Gene Expression Changes in the Prefrontal Cortex, Anterior Cingulate Cortex and Nucleus Accumbens of Mood Disorders Subjects That Committed Suicide

Sequeira, Adolfo; Morgan, Ling; Walsh, David; Cartagena, Preston; Choudary, Prabhakara V; Li, Jun; Schatzberg, Alan F.; Watson, Stanley J.; Akil, Huda; Myers, R; Jones, Edward G.; Bunney, William E.; Vawter, Marquis P.

doi:10.1371/journal.pone.0035367

Cited by 82 publications

(58 citation statements)

References 78 publications

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“…Only tissue from the left hemisphere (grey matter only) was used. These cortical regions are consistently implicated in depression [17][18][19][20] and are involved in higher order functioning such as decision-making, that is impaired in suicide 21 .…”

Section: Brain Samples Clinical Characterization and Group Compositionmentioning

confidence: 99%

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

et al. 2014

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Astrocytes are glial cells specific the central nervous system involved in numerous brain functions including regulation of synaptic transmission and of immune reactions. There is mounting evidence suggesting astrocytic dysfunction in psychopathologies such as major depression, however, little is known about the underlying etiological mechanisms. Here we report a two-stage study investigating genome-wide DNA methylation associated with astrocytic markers in depressive psychopathology. We first characterized prefrontal cortex samples from 121 individuals (76 who died during a depressive episode and 45 healthy controls) for the astrocytic markers GFAP, ALDH1L1, SOX9, GLUL, SCL1A3, GJA1, and GJB6. A subset of 22 cases with consistently downregulated astrocytic markers was then compared to 17 matched controls using MBD2-sequencing followed by validation with high resolution melting and bisulfite Sanger sequencing. With these data, we generated a genome-wide methylation map unique to altered astrocyte-associated depressive psychopathology. The map revealed differentially methylated regions (DMRs) between cases and controls, the majority of which displayed reduced methylation levels in cases. Among intragenic DMRs, GRIK2 and BEGAIN were the most significant, and also significantly correlated with genes expression. Cell sorted fractions were investigated and demonstrated an important non-neuronal contribution of methylation status in BEGAIN.Functional cell assays revealed promoter and enhancer-like properties in this region, which were markedly decreased by methylation. Furthermore, a large number of our DMRs overlapped known ENCODE identified regulatory elements. Taken together, our data indicate significant differences in the methylation patterns specific to astrocytic dysfunction associated with depressive psychopathology, providing a potential framework for better understanding this disease phenotype.

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Section: Brain Samples Clinical Characterization and Group Compositionmentioning

confidence: 99%

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

et al. 2014

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“…Gene expression changes associated with suicide in brains of mood disorder patients were studied by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex, in the anterior cingulate cortex and in nucleus accumbens [83]. Several MT-1 and MT-2 isoforms (MT-1E, MT-1F, MT-1G, MT-1H, MT-1X, and MT-2A) were down-regulated in the anterior cingulate cortex of suicide subjects compared with non-suicides, and three of them (MT-1F, MT-1G, and MT-1H) were also down-regulated in the nucleus accumbens.…”

Section: Hepatotoxicitymentioning

confidence: 99%

“…It was concluded that failed neuroprotection against stress due to decreased expression levels of MT-1 and MT-2 might be molecular risk factor for suicide [83].…”

Section: Hepatotoxicitymentioning

confidence: 99%

Microarray analysis of metallothioneins in human diseases—A review

Křížková

Kępińska

Emri

et al. 2016

Journal of Pharmaceutical and Biomedical Analysis

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 Microarray analysis of metallothioneins in human diseases AbstractMetallothioneins (MTs), low molecular mass cysteine-rich proteins, which are able to bind up to 20 monovalent and up to 7 divalent heavy metal ions are widely studied due to their functions in detoxification of metals, scavenging free radicals and cells protection against the oxidative stress. It was found that the loss of the protective effects of MT leads to an escalation of pathogenic processes and carcinogenesis. 3The most extensive area is MTs expression for oncological applications, where the information about gene patterns is helpful for the identification biological function, resistance to drugs and creating the correct chemotherapy. In other medical applications the effect of oxidative stress to cell lines exposed to heavy metals and hydrogen peroxide is studied as well as influence of drugs and cytokines on MTs expression and MTs expression in the adiposetissue. The precise detection of low metallothionein concentrations and its isoforms is necessary to understand the connection between quantity and isoforms of MTs to size, localization and type of cancer. This information is necessary for well-timed therapy and increase the chance to survival. Microarray chips appear as good possibility for finding all information about expression of MTs genes and isoforms not only in cancer, but also in other diseases, especially diabetes, obesity, cardiovascular diseases, ageing, osteoporosis, psychiatric disorders and as the effects of toxic drugs and pollutants, which is discussed in this review. List of abbreviations:HCC -hepatocellular carcinoma, HFD -high fat diet, MMP -matrix metalloproteinase, MT -metallothionein, MTF -metal transcription factor, MRE -metal responsive element, ROS -reactive oxygen species.

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“…The decrease of 5-HT2A expression in the suicide group was confirmed by qPCR (data not shown). Enrichment of canonical pathways analysis using Ingenuity confirmed that the serotonin receptor signaling pathway was altered in suicide brain tissue [128]. Another gene of interest previously shown to be involved in suicide [44] and that was altered in the DLPFC was the adenylate cyclase 1 (brain) (ADCY1) gene that codes for a brain specific form of adenylate cyclase responsible of the production of the second messenger cyclic AMP, ADCY was significantly down-regulated in suicide versus non-suicide patients [129].…”

Section: Genetic Criteriamentioning

confidence: 90%

“…In order to control for possible confounding effects, demographic variables, such as diagnosis and age, and RNA quality measures (RIN and slope) were used as covariates [128].…”

Section: Genetic Criteriamentioning

confidence: 99%

Correlation between Bipolar Affective Disorder and Suicide reviewing by the risk factors: a systematic review

Souza¹,

Ferreira²,

Oliveira³

et al. 2015

Int Arch Med

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Background: Because there are several reports associations between affective (AD) and bipolar disorder (BD) and suicide, the research develops a discussion of risk factors that influence the occurrence of suicide attempts in patients with BD. Objectives:To relate risk factors present in patients with bipolar disorder who committed suicide or some suicide attempt. Methods:A survey was made in Scopus with the keyword "bipolar" and the terms "suicide" and "attempted"and "risk factors" from Medical Subject Headings (MeSH). We use only Scopus as the data source, and the statistical information available in tables and graphs provided from this source. Results:Frequently the AD and BD were associated with suicide occurrence in the studies included in this review. They identified the main risk factors for suicide the previous suicide attempt and hopelessness. The main risk factors for nonfatal suicidal behavior included family history of suicide, early onset of bipolar disorder, extent of depressive symptoms, increasing severity of affective episodes, the presence of mixed affective states, rapid cycling, comorbid Axis I disorders, and abuse of alcohol or drugs. The suicide rate in this disorder reaches three times compared with other mental illnesses, and there are several risk factors: 3:1 ratio of suicide in men compared to women, but in females a greater number of attempts are observed. 25% of persons consume alcohol prior to suicidal attempt. The studies relate these factors and show how they can pose a risk to the carrier of the disorder. There are other risk factor for BD discussed on this review. IntroductionBipolar affective disorder (BD) is characterized by episodes of depression and hypomania and / or mania. BD has been responsible for the higher rate of suicidal behavior compared to any other mental disorder [1,2]. It is a potentially lethal disease with a high risk of suicide completed, which again is associated with a history of suicide attempts [2]. During life, about 61% of patients with BD experiencing suicidal ideation, 25% to 56% will attempt suicide, and between 10% and 19% die from suicide2. Several studies suggest that previous suicide attempts of bipolar patients may indicate that they are over than 50% more likely to complete suicide [2]. A better understanding of the characteristics and risk factors related to suicide attempts is the first step to prevent future attempts and early detection of risk patients [1,2].Suicide is a tragic potential outcome for patients with bipolar disorder, and unfortunately, this event is not uncommon. Twenty-five percent to 50% of all bipolar patients have been found to attempt suicide at leart once in their lifetime, with 11% to 19% of bipolar patients eventually dying of suicide and standardized mortality ratio for suicide of 12.3 [3-7].There is evidence that suicide rates among mood disorder patients are more than 20-fold higher than in the general population and that suicidal behavior is much more lethal in bipolar disorder than in the general populati...

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Gene Expression Changes in the Prefrontal Cortex, Anterior Cingulate Cortex and Nucleus Accumbens of Mood Disorders Subjects That Committed Suicide

Cited by 82 publications

References 78 publications

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

Microarray analysis of metallothioneins in human diseases—A review

Correlation between Bipolar Affective Disorder and Suicide reviewing by the risk factors: a systematic review

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