Tatom, Z.; Mignogna, K. M.; Macleod, L.; Sergi, Z.; Miles, M. F.

Anxiety disorders are the most common class of psychiatric disorder. Risk for anxiety disorders is thought to be influenced by many genes, each contributing a small effect. The light-dark box behavioral assay was designed to measure anxiety-like behavior in rodents. Diversity Outbred (DO) mice were designed for high-resolution quantitative trait loci (QTL) mapping on a genetically-diverse background. Here, we studied a population of 518 male DO mice for anxiety-like and locomotor behaviors from a light-dark box assay. Multivariate analysis of behavioral data identified two major subgroups of animals differing in basal anxiety behavior and subsequent ethanol consumption patterns. Behavioral QTL analysis identified a significant locus on Chromosome 14 associated with 3 anxiety-like behavioral phenotypes. Haplotype analysis revealed an effect of C57BL/6J alleles at this locus, with mice carrying those alleles exhibiting more anxiety-like behavior. An additional 9 suggestive loci were identified. Genes located within the confidence intervals for the Chromosome 14 locus were analyzed for coding sequence polymorphisms, prefrontal cortex expression QTLs, human GWAS data, and additional data sets related to psychiatric conditions including substance use. Results prioritized two candidate genes, Tbc1d4 and Lmo7, for further study. These results represent the highest-resolution genetic mapping of light-dark box behaviors in mice to date, revealing insights into the complex biology of anxiety disorders. Additionally the studies identify striking subgroups of animals where basal anxiety-like behavior predicts eventual ethanol consumption phenotypes.