BIPOLAR DISORDER: A DISCOVERY PROCESS UTILIZING MICROARRAY TECHNOLOGY
William E. Bunney; Edward G. Jones; Marquis P. Vawter; Hiroaki Tomita; Jun Li; Simon J. Evans; Blynn G. Bunney; Prabhakara V. Choud
24th Congress of the Collegium Internationale Neuro-Psychopharmacologicum (CINP). 2003.
Current microarray technology can survey up to thirty thousand genes in one experiment to investigate gene expression in postmortem brain tissues in disease states contrasted to matched controls. Findings from high throughput gene expression studies in postmortem brain tissue from limbic and associated areas of the cerebral cortex implicate significantly dysregulated genes and pathways specific to bipolar disorder. Data 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 which is 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. The above screening process increases confidence in the quality and reliability of microarray findings. In BPD, gene ontology terms enriched in dysregulated genes in cortical areas showed activation of the following terms: proteasome, oxidative phosphorylation, ATP synthesis and chaperone (heat shock proteins) suggesting the possibility of increased mitochondrial function and increased cellular activity. 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 show a significant directional increase in gene expression in BPD versus MDD. It is possible that unique biological genetic signatures for BPD 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.