Methylation and QTDT analysis of the 5-HT2A receptor 102C allele: Analysis of suicidality in major psychosis

Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College Road, Toronto, Ontario, Canada.
Journal of Psychiatric Research (Impact Factor: 3.96). 10/2008; 43(5):532-7. DOI: 10.1016/j.jpsychires.2008.07.007
Source: PubMed


Suicide is an act deliberately initiated and performed by a person with full knowledge that a fatal outcome is probable. The serotonin 2A (5-HT2A) receptor gene has been implicated in the pathogenesis of suicidal behaviour by a genetic association between the 5-HT2A T102C silent polymorphism and suicidality in patients with mood disorders and schizophrenia. However, a recent meta-analysis failed to confirm this association. We developed an improved quantitative assay for the measurement of allele-specific methylation of the 5-HT2A gene, and found that the methylation of the C allele in the pre-frontal cortex of heterozygous suicide victims (n=10) was not significantly different in comparison with the non-suicide group (n=10) (p=0.084). We also analyzed methylation of the C allele in white blood cell DNA from bipolar and schizophrenic attempters and found a significant difference in the schizophrenic attempters (p=0.00013) but not in the bipolar attempters (p=0.616). Because the 5-HT2A gene is subject to imprinting, the parent-of-origin may affect inheritance of suicidal behaviour. Thus, we examined the parental origin of specific alleles for genetic association in a genetic family-based sample of major psychoses in which information on suicidal behaviour was available. This result suggests that methylation of the 102C allele does not influence completed suicide.

26 Reads
    • "T102C was significantly decreased in the prefrontal cortex of 10 suicide victims compared to 10 non-suicidal participants , but found no association between the polymorphism and suicidal behavior. In a subsequent report on partly the same sample the authors found that the methylation of the C allele in the pre-frontal cortex of heterozygous suicide victims did not differ from that of the non-suicidal group (De Luca et al., 2009). Several other studies failed to find an association between the T102C and suicide ideation (Fanous et al., 2009) or suicide attempts (Yoon and Kim, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Suicide is one of the leading causes of death in the world. Its aetiology is complex and diverse, however, epidemiological studies show that suicidal behavior is partly heritable. Neurobiological evidence implicates serotonergic dysfunction in suicidality, stimulating genetic research to focus on genes related to the serotonergic system. In this paper, we review evidence from studies examining the association between various serotonergic genes (Tryptophan Hydroxylase genes: TPH1; TPH2, Serotonin Transporter gene: 5-HTTLPR in SLC6A4, Serotonin Receptor genes: HTR1A, HTR2A, HTR1B, HTR2C and Monoamine Oxidase A gene: MAOA) and suicidal behavior. The data show associations between variation on the TPH1 gene and 5-HTTLPR gene and violent suicidal behavior in Caucasian populations, with the least inconsistencies. Results are mixed for the TPH2 gene and serotonin receptor genes, but for some genes, studies that include haplotypic analyses or that examine a larger coding region of the genes tend to provide more reliable results. Findings on endophenotypes of suicidality, such as aggression and impulsivity traits, show positive associations for the TPH1, HTR2A, and MAOA genes, but need further replication, since negative associations are also occasionally reported. Since genes can only partially explain suicidal risk, several studies during the past decade have tried to incorporate environmental factors in the susceptibility model. Studies to date show that variation on the 5-HTTLPR, MAOA and HTR2A gene can interact with stressful life events to increase risk for suicidal behavior. Limitations of case-control studies are discussed and future considerations are put forward with regard to endophenotypic measurements and gene-environment interactions.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2013; 23(10). DOI:10.1016/j.euroneuro.2013.03.013 · 4.37 Impact Factor
  • Source
    • "All of the studies concerned with epigenetic factors in suicide assessed gene expression and methylation profiles in the post-mortem brains of suicide completers relative to non-suicide controls [14-25], although one study also included adjuvant data about methylation profiles in peripheral leukocytes [17]. Among studies regarding epigenetic factors in the etiology of depression, one study assessed methylation and expression profiles in the post-mortem brain [27], another assessed methylation and expression of tissue in buccal cells [28], and the remaining three assessed methylation and expression profiles in peripheral blood [12,26,29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic modifications are those reversible, mitotically heritable alterations in genomic expression that occur independent of changes in gene sequence. Epigenetic studies have the potential to improve our understanding of the etiology of mood and anxiety disorders and suicide by bridging the gap in knowledge between the exogenous environmental exposures and pathophysiology that produce common mood and anxiety disorders and suicide. We systematically reviewed the English-language peer-reviewed literature about epigenetic regulation in these disorders between 2001-2011, summarizing and synthesizing this literature with respect to directions for future work. Twenty-one articles met our inclusion criteria. Twelve studies were concerned with epigenetic changes among suicide completers; other studies considered epigenetic regulation in depression, post-traumatic stress disorder, and panic disorder. Several studies focused on epigenetic regulation of amine, glucocorticoid, and serotonin metabolism in the production of common mood and anxiety disorders and suicide. The literature is nascent and has yet to reach consensus about the roles of particular epigenetic modifications in the etiology of these outcomes. Future studies require larger sample sizes and measurements of environmental exposures antecedent to epigenetic modification. Further work is also needed to clarify the link between epigenetic modifications in the brain and peripheral tissues and to establish 'gold standard' epigenetic assays.
    Biology of Mood and Anxiety Disorders 06/2012; 2(1):10. DOI:10.1186/2045-5380-2-10
  • Source
    • "Serotoninergic and GABAergic systems have been deeply studied in the context of suicide. The C allele of 5-HT 2A receptor gene has been found hypermethylated in leukocytes of suicide ideator but not in prefrontal cortex (PFC) of suicide completers (De Luca et al., 2009). The methylation state of GABAA receptor α1 gene was increased in fronto-polar cortex of suicide subjects (Poulter et al., 2008) together with the expression of DNMT3b that was found increased in different brain areas including amigdala brain stem. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alterations of DNA methylation and expression of suicide-related genes occurring in specific brain's areas have been associated to suicidal behavior. In the BDNF pathway, TrkB gene in frontal cortex and hippocampus, and BDNF gene in Wernicke area have been found hypermethylated and down-regulated in suicide subjects as compared to controls. In this work we investigated whether epigenetic modifications of TrkB gene occur in Wernicke area of 18 suicide subjects as compared to 18 controls. MassArray analysis was performed to determine the methylation degree of TrkB promoter in post-mortem samples. TrkB full length and TrkB-T1 mRNA levels were assessed by quantitative RT-PCR. Geometric averaging of four internal control genes was calculated for normalization of results. We found that TrkB and TrkB-T1 expression and promoter methylation in Wernicke area did not correlate with suicidal behavior whereas, in the same samples, the BDNF promoter IV was significantly hypermethylated in suicide with respect of controls. Data from a single brain's area in this study's sample. Our data show that no correlation exists between TrkB gene methylation and suicide in Wernicke area, confirming that expression and methylation state of suicide-related genes, even belonging to the same pathway, may be specific for brain area.
    Journal of Affective Disorders 07/2011; 135(1-3):400-4. DOI:10.1016/j.jad.2011.07.003 · 3.38 Impact Factor
Show more