Using genomic signatures of natural selection to elucidate multiple sclerosis genetics

Multiple sclerosis (MS) prevalence shows a heterogeneous geographical pattern, with higher prevalence in populations of European ancestries, as well as increasing with distance from the equator within those populations. This pattern has likely been shaped by both natural selection and neutral genetic drift. Identifying genes that have undergone selection at MS risk loci will improve our understanding of the causative mechanisms behind the disease. Population genomics can be used to identify functional variation that has been subject to natural selection at loci associated with MS risk.

We carried out genome-wide scans for natural selection using F_ST and cross-population extended haplotype homozygosity in population genomic data. MS-related selection was localised by targeting genes prioritised in the large genome-wide association study carried out by the International Multiple Sclerosis Genetics Consortium. Strong signatures of natural selection in European and Asian populations were identified in several MS risk genes. Further analysis of these genes is underway to identify likely causes of selection and mechanisms by which they may contribute to MS risk. This approach allows us to narrow down candidate genes and pinpoint a small number of top causal candidates and mechanisms. This may enable more informed targeting of the molecular mechanisms behind the disease.