Genetic Susceptibility to Multiple Sclerosis Across Diverse Ancestral Backgrounds
Multiple Sclerosis (MS) is a complex immune-mediated neurological disease with a substantial heritable component. Over the past two decades, genome-wide association studies (GWAS) have identified hundreds of genetic loci contributing to MS susceptibility, predominantly in populations of European ancestry. While these studies have been transformative, their limited ancestral diversity constrains the generalisability of genetic risk models and hampers fine-mapping of causal variants. The study by Jacobs et al. directly addresses this gap by characterising the genetic architecture of MS susceptibility in individuals of South Asian and African ancestry living in the United Kingdom, thereby contributing to a more inclusive understanding of MS genetics.
An Ancestrally Diverse UK Cohort
The investigators assembled the ADAMS cohort, a genotyped and phenotyped collection of people with MS recruited through clinical sites, an online platform, and the UK Multiple Sclerosis Register. DNA was obtained via saliva sampling and genotyped using a commercial array, with imputation performed against established multi-ancestry reference panels. Importantly, cases were combined with ancestrally matched controls from UK Biobank, enabling within-ancestry case–control analyses. Genetic ancestry was inferred using principal component–based machine learning approaches, allowing the authors to focus on two well-defined groups: South Asian and African ancestry participants.
Genome-Wide Association Analyses Across Ancestries
Within each ancestry group, the authors conducted GWAS of MS susceptibility using mixed logistic regression models that accounted for sex and population structure. As anticipated from prior MS genetics research, the strongest association signals in both ancestries were located within the Major Histocompatibility Complex (MHC) on chromosome 6. In South Asian ancestry individuals, the lead variant mapped to the class II HLA region near HLA-DRB1, whereas in African ancestry individuals the strongest signal localised to the class I region near HLA-A. Outside the MHC, no variants reached genome-wide significance, reflecting the limited statistical power inherent to current non-European MS cohorts.
Concordance With European-Ancestry Risk Alleles
A central objective of the study was to quantify the extent to which MS risk alleles identified in European-ancestry populations exert similar effects in other ancestral backgrounds. By comparing established European GWAS signals with results from the South Asian and African cohorts, the authors demonstrated a clear over-representation of European susceptibility alleles among MS cases in both groups. This concordance was statistically robust in the South Asian cohort and weaker, though directionally consistent, in the African cohort. These findings support the notion that many core biological mechanisms underlying MS are shared across populations, even if effect sizes and allele frequencies differ.
Fine-Mapping the HLA Region
Given the central role of the MHC in MS risk, the authors performed detailed analyses of classical HLA alleles using two independent imputation approaches. Several risk-increasing and protective alleles were identified in both ancestries, including the well-established HLA-DRB115:01 allele, which showed consistent direction of effect across populations. However, the population attributable fraction of this allele was substantially lower in South Asian and African ancestry groups due to its reduced frequency. The study also highlighted potentially ancestry-enriched associations, such as HLA-DPB110:01 in South Asian individuals and HLA-A66:01 in African ancestry individuals, warranting further validation in larger datasets.
Polygenic Risk Scores Beyond Europe
The authors further evaluated the transferability of European-derived polygenic risk scores (PRS) to non-European populations. While these PRS were able to distinguish MS cases from controls in both South Asian and African ancestry cohorts, their predictive performance was markedly reduced compared with European populations. Specifically, European-derived PRS explained only a small proportion of MS liability in non-European groups. This finding underscores a critical limitation of current genetic risk prediction frameworks and reinforces the need for large, multi-ancestry GWAS to enable equitable clinical translation of genomic medicine.
Implications and Future Directions
Collectively, this study provides compelling evidence that the genetic architecture of MS susceptibility is broadly shared across ancestral groups, with the MHC locus remaining central to disease risk worldwide. At the same time, it illustrates how differences in allele frequency, linkage disequilibrium, and sample size shape the observed genetic signals. Although underpowered to detect novel loci, the work represents an important foundational step toward inclusive MS genetics. Future large-scale, multi-ancestry collaborations will be essential to refine causal variant mapping, improve polygenic risk prediction across populations, and ultimately ensure that advances in MS genomics benefit individuals of all ancestral backgrounds.
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. (2025). Genetic determinants of Multiple Sclerosis susceptibility in diverse ancestral backgrounds. medRxiv, 2025-01.
