Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, for which there is no adequate therapy. The majority of ALS patients are sporadic (i.e. they have no relatives with the disease). Sporadic ALS is considered to be a complex disease that is the result of an interplay of genetic and
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environmental risk factors, which act together to cause disease. Identifying the implicated genes will lead to a better understanding of the pathogenesis and will facilitate the development of novel therapies. This thesis describes several genetic studies that were aimed to identify genetic risk factors that are associated with ALS susceptibility, including genome-wide association studies (GWAS) to identify associated single-nucleotide polymorphisms (SNPs) and candidate gene studies, investigating the role of suspected genes. The focus of this thesis was the role of copy-number variation as a source of increased risk for ALS. We studied this in a genome-wide manner performed association analyses on rare and common CNVs. We identified several novel genetic loci that confer an increased risk for ALS, including a locus on chromosome 9p and UNC13A. Additionally, we found suggestive evidence for an association of NIPA1 deletions with an increased risk for ALS. We then examined this gene in more detail in a follow-up study. This study showed that expansions of a polyalanine repeat in this gene are associated with a higher risk of ALS and, in addition, with a shorter survival and with a lower age at onset of the disease. In another candidate gene study, we examined the role of SMN1, the causative gene for spinal muscular atrophy, a congenital motor neuron disease with some familiarities with ALS. Previous studies have shown that CNVs in this gene are associated with ALS, but results were contradictory. We found firm evidence for an association of SMN1 duplications and ALS susceptibility. We found no association with SMN1 deletions, which has been suggested previously. In conclusion, this thesis describes several novel risk loci for ALS, together with firm evidence for the implication of the previously suspected gene SMN1 in ALS pathogenesis. These findings are a starting point for functional studies investigating the underlying pathogenic pathways and will hopefully lead to better treatment strategies for this devastating disease
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