Nucleotide variation in central nervous system genes among male suicide attempters.

Despite marked morbidity and mortality associated with suicidal behavior, accurate identification of individuals at risk remains elusive. The goal of this study is to identify a model based on single nucleotide polymorphisms (SNPs) that discriminates between suicide attempters and non-attempters using data mining strategies. We examined functional SNPs (n = 840) of 312 brain function and development genes using data mining techniques. Two hundred seventy-seven male psychiatric patients aged 18 years or older were recruited at a University hospital psychiatric emergency room or psychiatric short stay unit. The main outcome measure was history of suicide attempts. Three SNPs of three genes (rs10944288, HTR1E; hCV8953491, GABRP; and rs707216, ACTN2) correctly classified 67% of male suicide attempters and non-attempters (0.50 sensitivity, 0.82 specificity, positive likelihood ratio = 2.80, negative likelihood ratio = 1.64). The OR for the combined three SNPs was 4.60 (95% CI: 1.31-16.10). The model's accuracy suggests that in the future similar methodologies may generate simple genetic tests with diagnostic utility in identification of suicide attempters. This strategy may uncover new pathophysiological pathways regarding the neurobiology of suicidal acts.

SAT-1 -1415T/C polymorphism and susceptibility to schizophrenia.

Patients suffering from psychosis show increased blood and fibroblast total polyamine levels. Spermidine/spermine N1-acetyltransferase (SSAT-1) and its coding gene (SAT-1) are the main factors regulating polyamine catabolism. The aim of the present study was to examine the association between the SAT-1 -1415T/C single nucleotide polymorphism (SNP) and schizophrenia. A case-control design was used in order to compare the genotypes for the SNP between schizophrenia patients (n=180, 83 females and 97 males), other non-psychotic psychiatric patients (n=413, 256 females and 157 males), and healthy controls (n=251, 101 females and 150 males). No significant differences in the distribution of the genotypes of the SAT-1 -1415T/C SNP were found groups among groups. We failed to demonstrate a significant association between the SAT-1 -1415T/C SNP and schizophrenia, but a mild association between allele C and psychopathology was found in the female group.

Positive association between SAT-1 -1415T/C polymorphism and anxiety.

Limbic glutamatergic neurotransmission plays a pivotal role in the pathogenesis of anxiety disorders. Polyamines modulate the activity of several ionotropic glutamate receptors and have been involved in the regulation of fear-conditioning response. Spermidine/spermine N1-acetyltransferase (SSAT-1) is the main enzyme regulating polyamine catabolism. The aim of the present study was to examine the association between anxiety disorders and the -1415T/C (rs1960264) single nucleotide polymorphism (SNP) of the gene (SAT1) coding for SSAT-1. A case-control design was used in order to compare the genotypes for the -1415T/C (rs1960264) SNP between anxiety patients (n = 218), other non-anxiety psychiatric patients (n = 362), and healthy controls (n = 251). DSM-IV diagnoses were provided using MINI 4.4. Genomic DNA was extracted from peripheral blood samples collected from participants. In males, there was a significant difference in the distribution of the two genotypes (T and C) for the SAT-1 -1415T/C SNP between anxiety patients, non-anxiety psychiatric controls, and healthy controls. The T genotype was significantly more frequent in males suffering from anxiety disorders than in male psychiatric controls and healthy controls. This is the first study linking polymorphic variants of genes involved in polyamine metabolism with anxiety disorders.

Association study of two polymorphisms of the serotonin-2A receptor gene and suicide attempts.

Serotonin (5-HT) receptors may have a role in suicidal behavior. Previous studies have shown an association between the T102C polymorphism of the 5-HT2a receptor gene and suicidal behavior. However, negative findings have also been reported. We examined the association between the T102C and C1354T (His452Tyr) polymorphisms of the 5-HT2a receptor gene and suicide attempts. Four hundred forty-one suicide attempters, 339 psychiatric patients, and 410 healthy controls were compared for genotypes of the T102C and C1354T (His452Tyr) polymorphisms. There were significant differences in the distribution of the three genotypes (TT, TC, and CC) of the T102C polymorphism in the three groups (controls, psychiatric patients, and suicide attempters). There was an excess of C/C genotypes in the suicide attempter group compared with the control group, but there were no significant differences between suicide attempters and psychiatric controls. We found no association between the C1354T polymorphism and suicide attempts. The C allele of the T102C polymorphism of the 5-HT2A receptor gene may be associated with biological susceptibility for suicidal behavior or psychiatric conditions.

Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene.

BACKGROUND: Pharmacological studies indicate a dysregulation of the serotonergic system in obsessive-compulsive disorder (OCD). A variable number tandem repeats (VNTR) polymorphism with three alleles (Stin2.9, Stin2.10, Stin2.12) has been described in intron 2 of the serotonin transporter (5-HTT) gene. This polymorphism has been associated with unipolar depression, bipolar disorder, schizophrenia, and anxiety disorders including OCD. METHODS: The association between OCD and the polymorphism is examined in 97 OCD patients, 578 psychiatric controls and 406 healthy controls, all Spanish Caucasians. RESULTS: Genotype frequencies for the polymorphism were significantly different in OCD patients, psychiatric patients and controls. There was a significant excess of 12/12 and 12/10 genotypes in OCD patients compared to psychiatric patients and controls. CONCLUSIONS: Our results indicate a possible association between the Stin2.12 allele of the VNTR polymorphism and OCD.

Association between the T102C polymorphism of the serotonin-2A receptor gene and schizophrenia.

Studies have shown an association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. However, negative findings have also been reported. We conducted a case-control study of the T102C polymorphism in Spanish Caucasians. We compared T102C polymorphism genotypes and allele frequencies in 188 schizophrenia patients and 440 healthy controls. There were significant differences in the distribution of the three genotypes (TT, TC and CC) and in the allele frequencies in controls and schizophrenics. The C allele was more frequent in schizophrenia patients than in healthy controls. The Cochrane-Armitage test for trend indicated a significant dosage effect for schizophrenia of the risk allele (C).

Genetic epistasis in female suicide attempters.

BACKGROUND: Complex behaviors such as suicidal behavior likely exhibit gene-gene interactions. The main aim of this study is to explore potential single nucleotide polymorphisms combinations with epistatic effect in suicidal behavior using a data mining tool (Multifactor Dimensionality Reduction). METHODS: Genomic DNA from peripheral blood samples was analyzed using SNPlex Technology. Multifactor Dimensionality Reduction was used to detect epistatic interactions between single nucleotide polymorphisms from the main central nervous system (CNS) neurotransmitters (dopamine: 9; noradrenaline: 19; serotonin: 23; inhibitory neurotransmitters: 60) in 889 individuals (417 men and 472 women) aged 18 years or older (585 psychiatric controls without a history of suicide attempts, and 304 patients with a history of suicide attempts). Individual analysis of association between single nucleotide polymorphisms and suicide attempts was estimated using logistic regression models. RESULTS: Multifactor Dimensionality Reduction showed significant epistatic interactions involving four single nucleotide polymorphisms in female suicide attempters with a classification test accuracy of 60.7% (59.1%-62.4%, 95% CI): rs1522296, phenylalanine hydroxylase gene (PAH); rs7655090, dopamine receptor D5 gene (DRD5); rs11888528, chromosome 2 open reading frame 76, close to diazepam binding inhibitor gene (DBI); and rs2376481, GABA-A receptor subunit γ3 gene (GABRG3). The multivariate logistic regression model confirmed the relevance of the epistatic interaction [OR(95% CI)=7.74(4.60-13.37)] in females. CONCLUSIONS: Our results suggest an epistatic interaction between genes of all monoamines and GABA in female suicide attempters.

Gender effect on association between DRD2 polymorphism and substance dependence in a Spanish sample.

Our aim was to examine a possible association between substance dependence and the TaqIA polymorphism of the D2 dopamine receptor (DRD2), a single nucleotide polymorphism (SNP) located at the 3' UTR region of the DRD2 gene. A case-control design stratified by gender was used to analyze the genotypes of this SNP in a sample of 125 substance-dependent patients according to DSM-IV and 203 blood donors recruited as controls in two general city hospitals in Madrid, Spain. Genomic DNA from peripheral blood samples was amplified through PCR to identify the variants of the SNP in the DRD2 gene. Analyses performed with Chi(2) tests revealed that the A1 allele (A1/A1 and A1/A2 genotypes) of the Taq 1A SNP of the DRD2 gene was significantly associated with substance dependence in males, but not in the whole sample. Male patients had significantly higher rates of the A1-containing genotypes than male controls. The finding of an association between substance dependence and the DRD2 gene TaqIA SNP only in males suggests the existence of gender-specific differences in the genetic underpinnings of substance dependence.