Approved Research

Genetic risk factors of cerebrovascular disorders

Yale University

Lay summary

Intracranial aneurysms (IA) are focal outpouchings that frequently arise at bifurcations of major cerebral arteries. Approximately 3% of the general population is estimated to carry an IA. However, patients are often unaware until a catastrophic rupture occurs, frequently without any warning signs. Aneurysmal subarachnoid hemorrhage is responsible of 500,000 hemorrhagic strokes worldwide annually. Approximately 25% of patients die suddenly before reaching to hospitals. Given the grim prognosis, molecular biology and genetic predisposition of IA should be investigated.

In this proposal, we aim (1) to identify the genes responsible for IA formation and (2) Subarachnoid hemorrhage, 3) assess enrichment of identified genes in Aim (1) and (2) in other forms of hemorrhagic stroke.

Scope extension:

With this proposal we aim to assess the impact of rare and deleterious variants in cerebrovascular disorders with a particular focus on cerebral aneurysms and hemorrhagic stroke (both subarachnoid hemorrhage and any types of cerebral hemorrhage). Our goal is to use the whole exome sequening data of >400.000 individuals generated by the UK Biobank and the clinical information of the individuals diagnosed with any cerebrovascular condition. If possible, we would like to have access to the entire WES database to be able to perform a case-control burden analysis, where the individuals with certain cerebrovascular conditions will be selected as cases and the rest as control. In our laboratory we recently completed whole exome sequencing of over 400 patients diagnosed with subarachnoid hemorrhage or unruptured cerebral aneurysms. We would like to increase the power of our study by including UK Biobank WES data.

Request for an Update: In our current request for an update, 1) In addition to the scope of our current application, which includes the analysis of WES data of entire cohort to be used as control and case-cohort (patients with cerebral aneurysms as well as hemorrhagic stroke (both subarachnoid hemorrhage and any types of cerebral hemorrhage)); we now aim to use WES data of patients with any type of cerebrovascular disorder diagnoses as well as all hypertension patients as part of our case-cohort. 2) We would like to have access to whole-genome sequencing of all individual diagnoses for all cerebrovascular conditions to be used as case-cohort and the whole genome sequencing data of the entire available cohort to be used as control for a statistical comparative analyses for both rare and common variants and for both gene-level and variant-level comparison in a case-control study.

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Request for additional Update: In addition to our current application's scope, which investigates cerebrovascular disorders using whole genome and whole exome data, we now aspire to delve deeper into the proteomic landscape of these conditions. 1) Specifically, we intend to integrate the proteomics data of patients diagnosed with any cerebrovascular disorder and those diagnosed with hypertension, leveraging these groups as integral components of our case-cohort. 2) Moreover, we request access to the proteomics data of the entire available cohort within the UK Biobank to serve as a control. This extensive data will be pivotal for rigorous comparative analyses, both at the protein expression level and through cross-referencing with genomic datasets. Our aim is to identify differentially expressed proteins, correlate these findings with genetic markers, and potentially unveil novel therapeutic avenues and stratification methodologies. By doing so, we anticipate uncovering invaluable insights into the complex interplay of genetics and proteomics in cerebrovascular pathologies.