The primary goal of this study is to perform analyses aimed at identifying novel genetic risk factors that increase the susceptibility for an intracrania aneurysm (IA). We will analyze data derived from two complementary approaches in order to determine the role of common variation using a case control genomewide association study (GWAS) and rare variation using whole exome sequencing (WES) in densely affected pedigrees. As part of a recently completed R01-funded study (FIA Study;PI: Joseph Broderick), we recruited both familial and sporadic IA cases. In addition, using ARRA funds, we expanded the scope of the study to employ the most current technologies to identify both common and rare variation. From this ongoing study and through collaborations, we have generated GWAS data from over 5,000 samples to test the role of common variation in IA susceptibility. In addition, we selected 7 densely affected families and performed WES to identify candidate genes harboring rare variants that may be implicated in IA. We are currently genotyping a set of IA cases to obtain further evidence for the candidate genes identified through WES. The focus of this R03 application is the analysis of the data generated using both the GWAS and WES approaches. These data were added to the scope of work proposed as part of ARRA funding due to the rapid decrease in the cost of these technologies. The scope of work completed as part of ARRA funding exceeded that initially planned and did not include analyses that are now required.
The specific aims of this project are: 1) To perform a case control GWAS in all available samples (2,600 IA cases and 2,568 controls) to identify common SNPs associated with IA susceptibility. 2) To analyze the sequences of 96 candidate gene and to test whether the frequency of rare variants is greater in ~ 400 familial IA cases as compared with publicly available controls.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
5R03NS083468-02
Application #
8660722
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Gwinn, Katrina
Project Start
2013-06-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$77,220
Indirect Cost
$27,720
Name
Indiana University-Purdue University at Indianapolis
Department
Genetics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Zhang, Xinjun; Lin, Hai; Zhao, Huiying et al. (2014) Impact of human pathogenic micro-insertions and micro-deletions on post-transcriptional regulation. Hum Mol Genet 23:3024-34
Foroud, Tatiana; Lai, Dongbing; Koller, Daniel et al. (2014) Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7. Stroke 45:3194-9