Anxiety and fear in a cross of C57BL/6J and DBA/2J mice: mapping overlapping and independent QTL for related traits

Anxiety, like other psychiatric disorders, is a complex neurobehavioral trait, making identification of causal genes difficult. In this study, we examined anxiety-like behavior and fear conditioning (FC) in an F-2 intercross of C57BL/6J and DBA/2J mice. We identified numerous quantitative trait loci (QTL) influencing anxiety-like behavior in both open field (OF) and FC tests. Many of these QTL were mapped back to the same chromosomal regions, regardless of behavior or test. For example, highly significant overlapping QTL on chromosome 1 were found in all FC measures as well as in center time measures in the OF. Other QTL exhibited strong temporal profiles over testing, highlighting dynamic relationship between genotype, test and changes in behavior. Next, we implemented a factor analysis design to account for the correlated nature of the behaviors measured. OF and FC behaviors loaded onto four main factors representing both anxiety and fear behaviors. Using multiple QTL modeling, we calculated the percentage variance in anxiety and fear explained by multiple QTL using both additive and interactive terms. Quantitative trait loci modeling resulted in a broad description of the genetic architecture underlying anxiety and fear accounting for 14-37% of trait variance. Factor analysis and multiple QTL modeling showed both unique and shared QTL for anxiety and fear; suggesting a partially overlapping genetic architecture for these two different models of anxiety.