(Project 3) The primary goal of the project is to find genetic variants underlying the individual differences in animal models of psychological traits often related to drug abuse, including sensation seeking, social approach, inattention, and impulsivity. In the current funding period (Year 5 began 3 months ago) we have almost reached our goal of phenotyping 1,600 heterogenous stock (HS) rats. We have estimated the SNP heritability of all the behavioral traits and confirmed that they are within a range suitable for genome-wide association (GWAS); indeed they are among the highest observed for any behavior studied by this center. By using genetic correlation, we have estimated shared genetic influences between our measures and those studied in Project 2 (Socially acquired nicotine self-administration). While our study is still ongoing, we have already identified many genome-wide significant associations. Several of the quantitative trait loci (QTL) associated with our phenotypes contain only a few genes. This extremely accurate mapping is a key feature of the HS population and will facilitate identification of the causal gene within each locus. In some cases, the list of candidate genes can be further narrowed by an overlapping gene expression QTL. Both human GWAS and our recently completed GWAS of several physiological traits (n~3,200) have shown that increasing sample size results in an exponential increase in genome-wide significant hits. Based on the success of our phenotyping pipeline during the previous funding period, we are proposing to phenotype an additional 1,600 male and female HS rats on these five behavioral tasks. Our proposed studies are arranged as follows:
In Aim 1. we will phenotype 1,600 HS rats provided by Core B (HS breeding core) on all five behavior tests. Each year we will study 400 rats (200M and 200F). Phenotyping will be conducted using existing protocols so that the entire dataset of 3,200 rats can be analyzed together.
In Aim 2, we will analyze the vast amount of behavior data (over 100 measures per rat) and prepare them for GWAS. After rigorous quality checking of these data, we will submit them to Core A (Administrative Core) to be entered into a database and subsequently used for GWAS by Core C (genotyping, RNA-Seq, and GWAS).
In Aim 3, we will conduct genetic correlation, phenome-wide association, and meta- analysis using traits obtained from different cohort of animals. We are in an unique position of being able to study the shared and unique genetic influences between three behavior models of impulsivity. We will also use these methods to examine the shared genetic factors between the psychological traits we study and the drug- related traits studied by Project 1 (cocaine), Project 2 (nicotine) and other affiliated U01s (cocaine, oxycodone).
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