Broadening the Genetic Horizon: A Global Perspective on Multiple Sclerosis

Multiple Sclerosis (MS) is a complex immune-mediated neurodegenerative disease. Research has primarily focused on populations of European ancestry, leading to significant discoveries in understanding MS's genetic architecture. However, the genetic basis of MS in non-European populations remains largely underexplored. This blog post delves into a 2022 article from Nature Reviews Neurology, which argues for the inclusion of ancestrally diverse populations in MS genetics research, outlining both the scientific and ethical imperatives for such efforts.

The Current State of MS Genetics
Genome-wide association studies (GWAS) have identified over 200 loci associated with MS in populations of European ancestry. These loci explain up to 50% of the genetic heritability of MS in these populations. Despite this progress, the extent to which these findings apply to non-European populations remains unclear. Given that 78% of GWAS participants are of European descent, there is a pressing need to broaden genetic studies to include diverse populations.

The Importance of Diversity in Genetic Research
Studying MS genetics in diverse ancestral groups is crucial for several reasons:
Identification of Novel Variants: Different populations have distinct genetic architectures, which could lead to the discovery of novel risk loci. For example, a GWAS of lipid traits in African American individuals identified 15 novel loci not seen in European populations.

Improved Disease Prediction: Polygenic risk scores (PRS), which predict disease risk based on the burden of risk alleles, perform poorly across ancestries. Incorporating ancestry-specific data can enhance the accuracy of PRS, making them more effective in predicting MS in non-European populations.

Causal Inference: Mendelian randomization studies, which use genetic variants to infer causal relationships, require accurate ancestry-specific data. Expanding GWAS to diverse populations can help clarify the role of environmental risk factors across ancestries.

Ethical Considerations
The exclusion of non-European populations from genetic research exacerbates health disparities. Advances in personalized medicine based on European-centric data may not translate to individuals of other ancestries, potentially leading to inferior clinical care. Ensuring diverse representation in MS genetics research is not only a scientific necessity but also an ethical imperative to promote equitable healthcare outcomes.

Challenges in Expanding Genetic Research
Several challenges hinder the inclusion of diverse populations in MS genetics studies:
Cost and Logistics: Large-scale genetic studies are expensive, and recruiting sufficient numbers of participants from non-European populations can be difficult.

Population Stratification: Differences in allele frequencies and linkage disequilibrium structures across populations complicate the interpretation of genetic data. Appropriate control groups and sophisticated statistical methods are required to avoid false discoveries.

Ethical and Logistical Issues: Conducting research in non-European populations requires careful consideration of historical abuses and collaboration with local researchers to build trust and ensure the research benefits the communities involved.

Case Study: The Sardinian Population
The article highlights the success of GWAS in the Sardinian population, where a variant near the TNFSF13B locus was associated with MS. This variant was not found in mainland European populations, illustrating how unique genetic architectures in isolated populations can lead to novel discoveries. The Sardinian study also demonstrated the importance of integrating genetic data with other types of biological data, such as immunophenotyping and whole-genome sequencing, to uncover the mechanisms underlying genetic associations.

Challenges in Expanding Genetic Research
Expanding MS genetics research to include ancestrally diverse populations is essential for a comprehensive understanding of the disease. Such efforts will likely lead to the discovery of novel genetic variants, improve the accuracy of disease prediction tools, and ensure that advances in personalized medicine benefit all individuals with MS, regardless of their ancestry. Despite the challenges, the scientific and ethical imperatives for broadening participation in MS genetics research are clear. The inclusion of diverse populations will ultimately enhance our understanding of MS and improve outcomes for all patients worldwide.

This article underscores the need for a global approach to MS genetics, where the benefits of research are shared across all populations, leading to more effective and equitable healthcare solutions.

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