Ancestry-specific genetic variants linked to multiple sclerosis risk

A study has uncovered novel ancestry-specific genetic variants linked to multiple sclerosis (MS), offering new insights that could reshape treatment approaches for diverse populations affected by the disease. The research, presented today at European Committee for Treatment and Research in Multiple Sclerosis 2024, is the result of efforts by the Alliance for Research in Hispanic MS (ARHMS) Consortium and is the first large-scale study to identify ancestry-specific genetic effects for MS risk.

In a comprehensive analysis of over 7,000 individuals from self-reported Hispanic (n=4,313; 2,201 MS, 2,112 controls) and African American (n=3,085; 1,584 MS, 1,501 controls) backgrounds, researchers discovered key genetic loci associated with MS risk. The findings highlight the potential of ancestry-informed genetic studies to uncover previously unidentified risk factors for MS and to improve the precision of fine-mapping efforts across different racial and ethnic groups.

A novel genetic locus was identified on chromosome 13q14.2, specifically within African haplotypes (genetic signatures). The variant, rs3803245, is located in a region of the chromosome that is highly open to certain proteins in T-cells, suggesting this region may serve as a regulatory area in T-cells, which are crucial in the pathology of MS.

On chromosome 1p35.2, the research identified two distinct genetic variants associated with MS risk—one specific to Native American haplotypes and the other to European haplotypes. The Native American variant, rs145088108, significantly increases the risk of MS in Hispanics and African Americans (OR=2.05), compared to the European variant, rs10914539 (OR=1.37) (European cohort = 15,000 MS and 27,000 controls).

Dr. McCauley, Professor at the University of Miami Miller School of Medicine and leader of the study, explains, “The variant found in Native American genetic signatures changes the structure of a protein, which might explain why it is more strongly linked to MS risk. In contrast, the variant found in European genetic signatures is in a non-coding part of the gene, making it less clear how it contributes to the disease.”

Through a trans-ethnic meta-analysis, the researchers achieved high-resolution fine-mapping of seven previously identified MS risk loci. Dr. McCauley furthers, “The variants identified within these loci could pave the way for new targeted treatments for MS, some of which may be population-specific. Refining the focus on these regions is highly valuable, and with further replication there is potential for discovering new drug targets in the future.

“While we anticipated some level of genetic diversity, the identification of African and Native American-specific alleles influencing MS risk is both exciting and encouraging. As our cohort grows, we expect to discover even more ancestry-specific alleles that could be critical for understanding phenotypic diversity and addressing health disparities in MS. We are extremely grateful to our study participants and their families for participating in this important research and we encourage additional patients from underrepresented populations to join our efforts.”

The study also highlights the importance of considering gene-environment interactions in future research. While the identified variants were largely population-specific, the researchers emphasized the need to explore how environmental and lifestyle factors might interact with these and other genetic variants to influence MS risk. This is especially relevant in diverse populations with varying socioeconomic backgrounds and diets.

Moving forward, Dr. McCauley and colleagues of the ARHMS Consortium plan to conduct functional studies to determine the causal pathways associated with the fine-mapped variants, and to expand their cohorts to discover additional ancestry-specific variants.

More information:
Novel ancestry-specific and putative causal genetic variants for multiple sclerosis identified by an ancestry-informed regression and trans-ethnic fine-mapping analysis, McCauley, J.L., et al. (2024). Presented at ECTRIMS 2024.

Provided by
European Committee for Treatment and Research in Multiple Sclerosis