Genetics of Multiple Sclerosis
Year: 2013
Type: dissertation
Study design: Observational Study
Abstract: Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. Current available treatments can slow down the disease progression in the majority of patients, but can neither stop the progression nor cure the patients. MS is a debilitating neurological disease of young adults and it affects 0.1% of the populations of Northern European descent. The prevalence of MS varies globally and locally, and there are several isolated high-risk populations. One such high-risk population is in the Southern Ostrobothnia region of Finland, where the incidence and prevalence are approximately twice those of the surrounding regions. Both environmental and genetic factors are thought to contribute to disease pathogenesis. Twin, half-sib and adoption studies all point towards underlying genetic factors that predispose to MS. In recent years, genome-wide association studies have revealed over fifty genes that are associated with MS. At the start of this thesis project, only one MS locus, HLA-DRB1, was known, whilst shortly after the start two more loci, IL2RA and IL7R, were reported. The aim of this thesis was to find new associated loci, confirm newly found loci and assess the relevance of these known loci within the Southern Ostrobothnian high-risk isolate, and in the Finnish population overall. The association analyses were performed using genome-wide association analysis methods, haplotype analysis and meta-analysis methods. In the first study, 68 Southern Ostrobothnian cases and 136 identity-by-state matched controls were analyzed in a genome-wide association analysis, where an association signal from the SNP rs744166 in the STAT3 gene was discovered. The association signal was replicated in an international sample set of 4487 MS cases and 9778 controls (OR 1.18, 95% CI 1.12-1.24, p=2.75×10-10). In order to further understand the association signal, a haplotype analysis was performed, revealing that the association signal was on a common haplotype. Further, in a genome-wide homozygosity analysis, excess homozygosity was found in the 68 cases compared to the 136 controls in three genomic loci, 1q42.12, 2q24.3 and 12q24.33. The importance of these loci requires further study. The second study aimed to replicate loci that had previously been observed to associate with MS in an international genome-wide meta-analysis. Three SNPs in three loci, IRF8, TNFRSF1A and CD6, were genotyped in 608 trios, 8439 MS cases, and 9280 controls from 11 populations of European origin, replicating the associations in all three loci. The SNP in IRF8 was strongly associated with MS, while the SNPs in TNTRSF1A and CD6 indicated slightly weaker association. The odds ratios for all the three loci were similarly modest: IRF8 OR 1.11, TNFRSF1A OR 1.12, and CD6 OR 1.11. Since the prevalence and incidence of MS is two-fold in the Southern Ostrobothnian region and there is evidence for founder effect, the aim of the last study was to assess the accumulation of recently identified genome-wide significant MS-associated common risk alleles in the Southern Ostrobothnian isolate MS cases and in familial samples. However, we could not detect accumulation of common variants in the isolate region or in the families compared to general Finnish samples or non-familial samples.
Source: Työväentutkimus Vuosikirja
Author: Virpi Leppä
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3232785