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.http://repub.eur.nl/res/pub/22089/Edited%20Version.pdf
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