Genetic characterization of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to progressive muscle wasting and weakness, eventually resulting in swallowing difficulties and respiratory failure. There is no cure, and only one drug has been proven irrefutably to increase survival by several months. ALS is considered a complex disease, with both genetic and environmental factors contributing to disease onset, and approximately 5-10% of patients describe a positive family history. This thesis contains multiple studies on the genetic architecture of ALS; ultimately aiming to gain more insight into disease processes and provide a basis for new (personalized) treatments. Using different research methods, we identified new DNA variants (C21orf2, NEK1, MOPB and SCFD1) associated with a higher risk of ALS. Interestingly, the proteins C21OF2 and NEK1 were previously identified as interactors, providing novel insights into ALS disease development. Also, we confirm that the previously identified genetic variant in the gene NIPA1 increases ALS risk, and we show that certain genetic risk factors co-occur more often than expected by chance. This thesis further elucidates the genetic background of ALS, and underlines the importance of future large-scale genetic studies on the disease.