Implication of SSAT by Gene Expression and Genetic Variation in Suicide and Major Depression

Sequeira, Adolfo; Gwadry, Fuad G.; Ffrench‐Mullen, J. M. H.; Canetti, Lilian; Gingras, Yves; Casero, Robert A.; Rouleau, Guy A.; Benkelfat, Chawki; Turecki, Gustavo

doi:10.1001/archpsyc.63.1.35

Cited by 163 publications

(167 citation statements)

References 31 publications

(40 reference statements)

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“…[21][22][23] Two genes involved in the catabolism of polyamines (SAT and SMOX), significant in several regions, suggest the possible association of suicide and depression with defects in the polyamine stress response system. Reduced expression of SAT in depressed and nondepressed suicide groups was previously shown in motor cortex, superior frontal gyrus and orbital gyrus, 9 with correspondingly reduced levels of SAT protein. A number of genes functioning in polyamine metabolism have also been implicated in schizophrenia through microarray analysis.…”

Section: Discussionsupporting

confidence: 53%

“…In comparison with microarray studies of schizophrenia and bipolar disorder, only a handful of studies have been reported on gene expression changes associated with major depression and completed suicide. [8][9][10] There is a clear need for further investigation of the gene expression changes associated with these phenotypes to gain better insight into their possible biological mechanisms. 11 We have carried out a microarray-based investigation of these brain regions in both depressed and nondepressed suicide victims in comparison with controls, to identify novel candidate systems and biological pathways that may be involved in suicide and major depression.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…The combination of the ANOVA and subsequent t-tests is commonly referred to as Fisher protected least significant difference (LSD) test. In the case of gene expression studies of complex traits such as psychiatric disorders, it has been suggested to use less stringent criteria in the initial analysis stages, 76 and the use of only t-tests or Fisher protected LSD test has been commonly accepted in psychiatric brain expression studies 50,64,65 as well as in other research areas. 77 Multiplicity is always a concern when performing microarray analysis and many correction procedures have been developed to address it such as the Bonferroni-method or false discovery rate-based methods.…”

Section: Discussionmentioning

confidence: 99%

“…More overlap was seen for instance in a previous study by our group exploring expression in cortical regions. 50 Some overlap was also observed between the SMD-S and S-C comparisons, suggesting that these genes are likely to be involved in suicide-related processes independently of underlying depressive psychopathology. In the amygdala, for instance four genes were observed in common for those comparisons (MAX, MYEF2, YWHAB and GRIPAP1) whereas only one was observed in BA24 (CIRBP) and three in BA29 (RGN, TDE1 and CKLFSF1).…”

Section: Nomentioning

confidence: 97%

Patterns of gene expression in the limbic system of suicides with and without major depression

et al. 2007

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The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides = 18, non depressed suicides = 8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.

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“…This pathway includes 3 rate-limiting enzymes, one of which is Sadenosylmethionine decarboxylase (AMD1). The initial support for the involvement of the polyamine system in suicide came from observations that spermidine/spermine N 1 -acetyltransferase (SAT1) gene expression was downregulated in numerous brain regions in suicide completers as compared to control subjects (Guipponi et al, 2009;Sequeira et al, 2006). Moreover, functionally characterized genetic variants in the promoter region of SAT1 were associated with suicide (Fiori, Mechawar, & Turecki, 2009;Sequeira et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Effects of promoter methylation on increased expression of polyamine biosynthetic genes in suicide

Gross

Fiori

Labonté

et al. 2013

Journal of Psychiatric Research

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Suicide is among the leading causes of death worldwide. The polyamine system has been increasingly implicated in the neurobiology of suicide. Previous research has indicated that epigenetic mechanisms play a role in explaining dysregulation of polyamine genes in suicide completers. Nevertheless, regulatory mechanisms explaining polyamine biosynthetic genes displaying dysregulated expression in suicide completers, including ornithine decarboxylase antizymes 1 and 2 (OAZ1 and OAZ2), S-adenosylmethionine decarboxylase (AMD1), and arginase 2 (ARG2), have yet to be elucidated. In this study, we investigated methylation patterns in the promoter region of OAZ1, OAZ2, AMD1, and ARG2 in Brodmann area 44 from a group of 33 suicide completers and 31 non-suicide controls. We found significant site-specific differences in methylation in the promoter of ARG2 and AMD1 that were also significantly negatively correlated with gene expression. These findings provide further support for a role for the involvement of epigenetic modifications in the regulation of genes associated with polyamine biosynthesis, and which may contribute to the complexity of suicidal behaviors.

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Implication of SSAT by Gene Expression and Genetic Variation in Suicide and Major Depression

Abstract: These data suggest a role for SSAT, the rate-limiting enzyme in the catabolism of polyamines, in suicide and depression and a role for the SSAT342 locus in the regulation of SSAT gene expression.

Cited by 163 publications

References 31 publications

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

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

Patterns of gene expression in the limbic system of suicides with and without major depression

Effects of promoter methylation on increased expression of polyamine biosynthetic genes in suicide

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