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

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.

Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population

“…This is consistent with our finding of a higher proportion of NAT ancestry in NMO cases as compared to controls, and with epidemiological data suggesting that NMO is more prevalent in non-European populations 9 – 11 . To our knowledge there is only one previous study analyzing local ancestry of demyelinating diseases, where HLA alleles DRB1 *16:02 and DRB1 *14:02 were inferred as of Native American ancestry in Hispanics 43 , also in consistency with our local ancestry findings. As expected, the well-known HLA- DRB1 *03:01 NMO risk allele was predominantly inferred as of European ancestry.…”

African Americans and European Americans exhibit distinct gene expression patterns across tissues and tumors that are associated with immunologic and infectious functions and environmental exposures

“…Human genetics contribute to the propensity and severity of diseases 21,[30][31][32][33][34][35][36][37] . Sometimes the contribution is straightforward; a single allele variation found in Ashkenazi Jews, causes the vast majority of Tay-Sachs disease 36 .…”

Differential expression of COVID-19-related genes in European Americans and African Americans

“…Genetics of human populations contribute to the propensity and severity of diseases 37,39,41,41,45,[93][94][95][96][97][98] . Sometimes the contribution is straightforward; a single allele variation found in Ashkenazi Jews, causes the vast majority of Tay-Sachs disease 99 .…”