Saccular intracranial aneurysms (IAs) are balloon-like dilations of the arterial wall with a risk of hemorrhage that can result in severe neurologic impairment or death. We have identified association of IA with common risk alleles through genome wide association analyses of a total of 5,891 cases and 14,181 matched controls. These, however, explain less than 10% of genetic risk emphasizing the need for alternative study designs. We now propose an innovative approach involving capture and sequencing of all coding regions in the genome (exome) of 1,000 IA cases, 250 controls from minority ethnic groups and already sequenced >1,500 Caucasian controls, followed by categorization of variants based on their population allele frequencies (PAFs). We will analyze rare variants (PAF<1%) using a variant accumulation test comparing the cumulative frequency of cases versus controls that carry at least one deleterious allele. For variants with PAF>1%, we will leverage the results of exome sequencing of nearly 3,000 subjects (available from other studies) as well as publicly available resources to impute missing genotypes for all GWA study cohorts and use gene-wise association test. We will rank genes based on these two tests and re-sequence the top ~75 ranking candidate genes using a replication cohort of 1,400 cases and 1,400 controls with the Raindance instrument. We will then combine the discovery and replication results through a meta-analytic approach. We will perform subphenotype analyses (such as ruptured vs, unruptured, familial vs. sporadic, female vs. male) for clinical applications and analyze population (ethnicity) specific variants. Finally, we will perform functional studies aimed at dissecting the biological consequences of identified mutations. The results of these analyses will allow us to discover IA disease genes in which rare coding mutations impart large effect on IA formation and rupture. These findings will form the basis of future biological experiments, including creation of animal models, which will allow for translation of these results into novel treatments.
We propose the use of a novel, cutting edge technology to sequence all protein coding regions of the genome in patients with brain aneurysms to discover disease genes. Identification of these genes will allow us to: 1) identify at-risk individuals prior to a devastating complication, and;2) understand the biology underlying the formation and rupture of aneurysms, which will potentially lead to novel treatments in the future.
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