The molecular pathogenesis of intracranial aneurysms and subarachnoid hemorrhage

• Applicants: Privatdozent Dr. Georg Rosenberger, Ph.D.; Dr. Thomas Sauvigny
• Subject Area: Human Genetics ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518892379

The prevalence of intracranial aneurysms (IA) is around 3% in the general population. Unruptured IAs (UIAs) are associated with a risk for rupture and subsequent aneurysmal subarachnoid hemorrhage (aSAH) which is characterized by a high mortality. The risk for UIA and aSAH is increased among patient’s family members. Thus, a genetic basis of IA/aSAH is obvious; however, it is poorly understood. Although several large exome/genome wide association studies and exome sequencing (ES) studies identified various risk loci and candidate genes, respectively, valid disease genes have not been described. This may be due to technical limitations of sequencing technologies, a genetically complex architecture of the disease (digenic/oligogenic inheritance) or somatic sequence alterations causing UIA/aSAH. Therefore, the main goal of this study is to solve the missing hereditability problem for UIA and aSAH. We established a cohort comprising 115 individuals either with a familial history of UIA/aSAH or with a substantial sporadic manifestation. We performed short-read ES in 37 unrelated patients (31 sporadic and 6 familial cases) and 10 affected family members (from the familial cases). By using a family-based approach (filtering for variants shared by affected family members) and sequencing of further affected individuals, we defined novel candidate risk variants in the genes EDIL3 and TAGLN, both of which encoding proteins that are strongly involved in vascular biology. Now, we aim to characterize the functional consequences of the identified sequence variants in EDIL3 and TAGLN in order to determine their relevance in the pathogenesis of UIA/aSAH. In parallel, we intend to expand our study: (i) We are going to perform ES in the rest of our cohort to increase the number of individual datasets that can be evaluated (this is crucial e.g. for statistical evaluations); in addition, genome-wide sequencing is to be carried out in three affected families. (ii) We adapt our bioinformatics pipeline and filter for altered genes which are enriched in our sub-cohort of unrelated patients (gene-based approach); in order to generate larger cohorts, we cooperate with other consortia. (iii) We will analyze paired-sample ES data (blood vs. aneurysmal tissue) to identify somatic variants. (iv) By performing thorough variant association testing (gene burden/non-burden tests) and gene×gene interaction testing with ES data we aim to uncover possible digenic and oligogenic inheritance; we also cooperate with other consortia for this. (v) We will carry out gene product-matched assays to characterize functional impact of identified sequence variants on vascular biology. Taken together, the results from our study should improve the management of UIA and risk stratification for aSAH in a routine clinical setting.

• DFG Programme: Research Grants