Genetic Determinants of Multiple Sclerosis Susceptibility Across Diverse Ancestral Backgrounds

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease whose genetic basis has been mapped predominantly in populations of European ancestry. This article addresses a major gap in the field: whether the established genetic architecture of MS susceptibility generalizes to people of South Asian and African ancestry living in the United Kingdom. The authors frame this as both a scientific and an equity problem. Without broader ancestral representation, genetic risk scores may perform poorly outside European populations, causal variants may remain incompletely resolved, and biologically relevant therapeutic targets may be missed. The study therefore asks a precise and timely question: to what extent are the known genetic determinants of MS shared across ancestral backgrounds, and where might ancestry-specific signals emerge? The paper is a medRxiv preprint and has not yet undergone peer review, which is important when interpreting the strength of its conclusions.

Cohort Design and Analytical Framework
The investigators assembled the ADAMS cohort, a UK-based genotype–phenotype study focused on individuals with MS from diverse ancestral backgrounds. Participants were recruited through clinical sites, an online platform, and the UK MS Register, and DNA was obtained from saliva for genotyping. After imputation and quality control, these cases were combined with ancestrally matched controls from UK Biobank. Genetic ancestry inference was then used to define two principal analytic groups: South Asian ancestry and African ancestry. The final datasets comprised 175 MS cases and 6,744 controls in the South Asian analysis, and 113 MS cases and 5,177 controls in the African analysis. Within each ancestry, the authors performed genome-wide association studies using logistic models adjusted for sex and genetic principal components, and they also imputed classical HLA alleles to interrogate the major histocompatibility complex (MHC), the best-established genetic region in MS.

Genome-Wide Findings and the Centrality of the MHC
The principal genome-wide result is that, in both ancestral groups, the strongest association signals localized to the MHC on chromosome 6. In the South Asian cohort, the lead signal was near HLA-DRB1 at chr6:32600515:G:A, with an odds ratio of 1.84 and a P value of 4.6×10⁻⁶. In the African cohort, the lead signal was near HLA-A at chr6:29919337:A:G, with an odds ratio of 2.24 and a P value of 4.3×10⁻⁵. These are not genome-wide significant by the conventional threshold, but they are biologically credible and consistent with decades of MS genetics showing that the MHC contains the strongest susceptibility effects. Outside the MHC, the study observed a number of nominally associated loci, yet none reached genome-wide significance and the authors appropriately caution that these are more likely to reflect limited power, statistical noise, or residual stratification rather than robust novel discoveries. In that sense, the study is less about finding entirely new loci than about testing whether known biology replicates across ancestries.

Cross-Ancestry Concordance of Established MS Risk Alleles
One of the most important contributions of the paper is its systematic comparison of non-European results with published European-ancestry MS GWAS. The authors examined 164 independent European susceptibility signals and asked whether these alleles tended to exert effects in the same direction in the South Asian and African cohorts. The answer was yes, but to different degrees. Concordance was strongest in the South Asian group, where 104 of 154 testable variants showed the same direction of effect and the correlation of effect estimates was statistically persuasive. In the African group, the same trend was present but weaker and not statistically compelling. This pattern has biological plausibility: cross-ancestry sharing of disease mechanisms can coexist with ancestry-specific allele frequencies, distinct linkage disequilibrium structures, and reduced portability of effect estimates derived from European populations. The study therefore supports a nuanced conclusion: the architecture of MS susceptibility is broadly shared across populations, but it is not identical in its measurable expression.

HLA Fine-Mapping and Population-Level Interpretation
The HLA analyses provide some of the most interesting mechanistic detail. The paper reports that major European MS-associated HLA alleles, particularly HLA-DRB1*15:01, show concordant risk effects in the South Asian and African ancestry cohorts, reinforcing the idea that core immunogenetic pathways are shared. At the same time, the population impact of these alleles differs substantially because allele frequencies differ between populations. The authors estimate that the population attributable fraction for HLA-DRB1*15:01 is much lower in South Asian and African ancestry groups than in European ancestry—approximately 9.8% and 4.5%, respectively, compared with a much larger estimate in Europeans. They also note additional signals, such as DPB1*10:01 in the South Asian cohort and A*66:01 in the African cohort, while clearly acknowledging that these may represent either ancestry-enriched biology or false-positive findings that require replication. This is a strong example of how fine-mapping in diverse populations can refine interpretation even when headline loci are already known.

Polygenic Risk Scores and the Limits of Portability
The polygenic risk score analysis addresses a clinically relevant issue: whether a score trained in European datasets can predict MS risk in other populations. The results are directionally positive but quantitatively modest. European-derived polygenic scores performed better than chance in both non-European groups, but they explained only 1.6% of MS liability in the South Asian cohort and 0.5% in the African cohort, with the latter not reaching conventional statistical significance. These findings are fully consistent with a broader pattern seen across complex disease genetics: polygenic predictors lose performance when transferred across ancestries because marker frequencies, haplotype structures, and tagging relationships differ between populations. The implication is not that polygenic risk scores are useless, but that their equitable clinical deployment requires training datasets that include the populations in which they will eventually be used. This paper therefore contributes to an emerging consensus that diversity is not an optional refinement in genomics; it is a methodological necessity.

Scientific Significance, Limitations, and Future Directions
Overall, this article makes a valuable contribution by showing that the major genetic architecture of MS susceptibility is largely conserved across ancestry groups, especially at the MHC, while also demonstrating that current non-European sample sizes remain too small for robust discovery of new loci. Its limitations are the same ones the authors recognize: relatively modest case numbers, restricted power outside the MHC, and the fact that this is a preprint rather than a peer-reviewed final publication. Yet those limitations do not diminish the importance of the study’s central message. The work shows that inclusive genetic research can both validate shared disease biology and expose where European-centric models fall short, particularly in HLA interpretation and polygenic prediction. The next step for the field is clear: much larger, well-phenotyped, ancestrally diverse MS cohorts will be needed to fine-map causal variants, improve risk prediction across populations, and move toward a genuinely global understanding of MS pathogenesis.

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:
Jacobs, B. M., Schalk, L., Tregaskis-Daniels, E., Scalfari, A., Nandoskar, A., Dunne, A., Gran, B., Mein, C. A., Sellers, C., Spilker, C. E., Rog, D. J., Visentin, E., Bezzina, E. L., Uzochukwu, E., Tallantyre, E. C., Wozniak, E., Sacre, E., Hassan-Smith, G., Ford, H. L., Harris, J., … Dobson, R. (2026). Genetic Determinants of Multiple Sclerosis Susceptibility in People From Diverse Ancestral Backgrounds. Neurology, 106(7), e214708. https://doi.org/10.1212/WNL.0000000000214708