Interspecies Trait Genetics Reveals Association of Adcy8 with Mouse Avoidance Behavior and a Human Mood Disorder

Background: Identifying susceptibility genes for endophenotypes by studying analogous behaviors across species is an important strategy for understanding the pathophysiology underlying psychiatric disorders. This approach provides novel biological pathways plus validated animal models critical for selective drug development. One such endophenotype is avoidance behavior. Methods: In the present study, novel automated registration methods for longitudinal behavioral assessment in home cages are used to screen a panel of recently generated mouse chromosome substitution strains that are very powerful in quantitative trait loci (QTL) detection of complex traits. In this way, we identified chromosomes regulating avoidance behavior (increased sheltering preference) independent of motor activity levels (horizontal distance moved). Genetic information from the mouse QTL-interval was integrated with that from the homologous human linkage region for a mood disorder. Results: We genetically mapped a QTL for avoidance behavior on mouse chromosome 15, homologous with a human genome region (8q24) linked to bipolar disorder. Integrating the syntenic mouse QTL-interval with genotypes of 1868 BPD cases versus 14,311 control subjects revealed two associated genes (ADCY8 and KCNQ3). Adenylyl cyclase 8 (Adcy8) was differentially expressed in specific brain regions of mouse strains that differ in avoidance behavior levels. Finally, we showed that chronic infusion of the human mood stabilizer carbamazepine (that acts via adenylyl cyclase activity) significantly reduced mouse avoidance behavior, providing a further link between human mood disorders and this mouse home cage behavior. Conclusions: our data suggest that Adcy8 might encode a translational behavioral endophenotype of bipolar disorder.