Genetics of intracranial aneurysms and amyotrophic lateral sclerosis

The current status of intracranial aneurysm (IA) genetics is reviewed in Chapter 1. In Chapter 2, we combined linkage analysis and whole genome sequencing and identified six rare genetic variants, in six different genes, carried by all IA cases in one of three large families with IA or aneurysmal subarachnoid hemorrhage (ASAH). For one family, no segregating rare damaging genetic variants were found, while for another family four variants were found on the same locus. For a third family all cases carried two variants on two distinct loci. Therefore, the six identified variants could be IA-causing mutations, but functional studies are required to conclusively confirm, and understand, the role of these variants in IA pathogenesis. This study added to a short list of previous family studies that highlighted potential disease-causing genetic variants in families. The association of these variants in the general population was also tested, and the association of previously identified rare, damaging, variants in family studies was assessed in Chapter 3. No evidence for a role of the variants in IA in general was found. This indicates there are many additional genetic causes, and previously identified rare, damaging, variants for IA are specific to single families.
We performed the largest genome-wide association study (GWAS) of IA in 10,754 cases and 306,882 controls (Chapter 4). In this study, we increased the number of genome-wide significant common variant risk loci to 17. The explained polygenic heritability was 21.6%, which is over half over the twin-based heritability. There was a strong genetic correlation between ruptured and unruptured IAs. Strong overlap of genetic associations was further found with conventional risk factors blood pressure and smoking, and with other (cerebro )vascular diseases. Enrichment of associations with drug targets for epilepsy and drug targets for sex hormone related drugs was found, and a potential role for endothelial cells was observed. The single-nucleotide polymorphism (SNP) associations for IA, supplemented with associations for related traits, were used to create a genetic risk score (metaGRS) for IA in Chapter 6. The metaGRS showed modest predictive performance for ASAH risk. We found an association between younger age at ASAH and higher genetic risk, and that patients with an IA at the internal carotid artery had lower genetic risk. These findings showed that genetics play a role in the clinical heterogeneity regarding location and age at rupture of IA.
The largest GWAS of amyotrophic lateral sclerosis (ALS) is described in Chapter 5. Here, 29,612 patients and 122,656 controls were included. A genome-wide significant association of 15 risk loci with ALS was found. We conducted whole-genome sequencing of 6,538 patients and 2,415 controls to detect rare variants and repeat expansions in order to map risk loci to genes and causal variants. Gene mapping, gene-based rare variant analysis, and repeat expansion association analysis showed distinct genetic architectures per locus. Gene-based enrichment analyses showed a role for vesicle mediated transport and autophagy in ALS pathogenesis. A potential causal effect of genetic risk for high cholesterol levels on ALS risk was found.