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 SUDs, and thereby 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 and 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, 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 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 experiments underway. 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 HTRAs, and the predictive models refined based upon the data. 2. Identify genes whose expression changes contribute to the risk for SUDs. We will use Mendelian Randomization-based methods based on the data derived from Aim 1 plus GWAS data from the 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.