Genetic Epidemiological Studies of Multiple Sclerose

The objective of this thesis was to find new risk alleles for MS. This may finally result in a better understanding of the pathogenesis of MS. Knowledge of MS disease pathways can direct strategies for prevention, diagnosis and therapy. In our study, we included MS patients from a genetically isolated population in the southwest of the Netherlands. We followed this strategy because of the relative genetic homogeneity of an isolated population and because relationships are known between patients. In chapter 2 we assessed whether MS patients from this population were more often related to each other compared to controls from the same population. We investigated the parental relationship of MS patients using extensive genealogical information available from the Genetic Research in Isolated Populations (GRIP) program in chapter 3. In chapter 4, the results of two replication studies of the 17 by the IMSGC identified risk SNPs are described. In chapter 4.1, we verified the association of the 17 risk SNPs in MS patients and controls from the genetically isolated population. The second replication study (chapter 4.2) was performed in three independent cohorts: from the Dutch genetically isolated population, from the Dutch general population, and from the Canadian Collaborative Project on the Genetic Susceptibility to MS. The results were pooled with those of a recently published Australian replication study and with those of the original IMSGC study. Finally, we conducted a GWAS in the isolate and replicated the results in four independent cohorts, as reported in chapter 5. In the last chapter (chapter 6), we reflect our main findings, discuss methodological issues, speculate on the implications of our results and propose future studies.

• View at Worldcat

Free Full Text ( Final Version , 5mb )