Laboratory of Neurophenomics | Candidate Genes, Pathways, Mechanisms CFG Approach

Candidate Genes, Pathways, and Mechanisms for Bipolar (Manic-Depressive) and Related Disorders Identified Through a Comprehensive Convergent Functional Genomics Approach

Cory Ogden ^1,2,3, Michael Rich ^1,2,3, Nicholas Schork ², Martin Paulus ^2,3, Mark Geyer ^2,3, James B. Lohr ^2,3, Ronald Kuczenski ^2,3, and Alexander B. Niculescu ^1,2,3*.

¹Laboratory of Neurophenomics; ²Department of Psychiatry, UC San Diego; ³VA San Diego Healthcare System VISN-22 MIRECC

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 pharmacological mouse model with human data (linkage loci from human genetic studies, changes in post-mortem brains from patients), as a Bayesian strategy of cross-validating findings.

Topping the list of candidate genes we have DARPP-32 (dopamine- and cAMP- regulated phosphoprotein of 32 kilodaltons, PENK (preproenkephalin), and TAC1 (tachykinin 1, substance P). 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.

Tables

Table 1. Category I and II Genes w/ FC, p values and convergence data
- pdf file (30 KB)
Table 2. Top Category III Genes w/ FC, p values and convergence data
- pdf file (19 KB)
Table 3. Top Category IV Genes w/ FC, p values and convergence data
- pdf file (13 KB)
Table 4. Gene Ontology Analysis of Category I-IV Genes and Analysis of Genes Changed in Multiple Brain Regions
- pdf file (15 KB)
Table 5. Genes in Functional Groups of Interest - In Whole Dataset (Categories I-IV)
- pdf file (22 KB)
Table 6. Genes in Linkage Loci of Interest - Whole Dataset (Categories I-IV)
- pdf file (16 KB)
Table 7. Genes That Show Postmortem Changes in Bipolar, Schizophrenia, Depression, and Related Disorders
- pdf file (15 KB)
Table 8. Candidate genes in our dataset encoding for targets of existing pharmacological agents
- pdf file (32 KB)

Figures

Figure 1. Experimental Design / Convergent Functional Genomics
- pdf file (33 KB)
Figure 2. Number of Genes Changed by Drug, Brain Region, and Category
- pdf file (56 KB)
Figure 3. Probability of Candidate Genes Based on Converging Lines of Evidence - Category I and II Genes
- pdf file (27 KB)
Figure 4. Behavioral Correlates of Methamphetamine and Valproate Treatment
- pdf file (1.71 MB)
Figure 5. Conclusion
- pdf file (18 KB)

Genechip Microarray Data

Raw and Processed Data for all GeneChip Experiments (Signal, Detection, Absent/Present, FC, p values, Descriptions)
- xls file (76.5 KB)
Quality Control Measures
- xls file (30.5 KB)