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.
"We believe this research, with novel approaches and analytical strategies like these, will help us to further elucidate the underlying molecular pathways involved in MS, which we hope in turn will pave the way for new targeted treatments for MS in all patient populations," lead author Jacob McCauley, PhD, professor at the University of Miami Miller School of Medicine, told NeurologyLive®.
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.
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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.
"These preliminary findings are some of the first to highlight the utility of a trans-ethnic approach to genetic variant discovery for MS risk and genetic fine-mapping efforts that benefited from the inclusion of diverse populations with shorter linkage disequilibrium blocks," McCauley said. "We anticipated that this work would provide novel insights, by leveraging the genetically complex ancestral background of these populations and complement the genetic studies that thus far have only been possible within the larger European ancestry analyses."
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.
“The variants identified within this region could pave the way for new targeted treatments for MS, some of which may be population-specific. We must continue to refine our biological understanding of the disease and findings like these may be critical to help us understand the phenotypic diversity we observe across various global populations.,” McCauley added.
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REFERENCES
1. McCauley JL., et al. Novel ancestry-specific and putative causal genetic variants for multiple sclerosis identified by an ancestry-informed regression and trans-ethnic fine-mapping analysis. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark.
2. Ancestry-specific genetic variants linked to multiple sclerosis, new study shows. News Release. ECTRIMS. Published September 18, 2024. Accessed September 18, 2024.
