Amyotrophic lateral sclerosis: risk factors in the genome and exposome

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in progressive weakness and death in three to five years on average. In most patients there are no family members with ALS, and therefore an interplay of genetic and environmental risk factors is thought to be causal for disease development. Unfortunately many risk factors are still unknown and mechanisms of ALS development are not yet unraveled. This thesis presents multiple new risk factors for ALS, both genetic and environmental factors. Also previously postulated risk factors are checked in replication experiments. The finding of mutations in NEK1 as a novel risk factor points toward cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity as potential new disease mechanisms that needs to be followed up in future research. Also, a new approach was postulated towards investigating the exposome, the total of environmental factors. In this study many new environmental risk factors were found and for the first time the associations between risk factors could be determined. This exposome-wide study points towards different and independent environmental risk profiles that all lead to the same disease entity, ALS. It revealed that for instance the risk effect of smoking was independent of the effect of alcohol intake or a beneficial vascular risk profile. This thesis not only gives more insight in the risk factors for ALS, but also provides new insight in disease etiopathogenesis, thereby providing a basis for future treatment development