Amyotrophic lateral sclerosis: genetic susceptibility factors and pleiotropy

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness, spasticity, dysarthria and, ultimately, respiratory muscle insufficiency. These symptoms are caused by the loss of motor neurons in both the brain and in the anterior horn of the spinal cord. The incidence rate for ALS is approximately 3 per 100,000 person-years in the European population. ALS is a rapidly progressive disease, with a median survival time from onset of three years. To date, no cure is available, and denervation of the respiratory muscles or dysphagia leading to respiratory complications are the most common fatal events. The etiology of sporadic ALS remains largely unknown. The general view is that sporadic ALS is a disorder of complex etiology, in which both environmental factors and genetic factors play a role. In the past years interest for the genetic causes of ALS has grown tremendously. A considerable heritability has been estimated of 20-60%. Classically, ALS is divided in two forms: sporadic ALS (in which there is no apparent family history of ALS) and familial ALS, defined as the presence of at least one affected first or second degree relative, which is the case in 5-10% of ALS cases. In familial ALS, nearly 20 causative genes have been identified, of which a repeat expansion in the C9orf72 gene accounts for a large proportion of cases, also demonstrating another neurodegenerative disease called frontotemporal dementia (FTD). By contrast, the genetic causes of sporadic ALS remain far more elusive. Mutations in some of the familial ALS genes have also been found in a small proportion of the sporadic ALS patients. However, these can explain only 6-15% of the sporadic ALS cases. The aim of this thesis was to identify genetic susceptibility factors in ALS. In order to achieve this aim we have investigated candidate genes, gene-environment interactions, expression quantitative trait loci (eQTLs), genetic pleiotropy, and disease modifiers in ALS. We have shown an example of gene-environment interaction for the paraoxonase 1 gene and population density. We have identified an ANG mutation in a pedigree of familial ALS, of which one patient, additionally, showed signs of frontotemporal dementia (FTD) and parkinsonism. By the genetic mapping of gene expression we have implicated CYP27A1 as a susceptibility gene in ALS. We have found that UNC13A modifies survival in ALS patients and, additionally, is a shared risk locus for both ALS and FTD. We did not find any shared susceptibility loci for ALS and multiple sclerosis (MS). Also, we were not able to identify additional genetic modifiers that determined phenotypic heterogeneity in C9orf72 repeat expansion carriers, but we confirmed TMEM106B as a disease modifier.