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

Multiple sclerosis (MS) is an example of a disease influenced by both genetic susceptibility loci and environmental factors. MS is known to be an autoimmune disease of the central nervous system, which results in loss of the myelin sheath around nerves (demyelination) and accompanying symptoms of paresthesia (‘tingling’ sensation), numbness, muscle loss, and difficulties in coordination. Genome-wide association studies (GWAS) in Caucasian non-Hispanic populations have revealed human leukocyte antigen (HLA) alleles (variants of genes) that provide “strong” risk, as well as protective effects, and ~200 non-HLA genetic risk variants conferring “modest” risk of MS. Together, identified

MS genetic risk factors are estimated to explain as much as 30% of total heritability — of which most is accounted for by HLA alleles.

There is evidence that those of African and Hispanic ancestry have a more severe disease course. Curiously, countries with majorities of Caucasian non-Hispanic individuals that experience highest MS prevalence are located at higher latitudes — suggesting a possible association with ultraviolet radiation and perhaps a causal role of low vitamin D levels as a MS risk factor. In the [attached] study, authors proposed that differences in worldwide MS prevalence might be explained by European ancestry. If European ancestry can explain this difference — then MS-associated alleles in admixed individuals can either be European, or confer increased risk on a European haplotype (group of alleles inherited together from a single parent, thereby being clustered together on same chromosome), compared to a non-European haplotype.

First, authors established that most alleles associated with MS are not necessarily European but are, in fact, “cosmopolitan” (existing in two or more ancestral groups). However, authors found, in African Americans, that the European HLA DRB1*15:01 allele was correlated with 3-fold greater risk, compared to the African DRB1*15:01 allele. Authors also observed genetic variations between European and African DRB1*15:01 alleles that, based on geographic region, could influence the function of antigen-binding proteins involved in MS. Consequently, it is plausible that ancestry could explain the risk, or protective effects, contributed by other MS-associated alleles. Authors also noted that chromosome 8 in Hispanics contains a region where MS cases have more European ancestry than controls — implying there may be new MS risk alleles to be discovered in Hispanics (although the HLA region is located on chromosome 6 ????).

Any differences in prevalence due to genetics might be partially explained by a combination of European risk alleles exerting greater risk (i.e. DRB1�15:01) compared to non-European risk alleles, or the presence of protective alleles in individuals of non-European ancestry. Yet, this does not rule out the possibility that observed prevalence differences could result from the influence of environmental risk factors or socioeconomic status — including (worldwide) differences in access to neurologists and diagnostic protocols using MRI, which may be population-specific. In conclusion, this study found evidence that the difference in MS prevalence might be partially explained by European ancestry, and the data further confirm that the ancestry of MS genetic risk factors is complex, to say the least. 🙁


PLoS Genet Jan 2o19; 15: e1007808

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