Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression.

The prefrontal cortex is believed to play a major role in depression and suicidal behavior through regulation of cognition, memory, recognition of emotion, and anxiety-like states, with numerous post-mortem studies documenting a prefrontal serotonergic dysregulation considered to be characteristic of depressive psychopathology. This study was carried out to detect changes in gene expression associated with both suicide and major depression using oligonucleotide microarrays (Affymetrix HG-U133 chip set) summarizing expression patterns in primarily ventral regions of the prefrontal cortex (BA44, 45, 46 and 47). A total of 37 male subjects were included in this study, of which 24 were suicides (depressed suicides=16, nondepressed suicides=8) and 13 were matched controls. All subjects were clinically characterized by means of psychological autopsies using structured interviews. Unique patterns of differential expression were validated in each of the cortical regions evaluated, with group-specific changes highlighting the involvement of several key neurobiological pathways that have been implicated in both suicide and depression. An overrepresentation of factors involved in cell cycle control and cell division (BA44), transcription (BA44 and 47) and myelination (BA46) was seen in gene ontology analysis of differentially expressed genes, which also highlights changes in the expression of genes involved in ATP biosynthesis and utilization across all areas. Gene misexpression in BA46 was most pronounced between the two suicide groups, with many significant genes involved in GABAergic neurotransmission. The pronounced misexpression of genes central to GABAergic signaling and astrocyte/oligodendrocyte function provides further support for a central glial pathology in depression and suicidal behavior.

Meta-analysis of the association between tryptophan hydroxylase and suicidal behavior.

Tryptophan hydroxylase (TPH) has been the candidate gene of focus in many of the association studies of suicidal behavior in recent years. Initial positive findings with respect to an association between the TPH gene and suicidal behavior have been replicated, but not consistently. Typically, individual studies have investigated small samples, and thus they repeatedly had insufficient statistical power to detect a positive association. Meta-analysis is one approach that can be used to achieve greater statistical power and may be helpful in providing a more conclusive understanding. We used meta-analytic techniques to investigate the association between an intron 7 polymorphism in the TPH gene and suicidal behavior. A total of 39 publications were identified and reviewed, 17 of which were selected for inclusion in this study. We performed two meta-analyses. One compared suicide attempters or completers (N = 1,290) with healthy controls (N = 2,295); the other compared suicide attempters (N = 625) with nonattempters (N = 1,475). None of these studies provided evidence for association (odds ratio (OR) = 1.14, 95% confidence interval (CI) = 0.97-1.34 for the former and OR = 0.96, 95% CI = 0.77-1.20 for the latter). The combined results from comparisons within both groups showed no overall association between suicidal behavior and an intron 7 polymorphism of the TPH gene.