Genetic Diversity in Multiple Sclerosis: What Multi-Ancestry Genomics Reveals About Disease Risk
Multiple sclerosis is a chronic immune-mediated disease of the central nervous system in which genetic susceptibility plays an important but complex role. For more than two decades, genome-wide association studies have identified hundreds of loci associated with multiple sclerosis risk, particularly within immune-related pathways and the major histocompatibility complex. However, the overwhelming majority of these studies have been conducted in populations of European ancestry. The article “Genetic determinants of Multiple Sclerosis susceptibility in diverse ancestral backgrounds” addresses this limitation by examining multiple sclerosis susceptibility in individuals of South Asian and African ancestry living in the United Kingdom, thereby contributing to a more inclusive and globally relevant understanding of disease genetics.
Why Ancestral Diversity Matters in Genomic Research
The underrepresentation of non-European populations in genomic studies is not merely a demographic gap; it has direct implications for biological discovery and clinical translation. Genetic risk scores developed in European ancestry cohorts often perform less accurately in other populations because allele frequencies, linkage disequilibrium patterns, and haplotypic structures differ across ancestries. In multiple sclerosis, this issue is especially important because the disease has historically been studied most intensively in European populations, despite occurring worldwide. By incorporating individuals of South Asian and African ancestry, the study seeks to determine whether known European-derived susceptibility alleles generalize across populations and whether ancestry-specific signals may reveal additional biology.
Study Design and Cohort Construction
The investigators assembled an ancestrally diverse United Kingdom-based cohort through the ADAMS project, clinical recruitment, online platforms, and the UK Multiple Sclerosis Register. Participants provided saliva samples for genotyping and completed standardized questionnaires capturing demographic features, multiple sclerosis history, treatment exposure, disability measures, and established risk factors such as smoking, body mass index, migration history, family history, and glandular fever. The case cohort was combined with ancestrally matched controls from UK Biobank, followed by rigorous quality control, imputation, and genetic ancestry inference. The final analyses focused on two broad genetically inferred ancestry groups: South Asian ancestry, comprising 175 cases and 6,744 controls, and African ancestry, comprising 113 cases and 5,177 controls.
Genome-Wide Association Findings
Within-ancestry genome-wide association analyses revealed the strongest signals in the major histocompatibility complex region on chromosome 6, consistent with prior multiple sclerosis genetics. In the South Asian ancestry cohort, the lead association was located near HLA-DRB1, with an odds ratio of 1.84, while in the African ancestry cohort the strongest signal was near HLA-A, with an odds ratio of 2.24. These findings reinforce the central role of antigen presentation and immune regulation in multiple sclerosis susceptibility across populations. Outside the major histocompatibility complex, several nominally associated loci were observed, but none reached genome-wide significance, and the authors appropriately interpret these signals cautiously given the limited sample size and potential for statistical noise.
HLA Associations and Shared Immunogenetic Mechanisms
A major strength of the study is its focused analysis of classical HLA alleles, which are central to immune recognition and autoimmune disease susceptibility. In South Asian ancestry participants, several suggestive HLA associations were identified, including risk-increasing effects for HLA-DPB1*10:01, HLA-B*37:01, HLA-A*26:01, HLA-DRB1*15:01, HLA-A*23:01, and HLA-DRB1*04:01, alongside protective associations for HLA-DRB1*13:01 and HLA-DQB1*06:03. In African ancestry participants, HLA-A*66:01 showed the strongest association, with additional suggestive evidence for HLA-DRB1*15:01 and other alleles. Importantly, HLA-DRB1*15:01, the best-established multiple sclerosis risk allele in European populations, showed concordant risk effects in both South Asian and African ancestry groups, although its lower frequency in these populations reduces its estimated population-level contribution.
Polygenic Risk Scores and Cross-Ancestry Prediction
The authors also evaluated whether European-derived polygenic risk scores could distinguish multiple sclerosis cases from controls in non-European ancestry groups. The scores performed better than chance in South Asian ancestry participants and showed weaker evidence of predictive performance in African ancestry participants. Specifically, the best-performing score explained approximately 1.6% of liability in the South Asian ancestry cohort and 0.5% in the African ancestry cohort, both lower than published estimates in European ancestry cohorts. This result is scientifically important because it demonstrates partial sharing of genetic architecture across ancestries while also highlighting the inequity that arises when predictive tools are trained predominantly in European populations.
Implications, Limitations, and Future Directions
This study provides valuable evidence that multiple sclerosis susceptibility has substantial cross-ancestry genetic overlap, particularly in immune-related regions such as the major histocompatibility complex. At the same time, it illustrates the limitations of small sample sizes in complex disease genetics: no novel loci reached genome-wide significance, and some ancestry-specific HLA signals require replication in larger cohorts. The reliance on imputed HLA alleles rather than direct sequencing and the use of cases and controls from different cohorts also introduce methodological constraints, although the authors applied stringent quality-control procedures to mitigate bias. Overall, the article represents an important step toward equitable multiple sclerosis genomics, emphasizing that larger international multi-ancestry studies will be essential for fine-mapping causal variants, improving genetic risk prediction, and identifying biologically meaningful therapeutic targets.
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., ... & Dobson, R. (2026). Genetic determinants of multiple sclerosis susceptibility in people from diverse ancestral backgrounds. Neurology, 106(7), e214708.
