American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:134–166 (2008) Rapid Publication Phenomic, Convergent Functional Genomic, and Biomarker Studies in a Stress-Reactive Genetic Animal Model of Bipolar Disorder and Co-Morbid Alcoho

We had previously identified the clock gene D-box binding protein (Dbp) as a potential candidate gene for bipolar disorder and for alcoholism, using a Convergent Functional Genomics (CFG) approach. Here we report that mice with a homo-zygous deletion of DBP have lower locomotor activity, blunted responses to stimulants, and gain less weight over time. In response to a chronic stress paradigm, these mice exhibit a diametric switch in these phenotypes. DBP knock-out mice are also activated by sleep deprivation, similar to bipolar patients, and that activation is prevented by treatment with the mood stabilizer drug valproate. Moreover, these mice show increased alcohol intake following exposure to stress. Microarray studies of brain and blood reveal a pattern of gene expression changes that may explain the observed phenotypes. CFG ana-lysis of the gene expression changes identified a series of novel candidate genes and blood biomar-kers for bipolar disorder, alcoholism, and stress reactivity. 2008 Wiley-Liss, Inc. KEY WORDS: clock gene; mouse; knockout; genomics;brain;biomarkers;stress