Researchers Identify Ancestry-Specific Genetic Variants That Impact MS Risk

An ancestry-informed regression analysis with fine-mapping successfully identified novel ancestry-specific genetic variants associated with the risk of developing multiple sclerosis (MS) in Native American and Black populations and replicated previously identified risk alleles in European populations. These are the findings of a study presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in Copenhagen, Denmark, from September 18 to 20, 2024.

Previous analyses into genetic risk for MS have identified approximately 200 autosomal risk variants, outside of the major histocompatibility complex (MHC), using data from European populations. Other racial and ethnic populations have allelic and locus heterogeneity which could increase the power of fine-mapping approaches to detect novel risk alleles.

Researchers from the Alliance for Research in Hispanic MS (ARHMS) Consortium sourced genome-wide data for this ancestry-informed fine-mapping analysis from Hispanic MS cases (n=2201), Hispanic control cases (n=2112), Black MS cases (n=1584), Black control cases (n=1501), European MS cases (n= approximately 15,000), and European control cases (n= approximately 27,000).

Using data from the Hispanic and Black populations, missing data were imputed, local ancestry was computed, and a genome-wide association was performed to make ancestry-specific effect sizes for Native American, African, and European groups. The European data were used to conduct a fixed-effect meta-analysis for ancestry-specific tract identification. Haplotypes reaching genome-wide significance were fine mapped.

In an African haplotype, a novel locus located at 13q14.2 reached genome-wide significance.

In a Native American haplotype, a known MS locus located at 1p35.2 reached genome-wide significance.

In the fine-mapping analysis, 2 credible sets representing 2 causal signals located at 1p35.2 were identified. A novel missense mutation rs145088108 was identified as a Native American allele and the previously identified variant rs10914539 was replicated as a European allele. The fine-mapping analysis identified 7 additional MS loci.

“We have demonstrated the power of ancestry-informed regression to identify novel population-specific risk alleles and the advantage of [fine-mapping] in diverse populations. These data highlight the utility of a trans-ethnic approach to facilitate treatment and prevention of MS in diverse ancestral populations,” the researchers concluded.

Disclosure: This research was supported by Genentech Health Equity Innovation Fund. Please see the original reference for a full list of disclosures.