Genetic Architecture of Multiple Sclerosis Across Diverse Ancestries
Multiple sclerosis (MS) is a complex autoimmune disease with a substantial heritable component. Over the past two decades, genome-wide association studies (GWAS) have transformed our understanding of MS susceptibility, identifying hundreds of genetic loci involved in immune regulation. However, these discoveries have been overwhelmingly driven by populations of European ancestry, raising concerns about the generalisability and equity of genetic insights across diverse populations. The study by Jacobs and colleagues addresses this imbalance by systematically examining the genetic determinants of MS in individuals of South Asian and African ancestry living in the United Kingdom.
Building an Ancestrally Diverse MS Cohort
A major strength of this work lies in the creation of a richly phenotyped and genotyped multi-ancestry MS cohort. Participants were recruited through clinical centres, national registries, and an online platform, enabling broad engagement with underrepresented communities. Genetic data derived from saliva samples were integrated with large-scale control data from the UK Biobank, ensuring robust comparative analyses. Crucially, genetic ancestry inference—rather than self-reported ethnicity alone—was used to define South Asian and African ancestry groups, enhancing analytical precision and reducing population stratification bias.
Genome-Wide Association Analyses Across Ancestries
Within each ancestry group, the authors conducted genome-wide association studies of MS susceptibility using mixed logistic models that account for population structure. Despite limited sample sizes, the analyses consistently identified association signals within the Major Histocompatibility Complex (MHC), long recognised as the strongest genetic contributor to MS risk. While no novel loci outside the MHC reached genome-wide significance, this outcome was anticipated given statistical power constraints and underscores the challenges inherent in studying rare and underrepresented populations.
The Central Role of the Major Histocompatibility Complex
Fine-mapping of the MHC region revealed both shared and ancestry-specific features of MS susceptibility. In individuals of South Asian ancestry, the strongest association mapped to the class II HLA region near HLA-DRB1, whereas in African ancestry participants, the lead signal arose in the class I region near HLA-A. Classical HLA allele imputation further demonstrated that established European risk alleles—most notably HLA-DRB1*15:01—exerted concordant effects across ancestries, although with markedly lower population impact due to reduced allele frequencies.
Cross-Ancestry Consistency of Genetic Risk
Beyond the MHC, the study evaluated whether MS risk alleles identified in European populations showed consistent effects in South Asian and African ancestry cohorts. The results revealed a clear enrichment of European-derived susceptibility alleles among MS cases in both groups, with stronger concordance observed in South Asian participants. These findings support the concept of shared biological mechanisms underlying MS across human populations, while also highlighting the imperfect transferability of effect sizes due to differences in linkage disequilibrium and allele frequency.
Limits of Genetic Risk Prediction in Diverse Populations
The authors further explored the performance of polygenic risk scores (PRS) derived from European-ancestry GWAS when applied to non-European populations. Although these scores successfully distinguished MS cases from controls at a population level, their predictive power was substantially attenuated compared with European cohorts. This reduction illustrates a critical limitation of current genetic risk models and reinforces the need for large, ancestry-diverse datasets to improve equity and accuracy in genetic prediction.
Towards an Inclusive Genomics of Multiple Sclerosis
Taken together, this study represents an important step toward a more inclusive understanding of MS genetics. It confirms that key elements of MS susceptibility are shared across ancestries, while simultaneously demonstrating how reliance on European-centric data limits discovery, fine-mapping, and clinical translation. The authors rightly emphasise that larger, international, multi-ancestry collaborations will be essential to unlock the full potential of genomic research—enabling more precise identification of causal variants, improved drug target discovery, and fairer application of genetic risk tools for 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.
