Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.Author summary: Multiple sclerosis (MS) is an autoimmune disease that is mostly found in populations with northern European ancestry. Our study investigates whether there is evidence that the difference in MS prevalence around the globe could be explained by European MS genetic risk factors in African Americans, Hispanics, or Asian Americans. Our work first established that most alleles associated with MS are not necessarily European, but are in fact, cosmopolitan. However, we also observed in African Americans that European HLA-DRB1*15:01 conferred three times the odds of MS compared to the African allele. The allele HLA-DRB1*15:01 has been shown to be a major genetic risk factor in Europeans and other admixed populations. In addition, we observed genetic variations between European and African HLA-DRB1*15:01 alleles that, based on location, could influence the function of antigen-binding proteins involved in MS. Consequently, it is plausible that ancestry could explain the risk or protective effects of other MS-associated alleles. Additionally, our study found on chromosome 8 in Hispanics a region where MS cases have more European ancestry than controls, implicating there may be new MS risk alleles to be discovered in Hispanics. In conclusion, our study found evidence that the difference in MS prevalence could be explained by European ancestry and established that the ancestry of MS genetic risk factors is complex.