Mitochondrial related gene expression in suicide

Marquis P. Vawter; Simon J. Evans; Prabha V. Choudary; Fan Meng; Mary E. Atz; Preston Cartagena; David M. Walsh; Jun Li; Hiro Tomita; Richard M. Myers; Huda Akil; Stanley J. Watson; Edward G. Jones; William E. Bunney
Neuropsychopharmacology. 2005; 30:S243.


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. Family studies are difficult to conduct, and case-control genetic studies require identification of candidate genes. 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 pre-frontal cortical regions (2).
Methods: Mitochondrial related gene expression classes (mitochondrial genes encoded by nuclear DNA, and proteasome, chaperone, re-active 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 gene expression and were used as a continuous covariate in downstream analysis of mitochondrial related gene expression.
Results: Few mitochondrial and related genes were dysregulated in BPD-suicide or MDD-suicide groups. There was minimal overlap in differential expression of mitochondrial-related genes between each separate suicide group (BPD or MDD). Five mitochondrial related pathways were not significantly over-represented in suicide. However, specific mitochondrial related genes were dysregulated in the amygdala-anterior cingulate regions of suicide groups. For all genes, BPD-suicide showed larger numbers of dysregulated genes in the anterior cingulate cortex, DLPFC, and amygdala compared to MDD-suicide.
Discussion: The results implicate specific genes in mitochondrial related pathways in the predisposition of suicide as worthy of further consideration. Specific genes were differentially expressed in mitochondrial and related classes (apoptosis, chaperone, proteasome, and reaction to oxygen stress) in one part of the limbic circuit involving the anterior cingulate and amygdala. The preliminary results suggest that more genes are dysregulated in individuals with BPD that commit suicide compared to MDD that commit suicide. More genes were dysregulated in limbic regions compared to the DLPFC in both suicide groups. These genes require confirmation by independent replication and validation studies. The alteration of specific candidate genes in limbic circuitry in BPD and MDD is a promising approach for study of the neurobiology involved in the predisposition to suicide.

The authors are members of the Pritzker Neuropsychiatric Disorders Research Consortium.

1. Gwadry, F.G., Sequeira, A., Hoke, G., Ffrench-Mullen, J.M., Turecki, G., Molecular characterization of suicide by microarray analysis. Am J Med Genet C Semin Med Genet, 2005. 133(1): p. 48-56.
2. Sibille, E., Arango, V., Galfalvy, H.C., Pavlidis, P., Erraji-Benchekroun, L., Ellis, S.P., et al., Gene expression profiling of depression and suicide in human prefrontal cortex. Neuropsychopharmacology, 2004. 29(2): p. 351-361.