Multi-Ethnic Study Identifies Ancestry-Specific Genetic Variants that Influence Risk of Multiple Sclerosis

A new multi-ethnic cohort study using novel ancestry-informed regression identified novel population-specific risk alleles associated with multiple sclerosis (MS) and successfully fine-mapped previously reported MS loci. These results suggest that novel ancestry-specific genetic variants impact the risk of MS, underscoring the advantage of a trans-ethnic approach for assisting with treatment decisions and prevention of MS in diverse ancestral populations.^1,2

All told, data of genome-wide genotypes were available for 4313 Hispanics patients (MS cases, n = 2201; controls, n = 2112) and 3085 African American patients (MS cases, n = 1584; controls, n = 1501). Investigators identified a novel genome-wide significant locus on chromosome 13q14.2 among alleles residing on an African haplotype. For alleles residing on a Native American haplotype, researchers identified a genome-wide significant signal within a known MS locus on chromosome 1p35.2.

“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,” lead author Jacob McCauley, PhD, professor at the University of Miami Miller School of Medicine, said in a statement.²

Presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, September 18-20, in Copenhagen, Denmark, researcher computed local ancestry with RFMixV2 and conducted genome-wide association with Tractor to acquire ancestry-specific effect-size estimates for alleles from an African, European, and Native American origin after TopMed imputation. Authors then performed a fixed-effects meta-analysis for the ancestry-specific tracts with summary statistics from a European cohort (MS cases, n = ~15K; controls, n = ~27K). Additionally, investigators utilized SuSieX for trans-ancestry fine-mapped in regions that showcased genome-wide significance.

Top Clinical Takeaways

The study identified novel genetic variants associated with MS in African and Native American populations, highlighting the importance of ancestry-informed research.
Researchers used advanced tools to fine-map MS loci and uncovered population-specific causal signals, some of which may lead to new, targeted treatments.
The findings underscore the need to explore gene-environment interactions and expand research to underrepresented populations to address health disparities in MS.

Researchers identified 2, when fine-mapping, of 95% credible sets that represented 2 distinct causal signals at 1p35.2. The first one identified was specific to Native American alleles, the top variant being missense mutation rs145088108, and the second one identified was specific to European alleles, the top variant being the previously identified rs10914539. Notably, investigators achieved 7 additional MS loci with fine-mapping of high resolution. McCauley said in a statement, “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."²

The findings also highlight the importance of exploring gene-environment interactions in further research in the future. Although the identified variants by investigators were largely population-specific, authors also underscored the need to assess how environmental and lifestyle factors might influence these and other genetic variants to impact MS risk which may be especially relevant in diverse populations with different socioeconomic backgrounds and diets. Thus, McCauley and colleagues of the Alliance for Research in Hispanic MS Consortium plan to perform functional studies to identify the causal pathways linked with the fine-mapped variants, and to lengthen their cohorts to discover additional ancestry-specific variants.

“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,” McCauley said in a statement.² “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."