Grant: $167,163 - National Institutes of Health - Sep. 30, 2009
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Award Description: Identification of G*E interaction terms for common diseases represents a top priority for the Gene Environment Association Studies (GENEVA) consortium of investigators. We propose a cohort specific, hypothesis-driven strategy to filter high throughput genotyping data and environmental exposures in a manner to accelerate the discovery of G*E interaction terms for common diseases. We hypothesize that wecan identify G*E interactions by assembling single nucleotide polymorphisms (SNPs) from disease-relevant biochemical pathways, assess their association with disease and then perform appropriate statistical tests to determine if they interact with designated environmental exposures. Assembling SNPs in biochemical pathways for estrogen metabolism, iron processing, adenosine metabolism, etc, will be valuable as these pathways are operative for the disease outcomes in GENEVA. Assessing the relation between biochemical pathway SNPs and disease allows genetic loci that may not reach genome-wide significance but may significantly interact with environmental exposures to be discoverable components of G*E interaction terms in disease. We will establish the bioinformatic approach to discover G*E interactions in the study of primary open-angle glaucoma (POAG), an intraocular pressure-dependent, slowly progressive optic neuropathy of public health importance. Preliminary data suggests that the NOS3 gene interacts with gender and postmenopausal hormones in POAG. 500 cases and 500 controls in the Nurses Health Study will undergo a genome-wide association study on the Illumina 650K platform in fall 2009. We will study the relation between all SNPs in the estrogen metabolizing pathway and POAG and then evaluate whether the SNPs with strongest association interact with the attributes of female reproductive aging in POAG. Subsequently Dr. John Heit, a GENEVA investigator, will study the top SNPs in the estrogen-metabolizing pathway associated with venous thromboembolism and determine if they interact with postmenopausal hormone use. We will also study other biochemical pathways relevant to POAG (adenosine metabolism pathway) and type 2 diabetes (iron metabolizing pathway) in a similar manner. The disease-specific approach to discover G*E interactions in common disease using GWAS data stratified by environmental exposures complements other approaches used by GENEVA investigators to discover G*E interactions in chronic disease.
Project Description: Sub Recipient: At the Vanderbilt site, we will develop and test methods to test for gene x environment interactions. In particular, we will extend current methodologies that we have developed that use biological pathway information to identify subsets of GWAS data for detailed analysis. The extension will allow inclusion of non-biological (e.g. environmental) data to prioritize subsets of GWAS data. Such data might include data on the effects of diet, smoking, alcohol, medications or other exposures on specific biological pathways. Of particular interest is using such information on both an outcome dependent and an outcome independent manner. We will develop these extensions, test them on simulated data, and then test/apply them on actual available GWAS datasets.
Jobs Summary: Prime recipient retained Primary Investigator and Co-Investigator positions. Glaucoma Genetics Research Coordinator position was created. Sub Recipient: (0.4) The position that has been created is for a Post Doctoral Research Fellow. This individual will have expertise in computational genomics with a strong focus on developing and applying methods to detect gene x gene interactions. They will be the primary person responsible for performing the work on this project. (Total jobs reported: 0)
Project Status: Not Started
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