. S., Hu, C., Bernstein, C. N., Lublin, F., Wolinsky, J. S., Cutter, G. R., ... & Fitzgerald, K. C. (2022). Association of vitamin D polygenic risk scores and disease outcome in people with multiple sclerosis. Neurology: Neuroimmunology & Neuroinflammation, 10(1), e200062.
