Abstract
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.
Highlights
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that results in demyelination and tissue loss
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
Summary
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that results in demyelination and tissue loss. Association studies in White, non-Hispanic populations have discovered human leukocyte antigen (HLA) alleles conferring strong risk and protective effects and 200 non-HLA genetic risk variants conferring modest risk of MS[1,2]. Evidence that HLA class II alleles interact to confer greater risk of MS have been found[3]. The prevalence of MS varies across the globe but is highest in White, non-Hispanic populations. Countries with majority White, non-Hispanic individuals and experience highest MS prevalence are located at higher latitudes. We investigate another hypothesis—that the difference in MS prevalence across the globe can be explained by European ancestry. If European ancestry can explain this difference, MS-associated alleles in admixed individuals can either be European or confer increased risk on a European haplotype compared to a non-European haplotype
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