1. ¹Laboratory of Neurophenomics, University of California, San Diego, CA, USA
2. ²Department of Psychiatry, University of California, San Diego, CA, USA
3. ³VA San Diego Healthcare System VISN-22 MIRECC, San Diego, CA, USA

Correspondence: Dr AB Niculescu III, MD, PhD, Current address: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, 791 Union Dr., Indianapolis, IN 46202-4887, USA. E-mail: anicules@iupui.edu

Received 26 February 2004; Revised 25 May 2004; Accepted 26 May 2004; Published online 17 August 2004.

Abstract

Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant—methamphetamine, and a mood stabilizer—valproate), with human data (linkage loci from human genetic studies, changes in postmortem brains from patients), as a bayesian strategy of crossvalidating findings. Topping the list of candidate genes, we have DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) located at 17q12, PENK (preproenkephalin) located at 8q12.1, and TAC1 (tachykinin 1, substance P) located at 7q21.3. These data suggest that more primitive molecular mechanisms involved in pleasure and pain may have been recruited by evolution to play a role in higher mental functions such as mood. The analysis also revealed other high-probability candidates genes (neurogenesis, neurotrophic, neurotransmitter, signal transduction, circadian, synaptic, and myelin related), pathways and mechanisms of likely importance in pathophysiology.