Study on genes of the serotonergic system and suicidal behavior: protocol for a case–control study in Mexican population

BACKGROUND: Suicidal behavior is a leading cause of injury and death worldwide. Several studies have provided a possible relationship between genetic factors and suicidal behavior. Also, these studies have shown evidence for altered serotonergic neural transmission in the pathogenesis of suicidal behavior. In addition, genes pertaining to the serotonergic system have been proposed as candidates to establish biological correlates between suicidal behavior and the serotonergic system. The most studied genes are SCL6A4, HTR2A, HTR2C, HTR1A, HTR1B, TPH-1, and TPH-2. To get a comprehensive understanding of the association with suicidal behavior we will conduct genotype assays studies in a Mexican population. METHODS/DESIGN: We will conduct a case–control study. The population sample will comprise adolescent and adult patients admitted for attempted of suicide and diagnosed by a psychiatrist. A peripheral blood sample will be taken from all the subjects (cases and controls). Genomic DNA from the leukocytes blood sample will be extracted. The genotypes of interest are distributed in the following genes: SCL6A4, HTR2A, HTR1A, HTR1B, HTR2C, TPH-2 and TPH-1. All the samples will be analyzed using a polymerase chain reaction (PCR) end-point method. We will evaluate the Hardy-Weinberg Equilibrium. The chi-squared test or Fisher’s exact test will be used to compare genotype and allele frequencies between control and case groups. The Quanto 1.2 software will measure the sample size of the association. For all the association analyses the level of significance will be set at p = 0.05 and the confidence interval at 95%. DISCUSSION: Suicidal behavior has been increase in Mexico, principally in young population. Our study will demonstrate the association between serotoninergic genes and suicide behavior in Mexican population

Association study of suicidal behavior and affective disorders with a genetic polymorphism in ABCG1, a positional candidate on chromosome 21q22.3

The gene that codes for the ABC transporter ABCG1 is located in a chromosomal susceptibility region (21q22.3) for affective disorders. Genetic variations in ABCG1 have been associated with affective disorders in Japanese males. In this study, we investigated the distribution of a G2457A polymorphism in patients with affective disorders, suicide attempters with various psychiatric diagnoses and healthy subjects, We initially found a trend towards a modest association with affective disorders in males (p = 0.046 for allele frequencies and p = 0.046 for AA versus GG). We conducted a replication study with independent patients and controls, There was no association with affective disorders, either in the replication or in the combined group, Furthermore, we found no association with suicidal behavior, These findings do not support the hypothesis that ABCG1 is a susceptibility gene for affective disorders or suicidal behavior. Copyright (C) 2000 S. Karger AG, Basel

Functional promoter polymorphism of the neuronal isoform of tryptophan hydroxylase (Tph2) in suicide

The association between suicide and G-703T polymorphism of the tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin, was studied in a sample of 291 suicide victims and 280 healthy subjects of Croatian origin. No significant differences were found between the groups. Obtained results do not support involvement of the investigated polymorphism in the susceptibility to suicide completion

NCAM1, TACR1 and NOS Genes and Temperament: A Study on Suicide Attempters and Controls

Suicide, one of the leading causes of death among young adults, seems to be plausibly modulated by both genetic and personality factors. The aim of this study was to dissect the potential association between genetics and temperament in a sample of 111 suicide attempters and 289 healthy controls. We focused on 4 genes previously investigated in association with suicide on the same sample: the nitric oxide synthase 1 and 3 (NOS1 and NOS3), the neuronal cell adhesion molecule 1 (NCAM1), and the tachykinin receptor 1 (TACR1) genes. In particular, we investigated whether a set of genetic variants in these genes (NOS1 : rs2682826, rs1353939, rs693534; NOS3 : rs2070744, rs1799983, rs891512; NCAM1 : rs2301228, rs1884, rs1245113, rs1369816, rs2196456, rs584427; TACR1 : rs3771810, rs3771825, rs726506, rs1477157) were associated with temperamental traits at the Temperament and Character Inventory (TCI). No strong evidence was found for the association between TCI personality traits and the polymorphisms considered in the 4 genes, with the exception of an association between reward dependence trait and the rs2682826 SNP in NOS1 in the healthy sample. However, this result could be plausibly interpreted as a false-positive finding. In conclusion, our study did not support the thesis of a direct modulation of these genes on temperament; however, further studies on larger samples are clearly required in order to confirm our preliminary findings and to exclude any possible minor influence. Copyright (C) 2011 S. Karger AG, Base

Impulsive traits and 5-HT2A receptor promoter polymorphism in alcohol dependents: Possible association but no influence of personality disorders

Objective: Impulsive behavior in alcoholics puts them at serious risk of severer course of disease and has been related to the serotonergic neurotransmission dysfunction. The aim of this study is to investigate the association between impulsive aggression in alcohol dependents with regard to the G-1438A polymorphism in the promoter region of the 5-HT2A receptor gene. Furthermore, we investigated the statistical interaction between 5-HT2A alleles, antisocial personality disorder (APD) and impulsive aggression in alcohol dependents. Alcohol dependents were investigated because these personality disorders and impulsive behavior are very frequent in alcohol dependence anf of clinical relevance. Methods: One hundred and thirty-five patients of German descent meeting DSM-IV criteria of alcohol dependence were recruited. Blood samples were taken from alcohol dependents to determine 5-HT2A promoter polymorphisms using PCR (polymerase chain reaction) of lymphocyte DNA. Impulsive aggression was assessed using a German version of the Barratt Impulsiveness Scale which was translated and backtranslated. Alcohol dependents were subdivided into low- or high-impulsivity groups using a median split of the Barratt score. APD and borderline personality disorder (BPD) were assessed using the SCID-II interview. Results: The low-impulsivity group was slightly older and showed a later age at alcoholism onset than the highly impulsive group. Alcohol dependents with high impulsive traits showed a significant association with 5-HT2A 1438 A alleles. After excluding alcohol dependents with APD or BPD from the analysis, this association remained significant. Furthermore, no association between APD, BPD and 5-HT2A alleles was noted. Conclusions: Inpatient alcohol dependents showed a significant association between 5-HT2A A alleles and impulsive traits, independent of the presence of APD or BPD. No association was noted between personality disorders and the polymorphism. This is the first report about an association of 5-HT2A promoter polymorphism and impulsive behavior in alcohol dependents. This finding may refer only to impulsive traits and may be independent of personality disorders in this sample. These results have to be confirmed in larger samples and in healthy control subjects to determine whether this association is of general validity. Copyright (C) 2001 S. Karger AG, Basel

The Effects of Epigenetics on Stress Response

Despite the vast amount of resources at the disposal of humanity today, the intricacies of human biology are often a mystery. The chemical and biological products of the human genome have been well studied and documented, but many of the chemical and neurological pathways are missing quite a few details. The human stress response is one of the most primal and valuable functions of this code that developed as a self- preservation mechanism (Hans, 1975) to naturally increase the odds of procreation. However, this function is prone to overload, particularly in individuals with certain epigenetic traits instilled by early life events, or even events taking place before their life began. Left unchecked, this overclocked stress response can lead to irate outward behavior with no known cause, and even worse, no known treatments. These irate behaviors can be seen on the experimental level; mice who are not adequately groomed by their mothers expressed an increase glucorticoid receptor (GR) response than mice with adequate grooming (Radtke et al., 2011). In human studies, these GR reactions are responsible for a myriad of mental disorders including suicidal tendencies, psychopathy, and increased aggression. Gene therapy is possible for these epigenetic factors, opening up new possibilities for treatment of mental disorders

TRYPTOPHAN HYDROXYLASE 2 (TPH 2) SINGLE NUCLEOTIDE POLYMORPHISMS, SUICIDE, AND ALCOHOL-RELATED SUICIDE

Background: Suicide has been identified as a serious public health problem that is often accompanied by alcohol misuse and dependence. It seems that suicide is a result of an interplay between distal (e.g. genetic loading, family history of suicide) and proximal factors (e.g. existence of psychiatric disorder, events conferring acute stress), as well as their interactions. However, like suicide, alcohol dependence seems to be a multifactorial disorder caused by genetic and environmental factors. Serotonergic dysfunction has been implicated to be involved in the pathophysiology of substance abuse, and has also an important role in suicidal behaviour. Studies investigating suicide, alcohol-related suicide and the rate limiting enzyme of serotonin synthesis, tryptophan hydroxylase 2 (TPH2), remain to date rather limited. Results: Recent studies of TPH2 showed a range of strong, mild or no association with suicide and alcohol-related suicide, depending on a study group and genetic variants tested. Overall, to date the clinical effects seems to be quite modest. Among suicide victims with more impulsive and verbal aggressive behaviour more alcohol misuse or dependency was present. Conclusions: Suicide and alcoholism are often comorbid disorders with a complex nature. They are both strongly linked to serotonin modulation, and therefore association studies of SNPs in genes from the serotonergic system could provide an insight into the genetic background of such disorders. However, based on current results we cannot draw any conclusions, but further research to clarify the interplay between serotonergic system dysfunction, suicide, alcohol dependence, impulsivity and the role of TPH2 enzyme is needed