Highlights
- Major Histocompatibility Complex (MHC) variants remain the primary genetic determinants of MS susceptibility across European (EUR), South Asian (SAS), and African (AFR) ancestries.
- The performance of European-derived Genetic Risk Scores (GRS) is significantly attenuated in non-European populations, explaining only 1.9% to 3.9% of disease liability.
- The HLA-DRB1*15:01 allele confers risk across all groups, but its population-attributable risk is lower in SAS and AFR cohorts due to lower allele frequencies.
- A novel, SAS-enriched protective allele, HLA-A*33:03, has been identified, suggesting population-specific genetic modifiers of autoimmune risk.
Background
Multiple sclerosis (MS) is a complex immune-mediated disease of the central nervous system characterized by inflammation, demyelination, and neurodegeneration. While the prevalence of MS is historically highest in populations of Northern European descent, the global incidence is rising across all ethnic groups. Over the past two decades, large-scale genome-wide association studies (GWAS) and meta-analyses, such as those conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC), have identified over 200 susceptibility loci. However, the vast majority of these findings are derived from cohorts of European (EUR) ancestry.
This Eurocentric bias in genomic research limits the clinical utility of genetic risk scores in non-European populations and potentially masks novel biological pathways relevant to MS pathogenesis. Understanding the genetic architecture of MS in diverse populations is critical for achieving equitable precision medicine and for identifying universal versus population-specific therapeutic targets.
Key Content
Methodological Framework: Integration of UK Biobank and Diverse Cohorts
In a landmark study, Jacobs et al. (2026) addressed this evidence gap by recruiting a diverse cohort of people with MS (pwMS) from across the United Kingdom. This cohort was integrated with data from the UK Biobank (UKB) to perform within-ancestry case-control genetic association studies. The researchers utilized sophisticated genetic ancestry inference to categorize participants into South Asian (SAS) and African (AFR) genetic ancestral backgrounds, ensuring that findings were not confounded by population stratification. The study analyzed 676 pwMS from the new diverse cohort and 2,426 pwMS from the UKB, using 27,640 UKB individuals as controls.
MHC Association and Allelic Overlap
The Major Histocompatibility Complex (MHC) on chromosome 6 remains the strongest locus for MS susceptibility globally. The study identified lead single nucleotide polymorphisms (SNPs) within the MHC for both non-European groups:
- South Asian (SAS): Lead SNP chr6:32635095:G:C (near HLA-DQA1), OR = 1.7, p = 4.2 × 10⁻⁸.
- African (AFR): Lead SNP chr6:32593550:T:C (near HLA-DRB1), OR = 1.7, p = 1.2 × 10⁻⁵.
A critical finding was the high degree of concordance between EUR-derived risk alleles and those found in SAS and AFR cases. Spearman correlation analysis showed a stronger concordance for the SAS cohort (ρ = 0.46) than for the AFR cohort (ρ = 0.35). This suggests that the fundamental immunological mechanisms driving MS susceptibility are largely conserved across human populations, although the magnitude of effect may vary.
Limitations of European-Derived Polygenic Risk Scores (PRS)
Genetic Risk Scores (GRS), or Polygenic Risk Scores (PRS), are increasingly explored for their potential to identify high-risk individuals before symptom onset. However, this study underscores the lack of portability of current EUR-centric GRS tools. While the GRS performed better than chance in all groups, it explained significantly less of the liability to MS in diverse populations:
- European (EUR): 9.6% of liability explained.
- South Asian (SAS): 3.9% of liability explained.
- African (AFR): 1.9% of liability explained.
This decline in performance is likely due to differences in linkage disequilibrium (LD) patterns and allele frequencies between populations, as well as the presence of ancestry-specific risk variants not captured in European GWAS.
The Role of Classical HLA Alleles
The HLA-DRB1*15:01 allele is the strongest known genetic risk factor for MS in Europeans. Jacobs et al. confirmed that this allele also confers risk in SAS and AFR populations. However, its population-level impact—often measured as population attributable fraction—is markedly lower in these groups. In the SAS cohort, it explained 8.8% of the risk, and in the AFR cohort, only 2.9%, compared to much higher figures in EUR populations.
Intriguingly, the study identified a novel association with the HLA-A*33:03 allele in the South Asian cohort. This allele appeared to have a protective role, an observation not previously described in European-heavy datasets. This finding highlights how studying diverse populations can uncover novel genetic variants that modulate immune tolerance and susceptibility.
Expert Commentary
The findings by Jacobs et al. emphasize both the biological universality of MS and the distinct genetic nuances shaped by ancestry. From a mechanistic standpoint, the shared risk within the MHC across ancestries reinforces the hypothesis that antigen presentation is the central checkpoint in MS pathogenesis. However, the attenuation of GRS performance in SAS and AFR cohorts is a significant hurdle for clinical translation.
Health policy experts and clinicians must recognize that applying European-derived genetic risk models to diverse patient populations may lead to inaccurate risk stratification and further widen healthcare disparities. The discovery of the HLA-A*33:03 protective allele in South Asians suggests that we have only scratched the surface of the genetic diversity underlying autoimmunity. There is an urgent need for global consortia to expand genotyping efforts in Africa, Asia, and Latin America to refine our understanding of the “missing heritability” in MS.
Conclusion
This research provides a critical step toward a more inclusive understanding of multiple sclerosis genetics. While the core MHC risk signals are shared across ancestral backgrounds, the lower performance of European-based risk scores in South Asian and African populations demonstrates the necessity of population-specific research. Future studies with larger sample sizes in diverse global populations are essential to identify novel pathways, improve the accuracy of risk prediction, and ensure that the benefits of genomic medicine are available to all people with MS, regardless of their ancestral background.
References
- Jacobs BM, Schalk L, Tregaskis-Daniels E, et al. Genetic Determinants of Multiple Sclerosis Susceptibility in People From Diverse Ancestral Backgrounds. Neurology. 2026;106(7):e214708. PMID: 41791023.
- International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365(6460). PMID: 31604244.
- Patsopoulos NA. Genetics of Multiple Sclerosis: An Overview and New Directions. Cold Spring Harb Perspect Med. 2018;8(7):a028951. PMID: 29431627.
