Genome-wide association and whole exome sequencing approaches to gene discovery in multiple sclerosis

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Multiple sclerosis (MS) is a neurodegenerative disease in which inflammation causes and autoimmune response. Increased familial risk (up to 40-fold in first degree relatives) strongly indicates a genetic component to this disease. The occurrence of both sporadic and familial cases of MS suggests a heterogeneous genetic background. This project encompasses two different approaches to gene discovery in MS. These approaches include a genome-wide association study (GWAS) to identify common variants of small effect in a (relatively) large, unrelated cohort of MS patients and a familial whole exome sequencing (WES) study to identify rare variants of large effect in families with multiple MS-affected members. Additionally, literature analysis on twelve GWAS and six WES studies into MS is performed. For the GWAS participant collection is ongoing and so far, 192 cases have been used for genome-wide genotyping. These participants will be compared with matched controls. For the GWAS cases we collect EDSS and MSIP scores. In this article an analysis script for the MSIP is presented. Additionally, previous GWASs into MS are reviewed. For the WES study seven high-incidence MS families have been selected, of which four have been used for WES currently. For one of these families the results of WES are further discussed and phenotypic data in the form of the MSIP and a semi-structured lifestyle interview (SSLI) are discussed. Based on the WES data from this family, we hypothesise that the RHOD gene, which regulates the platelet-derived growth factor receptor ß involved in myelination, may cause MS in this family. We can conclude that combining WES and GWAS studies is useful for generating hypotheses about novel targets for intervention in MS.
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