Dysregulated Gene Expression In Suicide

Vawter, Marquis P.; Evans, Simon J.; Choudary, Prabha V.; Meng, Fan; Atz, Mary E.; Cartagena, Preston; Walsh, David M.; Li, Jun; Tomita, Hiro; Myers, Richard M.; Akil, Huda; Watson, Stanley J.; Jones, Edward G.; Bunney, William E.
ACNP 44th Annual Meeting. 2005.


Background: Suicide affects approximately 5-15% of individuals with mood disorders and is a leading cause of death for males under 40 years of age(1). The neurobiology of suicide and mood disorders is not understood, and may involve alterations in limbic-cortical brain circuits. A neurobiological predisposition to alterations in circuitry might in part have genetic components. Microarrays allow for the simultaneous analysis of gene expression patterns in multiple brain regions for thousands of gene targets. One previous microarray analysis of suicide showed that gene expression differences were not significantly different in monoaminergic mediated pathways compared to controls in prefrontal cortical regions. Methods: Mitochondrial related gene expression classes (mitochondrial genes encoded by nuclear DNA, and proteasome, chaperone, reactive oxygen stress, and apoptotic genes) were investigated in major depressive disorder (MDD) and bipolar disorder (BPD) subjects that died by suicide compared to MDD and BPD subjects that died by other causes. Cases were included in the microarray analysis that had no agonal factors, brain tissue pH => 6.6, RNA quality => 1.4 by Agilent, and agreement between two post-hoc microarray measures for chip similarity. Aging and pH are known to significantly correlate to mitochondrial related gene expression and were used as a continuous covariate in downstream analysis of mitochondrial related gene expression. Independent synthesis and hybridization of cRNA to Affymetrix Human Genome U133A Arrays. Data was analyzed for each brain region with RMA for individual probeset condensation summary (Bioconductor.org). Each mitochondrial probeset (n = 379) was extracted from a custom cdf unigene file (M. Dai et al, 2005.) Brain collection, psychological autopsy (P. Cartagena, D. Walsh) pH, RNA quality (K.Overman, M. Atz) Evaluated Gene Expression In 4 brain regions (Anterior Cingulate, Amygdala, Hippocampus, Cerebellum) Compared 3 Groups (Suicide with Mood Disorder, No Suicide with Mood Disorder, Controls) Affymetrix U133A chips, all samples run in technical replicates. Covariant analysis using general linear model with age and pH conducted since slight differences among groups. Conclusions: Specific genes were differentially expressed in non-mitochondrial classes in limbic circuitry in suicide. The preliminary results show a large variation in individual gene expression between subjects. These genes require confirmation by independent replication and validation studies. The alteration of specific candidate genes in limbic circuitry in suicide is a promising approach for study of the neurobiology involved in the pathogenesis of suicide.