Functional variants associated with complex traits tend to fall in non-coding regions and affect regulatory mechanisms that are not yet well characterized. Furthermore, it is generally difficult to determine in which tissues and conditions they may have a functional impact. This is because the effect of a genetic variant on a molecular pathway, and ultimately on the individual's phenotype, may be modulated by environmental factors. We denominate such variants gene-expression environment-specific quantitative trait nucleotides GxE-QTNs. Achieving a better understanding of the mechanisms underlying GxE-QTNs is a critical step in understanding the link between genotype and complex phenotype. It is also crucial to develop computationally efficient and statistically sound methods capable to integrate tissue/condition-specific functional genomics data to predict and validate when a sequence variant is functional. We propose to develop novel experimental and computational approaches to screen, analyze and functionally characterize genetic variants for complex traits modulated by environmental exposures. To identify and characterize GxE-QTNs, we will analyze allele specific gene expression in a panel of relevant tissues (e.g. the vascular endothelium for cardiovascular diseases) under a series of controlled environmental conditions (e.g. glucocorticoids treatment, as a proxy for stress exposure). The proposed computational tools will integrate different sources of evidence including data collected by ENCODE, Road Map Epigenome and GTEx projects to functionally annotate GWAS variants. The experimental and computational tools developed by this project have widespread applicability; for example, can be used to tackle the functional basis of complex traits in other environmental contexts (e.g. other types of stress and hormonal levels) and genetic backgrounds. Relevance to public health: Our findings will represent the first comprehensive catalog of genetic variants that interact with environmental exposure in determining human complex traits.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM109215-02S1
Application #
9022143
Study Section
Special Emphasis Panel (ZGM1 (CP))
Program Officer
Krasnewich, Donna M
Project Start
2014-07-15
Project End
2018-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
2
Fiscal Year
2015
Total Cost
$201,150
Indirect Cost
Name
Wayne State University
Department
Genetics
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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