R01DA053722

Functional Genetic Variants in Substance Use Disorders - Project Summary

The long-term goal of this study is to identify functional genetic variants that are associated with Substance Use Disorders (SUDs) and contribute to understanding the mechanisms underlying these devastating disorders. Our overall objectives are to (I) design and implement a series of experimental methods to assess the impact of genetic variants relevant to SUDs and related traits, as well as computational models to predict the impact of additional variants, and (II) establish a statistical genetics framework to more effectively identify additional genes that contribute to the disorders.

This proposal builds upon our previous studies on the role of genomic variation in gene regulation and will generate new data to combine with existing multi-omics data and modeling. We propose the following specific aims:

1. Identify functional genetic variants that contribute to the risk for Substance Use Disorders and related phenotypes by affecting gene regulation. This will be done using a series of high-throughput reporter assays to evaluate the impact of tens of thousands of non-coding variations in enhancers, promoters, and 3'UTRs on gene expression in eight cell lines representing four major cell types in the brain (neurons, microglia, astrocytes, and oligodendrocytes). Variants with a modest association with Substance Use Disorders and related traits will be selected from the GWAS catalog and ongoing experiments. Data on the initial large sets of variants will be used to predict, using machine learning approaches, the functional impact of additional regulatory variants. A large subset of the variants predicted to be functional will then be tested with follow-up high-throughput reporter assays, and the predictive models refined based upon the data.

2. Identify genes whose expression changes contribute to the risk for Substance Use Disorders. We will use Mendelian randomization-based methods based on the data derived from Aim 1, as well as GWAS data from the Psychiatric Genomics Consortium (PGC) and other large consortia, to identify causal genes whose expression changes in specific cell types contribute to SUD-related phenotypes.

Upon completion of these studies, we will have created a unique, accessible resource of SUD-associated genetic variants that regulate target gene expression in specific brain cell types. These genes can serve as high-priority candidates for future functional and animal-based studies.

Trustees Of Indiana University

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Indianapolis, Indiana 46202 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 434% from $582,965 to $3,110,300.