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The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt.

ABSTRACT: BACKGROUND: Serotonergic neurotransmission has been implicated in suicidal behavior. Association between suicidal completers and a regulatory C(-1019)G polymorphism (rs6295) in the serotonin 1A receptor (HTR1A) gene was previously reported, whereas a following study showed no association in a sample of suicide attempters. METHODS: The involvement of the implicated G-allele of the 5-HTR1A C(-1019)G polymorphism (rs6295) was analyzed with the transmission disequilibrium test (TDT) in a sample of 272 suicide attempter families. RESULTS: No overtransmission of the G-allele was found in the entire sample of suicide attempters (p = 0.1460; n = 272 trios). However, a strong trend for overtransmission of the G-allele was observed in a sub-sample selected for a high level of previous traumatic and/or stressful life events prior to the suicide attempt (p = 0.0630, two-tail; n = 94 trios). CONCLUSION: The current results show that variation at the rs6295 polymorphism of the HTR1A gene is not associated with suicide attempts generally. However, the results indicate a possible role of the G-allele in suicidal behavior in connection with high exposure to traumatic and/or stressful life events, which is in need of future investigation.

SUBMITTER: Wasserman D

PROVIDER: S-EPMC1459178 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt.

Wasserman Danuta D Geijer Thomas T Sokolowski Marcus M Rozanov Vsevolod V Wasserman Jerzy J

Behavioral and brain functions : BBF 20060420

<h4>Background</h4>Serotonergic neurotransmission has been implicated in suicidal behavior. Association between suicidal completers and a regulatory C(-1019)G polymorphism (rs6295) in the serotonin 1A receptor (HTR1A) gene was previously reported, whereas a following study showed no association in a sample of suicide attempters.<h4>Methods</h4>The involvement of the implicated G-allele of the 5-HTR1A C(-1019)G polymorphism (rs6295) was analyzed with the transmission disequilibrium test (TDT) in ...[more]

PMID: 16626484

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Project description:BackgroundSerotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities.MethodsFourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C-49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed.ResultsVolunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged.Conclusion/significanceTo the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a 'hypo- to hyperalgesic' response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted.

Project description:The G/C single-nucleotide polymorphism in the serotonin 1a receptor promoter, rs6295, has previously been linked with depression, suicide and antidepressant responsiveness. In vitro studies suggest that rs6295 may have functional effects on the expression of the serotonin 1a receptor gene (HTR1A) through altered binding of a number of transcription factors. To further explore the relationship between rs6295, mental illness and gene expression, we performed dual epidemiological and biological studies. First, we genotyped a cohort of 1412 individuals, randomly split into discovery and replication cohorts, to examine the relationship between rs6295 and five psychiatric outcomes: history of psychiatric hospitalization, history of suicide attempts, history of substance or alcohol abuse, current posttraumatic stress disorder (PTSD), current depression. We found that the rs6295G allele is associated with increased risk for substance abuse, psychiatric hospitalization and suicide attempts. Overall, exposure to either childhood or non-childhood trauma resulted in increased risk for all psychiatric outcomes, but we did not observe a significant interaction between rs6295 and trauma in modulating psychiatric outcomes. In conjunction, we also investigated the potential impact of rs6295 on HTR1A expression in postmortem human brain tissue using relative allelic expression assays. We found more mRNA produced from the C versus the G-allele of rs6295 in the prefrontal cortex (PFC), but not in the midbrain of nonpsychiatric control subjects. Further, in the fetal cortex, rs6295C allele exhibited increased relative expression as early as gestational week 18 in humans. Finally, we found that the C:G allelic expression ratio was significantly neutralized in the PFC of subjects with major depressive disorder (MDD) who committed suicide as compared with controls, indicating that normal patterns of transcription may be disrupted in MDD/suicide. These data provide a putative biological mechanism underlying the association between rs6295, trauma and mental illness. Moreover, our results suggest that rs6295 may affect transcription during both gestational development and adulthood in a region-specific manner, acting as a risk factor for psychiatric illness. These findings provide a critical framework for conceptualizing the effects of a common functional genetic variant, trauma exposure and their impact on mental health.

Project description:Background: Suicide is moderately heritable and also more common in those who report childhood abuse. Previously, it was found that allele A of GABRG2 (GABA A receptor subunit gamma2) polymorphism rs211034 was protective in a suicide attempt (SA). Hence, it was proposed that rs211034 may interact with childhood trauma to influence cognitive deficits related to SA or depression risk. Genetic variants may predict the benefits of certain cognitive treatments. Methods: A total of 52 individuals who had attempted suicide, 59 individuals with major depressive disorder (MDD) or bipolar depression who had not previously attempted suicide, and 90 healthy volunteers were subjected to the modified Suicide Stroop task and were clinically assessed using the Childhood Trauma Questionnaire (CTQ) and Hamilton Depression Scale-24 items (HAMD-24). rs211034 was genotyped using Sanger sequencing. Results: After correcting for covariates, depressed participants displayed longer reaction times for all emotional conditions, including suicide-related words, compared with healthy controls. Depressed suicide attempters displayed longer reaction times for negative words than depressed non-attempters. Depressed non-attempters displayed higher interference scores for negative words compared with healthy controls. There was an interaction between rs211034 risk allele and the effects of reported childhood sexual abuse (CSA) on reaction time for all emotional words and suicide-related words. Carriers of the rs211034 risk allele A exhibited shorter reaction times, but the protective effects of this allele were eliminated in those exposed to reported CSA. Conclusion: Only limited results were found regarding effects of a past suicide attempt on response times to emotional and suicide-related words, but there was an overall effect of major depression on slower response time. Protective genetic effects of the rs211034 A allele on this slowing were eliminated in those with a history of sexual abuse during childhood. Further research is needed to better characterize the mechanisms underlying the effects of childhood trauma on these genetic effects.

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The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt.

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The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt.

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