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Candidate genes, pathways and mechanisms for bipolar (manic–depressive) and related disorders: an expanded convergent functional genomics approach

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.

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Acknowledgements

We acknowledge UCSD/VA Gene Chip Core Facility (Drs William Wachsmann, and Robert Stuart—in memoriam) for technical assistance and advice regarding microarray experiments and data analysis; Drs David Segal, John Kelsoe, Richard Hauger, Eric Turner, Husseini Mauji and Dan Salomon, for early discussions, encouragement, and advice; Jennifer Wessel and Ian Nicastro for excellent technical assistance regarding convergent genetic linkage and behavioral data analysis, respectively. This work was supported by an NIMH Postdoctoral Fellowship in Biological Psychiatry and Neuroscience (T32 MH018399), Pfizer Postdoctoral Fellowship in Biological Psychiatry, NARSAD Young Investigator Award and VA MIRECC Pilot Funding Award to ABN.

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Correspondence to A B Niculescu.

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The authors declare that they have no competing financial interests.

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Ogden, C., Rich, M., Schork, N. et al. Candidate genes, pathways and mechanisms for bipolar (manic–depressive) and related disorders: an expanded convergent functional genomics approach. Mol Psychiatry 9, 1007–1029 (2004). https://doi.org/10.1038/sj.mp.4001547

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