Genetic architecture of amyotrophic lateral sclerosis and intracranial aneurysms

This thesis contains the largest GWAS study of ALS to date and identifies 15 risk loci that contribute to ALS risk. The genetic architecture of ALS appears to be complex, with contributions from rare coding variants that may be causal, repeat expansions with large effects, and common and rare variants that converge on specific genes and loci with regulatory effects.

This thesis also includes the largest GWAS study of intracranial aneurysm (IA) to date and identifies 17 genome-wide significant loci. In addition, it explains 21.6% of the polygenic heritability. The genetic correlation between ruptured and unruptured aneurysms is very high. Overlap was also found with the clinical risk factors blood pressure and smoking. Furthermore, an enrichment of association signals was observed for receptors targeted by antiepileptic drugs.

There is currently insufficient evidence for the involvement of TIA1 in ALS pathophysiology, highlighting the importance of careful selection of clinical targets. Common genetic variants that increase the risk of ALS appear to have little influence on survival and age at onset, suggesting that the genetic factors influencing age at onset and progression of ALS may differ. In addition, genetic overlap has been demonstrated between ALS and other neurodegenerative diseases. The research emphasizes the role of glutamatergic neurons in ALS and points to the importance of vesicle-mediated transport and autophagy. Furthermore, we find evidence that high total cholesterol levels play a causal role in ALS.

The literature review of unresolved linkage regions underscores the importance of further research into (distant) family members with ALS. Future genetic studies are expected to yield substantial additional insights from the analysis of rare variation and poorly characterized structural variation.

Finally, each chapter in this thesis emphasizes the importance of collaboration for new genetic insights. With the advent of antisense oligonucleotide therapies and the direct translation of genetic findings into treatments, acquiring genetic knowledge is more important than ever. Given the complex genetic architecture of ALS, collaboration will be crucial to gain deeper insight into this devastating disease.