Expanding Genetic Research in Multiple Sclerosis: The Need for Global Inclusion

Multiple sclerosis (MS) is a chronic neuroimmunological disorder that disproportionately affects individuals of European ancestry, particularly in regions of high latitude such as North America and Northern Europe. With genome-wide association studies (GWAS) identifying over 200 loci linked to MS susceptibility, our understanding of MS genetics in European populations has advanced significantly. However, non-European populations remain severely underrepresented in these studies, a gap that limits both our scientific knowledge and our ability to develop equitable clinical interventions for MS.

In this article, Jacobs and colleagues argue for a broader, more inclusive approach to MS genetics. Their discussion highlights the significant scientific benefits that come from studying diverse ancestral backgrounds, which could provide crucial insights for all patients with MS, regardless of their ethnic origins.

Disparities in MS Genetic Research
One of the most striking statistics highlighted in the article is the overwhelming dominance of European ancestry in GWAS, where about 78% of participants are of European descent, while only 11% are of Asian ancestry, and even fewer are of African ancestry. This imbalance not only reflects a scientific oversight but also presents ethical challenges. Current genetic findings may not be applicable to individuals from non-European backgrounds, perpetuating health disparities in MS care. Jacobs et al. emphasize that these disparities in participation could hinder the application of personalized genomic medicine in MS treatment for non-European populations​.

The Potential Benefits of Cross-Ancestry Research
Expanding MS genetic research to include more diverse populations could lead to several key advances:
Fine Mapping of Causal Variants: In populations with differing linkage disequilibrium patterns, it may become easier to pinpoint causal variants associated with MS. By comparing genetic variants across populations, scientists can narrow down the list of potential causal variants, improving our understanding of MS pathogenesis.

Improved Polygenic Risk Scores: Currently, polygenic risk scores (PRS) derived from European populations perform poorly in non-European groups. Developing ancestry-specific PRS could significantly improve risk prediction in diverse populations, ultimately guiding more effective MS prevention strategies​.

Discovery of Novel Risk Loci: Genetic studies in non-European populations may uncover novel loci that have been overlooked in European-focused research. This could reveal new biological pathways involved in MS and contribute to the identification of new therapeutic targets​.

The Role of the MHC Locus Across Populations
The major histocompatibility complex (MHC) locus, particularly the HLA-DRB1 allele, is one of the strongest genetic risk factors for MS in European populations. However, MHC allele frequencies and haplotype structures vary significantly across populations. For instance, while HLA-DRB115:01 is common in European populations, it is much rarer in populations of Asian ancestry. In contrast, alleles like HLA-DRB104:05*, which are absent in European populations, have been associated with MS risk in Japanese and other non-European groups. Studying these population-specific variations may provide valuable insights into MS pathogenesis and disease mechanisms​.

The Global Epidemiology of MS
One of the major challenges in understanding MS is the global variation in disease prevalence. Age-standardized estimates of MS prevalence range from 2.0 per 100,000 people in Oceania to 164.6 per 100,000 in North America. Jacobs et al. argue that differences in MS epidemiology across populations can be attributed not only to environmental factors but also to genetic variation. Studies of migrant populations, for example, have shown that moving from a low-prevalence region to a high-prevalence region increases the risk of MS, particularly if the migration occurs before adolescence. Such studies provide a unique opportunity to disentangle genetic and environmental contributions to MS risk​.

Ethical Implications and the Future of MS Research
In addition to the scientific benefits, the inclusion of diverse populations in MS research is an ethical imperative. As genetic research increasingly informs clinical practice, the exclusion of non-European populations could exacerbate existing health inequalities. Individuals from underrepresented populations may not benefit from advancements in MS diagnosis and treatment that are informed by European-centric genetic data. Ensuring that future genetic studies are inclusive will be essential for providing equitable healthcare to all MS patients​.

The authors conclude by urging for consortium-scale efforts to tackle these challenges. The cost and logistical difficulties of expanding GWAS to diverse populations are significant but achievable with international collaboration. Ultimately, the inclusion of non-European populations will not only address ethical concerns but will also lead to scientific breakthroughs that benefit all patients with MS worldwide.

By highlighting both the scientific and ethical reasons for expanding MS genetic research, Jacobs et al. provide a compelling case for the importance of global inclusivity in the study of this complex disease. The insights gained from cross-ancestry research will not only deepen our understanding of MS but also pave the way for more effective and equitable treatments for all individuals affected by the disease.

References:
Jacobs, B.M., Peter, M., Giovannoni, G. et al. Towards a global view of multiple sclerosis genetics. Nat Rev Neurol 18, 613–623 (2022).