Mood Disorders: The Search for Candidate Genes and Pathways

W. E. Bunney
Thirty-Sixth Annual Winter Conference on Brain Research. 2003.


This panel will review the recent difference in gene expression revealed in cDNA array analysis in postmortem brain tissue of bipolar disorder patients using a variety of novel strategies. Bunney will present functional genomic differences, suggesting specific candidate genes and neuronal system pathways involved in bipolar disorder through contrasts in matched normal controls. RT-PCR and in situ hybridization data will be presented which confirms differential expression patterns of specific genes observed by microarrays. Initial studies of 12,600 transcripts suggest specific pathways consistently altered in the anterior cingulate, in accord with brain imaging studies implicating cingulate dysfunction in mood disorders. Young, in the first recently published cDNA expression array study, observed a decrease in transforming growth factor beta1 (TGF-b1) and an increase in capase-8 precursor (casp-8) expression in bipolar disorder. These results suggest down regulation of neural protective inhibitory cytokines could lead to neurotoxic insults etiologically related to mood disorders. In addition, Young has has identified gene expression changes associated with lithium treatment response in transformed lymphoblasts. Animal models with differential expression can be used to generate candidate genes for bipolar disorder. Kelsoe will present results from microarray expression profiling studies of acute and chronic amphetamine treatment in rats, and a convergent approach that cross-indexes these results to linkage studies to identify candidate genes. Thus, G protein receptor kinase 3 gene on 22q ii was identified and mutations in the promoter associated with bipolar disorder discovered. Gershon will present a novel meta-analysis technique, Multiple Scan Probability, which can applied to whole genomic scans. Strong evidence for a susceptibility locus was found on 13q and 22q for bipolar disorder. The panel will summarize the power of these new approaches and recent data suggesting novel neural circuits underlying bipolar disorder.