Zachary Tatom1 , Maya Eid2 , Thiago Missfeldt Sanches1 , Apurva S. Chitre1 , Denghui Chen1 , Benjamin Johnson1 , Elaine Keung1 , Oksana Polesskaya1 , Tom Jhou2 , Abraham A. Palmer1,3

Many substances of abuse produce initial rewarding eHects (euphoria) followed by a period of aversive eHects including anxiety, craving, anhedonia, and withdrawal. Dysregulation of these aversive eHects has been suggested to contribute to the etiology of substance use disorders through aberrant avoidance-based learning. We hypothesize that GWAS of avoidance-based learning using both food-based and cocaine-based behavioral assays in Heterogenous Stock (HS) rats will enable estimation of the heritability of these behaviors and identify new loci associated with them in rats. We exposed 1,074 HS rats (379 male, 695 female) to behavioral testing including runway operant cocaine-seeking, food-based progressive ratio and punishment testing, and locomotion assays. Our results demonstrate that behavioral phenotypes derived from these assays are significantly heritable (with h2 estimates ranging from 0-0.307) and identify significant (p < 0.05) genetic loci related to avoidance-based learning including from the punishment task on Chromosomes 2, 3, 5, and 6, and the cocaine-operant runway latency task on Chromosome X. 172 positional candidate genes were identified from significant and suggestive loci, including genes from the cadherin family and genes associated with primary neuronal cilia. Lead GWAS SNPs were also associated with novelty-related and social interaction phenotypes in PheWAS from independent samples of HS Rats. Our results suggest that these avoidance-based learning traits are themselves complex heritable traits which may pleiotropically aHect other aspects of addiction biology.

1 Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; 2 Department of Neurobiology, School of Medicine, University of Maryland, Baltimore, MD, USA; 3 Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA Funding Support: R37DA054370, P30DA060810, T32AA013525