Bipolar and Major Depressive Disorders: A Discovery Process Utilizing Microarray Technology

W. Bunney; E. Jones; M. Vawter; H. Tomita; J. Li; S. Evans; B. Bunney; P. Choudary; R. Myers; S. Watson; H. Akil
42nd Annual Meeting of the American College of Neuropsychopharmacology. 2003.


New microarray technology can survey up to thirty thousand genes in one experiment to contrast gene expression in postmortem brain tissues in disease states versus matched controls. Results from high throughput gene expression studies in postmortem brain tissue results from limbic and associated areas of the cerebral cortex implicate significantly dysregulated genes and pathways specific to bipolar disorder (BPD) and major depression (MDD). Results from these technologies are dependent on an extensive screening process to ensure the quality of biological (microarray) data. Serial screens include neuropathological examination, evaluation of medical records to confirm diagnosis in both patients and controls and to rate agonal condition, next-of-kin interviews to evaluate patient diagnoses and to rule-out mental illness in controls and/or their relatives, and evaluation of brain pH and ribosomal RNA which are performed prior to the dissection of selected implicated brain regions. Following the microarray experiments, a further index of the quality of microarray data involves the utilization of an Average Correlation Index (ACI) algorithm that will be presented. The above screening process increases confidence in the quality and reliability of microarray findings. In BPD, cortical areas showed activation of the following pathways: proteasome, oxidative phosphorylation, ATP synthesis and chaperone (heat shock proteins) suggesting the possibility of increased mitochondrial function and increased cellular activity. Findings suggest that signaling pathways dysregulated in BPD include G-protein coupled receptors, phosphatidylinositol pathway, cAMP pathway, mitogen-activated protein kinase (MAPK) pathway and cytoskeletal systems. Cortical GABA and glutamate systems are also implicated. In MDD, gene ontological terms enriched in dysregulated genes include transmission of nerve impulse, neurogenesis, and the fibroblast growth factor system. Evidence will be presented that BPD and MDD have distinct neural phenotypes or biological signatures as identified by a significant set of non-overlapping expression patterns of genes and pathways. A smaller set of genes are shared in common between the two disorders and may represent common vulnerability factors. Finally, a subset of overlapping BPD and MDD genes shows a significant directional increase in gene expression in BPD vs. MDD. Conversely, MDD vs. BPD overlapping genes have a directional decrease in differentially expressed genes. It is possible that unique biological genetic signatures for BPD and MDD could start to provide sensitive and reproducible diagnostic predictions and thus could contribute to information for developing specific new antidepressants for genetically similar subgroups and may also assist in evaluating therapeutic responses for specific drugs.