Suicide: Genetics and Heritability.

Nature vs nurture is, and has been, a never stopping debate since Lamarck and Darwin exposed their corresponding theories on evolution, and even before them, such discussion already existed. Is suicide a heritable conduct? Is it learnt? Maybe the answer is both and none, at the same time. From genetic twin studies to epigenetic and environmental influence on development, this chapter aims to take a look at different points of view and most relevant theories in one of the worlds leading causes of death, specially for young individuals. We explore different studies aiming to find biomarkers for suicide, as well as other traits frequently encountered in individuals who engage in suicidal behavior, such as impulsivity, aggressivity, and hopelessness. Finally, this chapter also looks at some of the most recent approaches in treatment and prevention of suicidal behavior, in order to highlight what they have in common and try to explain (at least partially) why they could be effective.

5-HTTLPR-brain-derived neurotrophic factor (BDNF) gene interactions and early adverse life events effect on impulsivity in suicide attempters.

OBJECTIVES: An expanding body of research suggests that childhood adverse experiences can lead to different negative health outcomes, including attempted suicide. Serotonergic genes such as the promoter region of the serotonin transporter gene (5-HTTLPR) have been associated both with impulsivity in suicide attempts and reactivity to environmental stress exposure. BDNF gene may play an epigenetic role. METHODS: We studied the influence of childhood stressful events and 5-HTTLPR genotype on impulsivity measured by Barratt Impulsivity Scale (BIS-10) in a multicentre sample of 1,655 suicide attempters (69.4% women, 30.6% men; mean age 40.13 years). A co-dominant additive genetic model was used for the statistical analyses. Interaction between 5-HTTLPR genotype and early trauma exposure was tested using moderated and multiple regression techniques. Interaction plots were used to explore BDNF genotype modulation. RESULTS: Mildly higher impulsivity scores were found in men with SS compared with SL or LL genotypes, and men with childhood emotional and physical abuse. Interaction analyses showed that combination of 5-HTTLPR-SS genotype and early trauma exposure increase impulsivity scores independently. Impulsivity scores were not affected by the modulation of BDNF genes. CONCLUSIONS: Childhood trauma and 5-HTTLPR genotype seem to be independently involved in suicide attempts, sharing a common pathway of increasing impulsivity.

RNA-Seq reveals the existence of a CDKN1C-E2F1-TP53 axis that is altered in human T-cell lymphoblastic lymphomas.

BACKGROUND: Precursor T-cell lymphoblastic lymphomas (T-LBL) are rare aggressive hematological malignancies that mainly develop in children. As in other cancers, the loss of cell cycle control plays a prominent role in the pathogenesis in these malignancies that is primarily attributed to loss of CDKN2A (encoding protein p16INK4A). However, the impact of the deregulation of other genes such as CDKN1C, E2F1, and TP53 remains to be clarified. Interestingly, experiments in mouse models have proven that conditional T-cell specific deletion of Cdkn1c gene may induce a differentiation block at the DN3 to DN4 transition, and that the loss of this gene in the absence of Tp53 led to aggressive thymic lymphomas. RESULTS: In this manuscript, we demonstrated that the simultaneous deregulation of CDKN1C, E2F1, and TP53 genes by epigenetic mechanisms and/or the deregulation of specific microRNAs, together with additional impairing of TP53 function by the expression of dominant-negative isoforms are common features in primary human T-LBLs. CONCLUSIONS: Previous experimental work in mice revealed that T-cell specific deletion of Cdkn1c accelerates lymphomagenesis in the absence of Tp53. If, as expected, the consequences of the deregulation of the CDKN1C-E2F1-TP53 axis were the same as those experimentally demonstrated in mouse models, the disruption of this axis might be useful to predict tumor aggressiveness, and to provide the basis towards the development of potential therapeutic strategiesin human T-LBL.

CYP2D6 polymorphism and mental and personality disorders in suicide attempters.

Prior studies on the association between the CYP2D6 polymorphism and suicide did not explore whether mental and personality disorders mediate this association. The main objective of the present study was to test an association between CYP2D6 polymorphism and mental and personality disorders among suicide attempters. The MINI and the DSM-IV version of the International Personality Disorder Examination Screening Questionnaire were used to diagnose mental and personality disorders, respectively, in 342 suicide attempters. Suicide attempters were divided into four groups according to their number of CYP2D6 active genes (zero, one, and two or more). Differences in mental and personality disorders across the four groups were measured using linear-by-linear association, chi square-test, and 95% confidence intervals. Suicide attempters carrying two or more active CYP2D6 genes were more likely to be diagnosed with at least one personality disorder than those with one or zero CYP2D6 active genes.

Putative association between the -1415 T/C polymorphism of spermidine/spermine N1-acetyltransferase (SSAT1) gene and alcohol use disorders in women and men.

BACKGROUND: The activity of N-methyl-D-aspartate (NMDA) glutamate receptor, which responds to the levels of polyamines, modifies the neurotoxicity caused by ethanol. We aimed to investigate if the functionality of the spermidine/spermine N1-acetyltransferase (SSAT1) gene could be associated with a differential risk for alcoholism. METHODS: We studied a sample of 586 subjects: 104 alcohol-dependent patients, 273 patients with psychiatric disorders but without substance dependence, and 209 healthy controls. After gender stratification, the allele frequency distribution of the SSAT1 gene was compared between these three groups. RESULTS: In females, the TC genotype was significantly more frequent in alcohol-dependent patients than in non-alcohol-dependent psychiatric controls (χ(2 )= 7.509 df = 2, p = 0.023). A trend was found when alcohol-dependent females were compared with the healthy control group (χ(2 )= 4.897 df = 2, p = 0.086). No statistical differences were found among the males. DISCUSSION AND CONCLUSION: Gender differences in the regulation of SSAT1 gene expression may possibly be due to gender-specific effects of stress, ethanol toxicity, and/or polyamines levels. Further studies are needed to confirm our findings.

CYP2D6 poor metabolizer status might be associated with better response to risperidone treatment.

The variability in the antipsychotic response is, to some extent, genetically determined. Several studies have attempted to establish a role for genetic variation in genes coding pharmacokinetic and pharmacodynamic targets, but to date, no definite genetic predictive marker has been identified. We aimed to explore the putative role of 19 genetic variants and risperidone clinical improvement in 76 White schizophrenic inpatients, measured as change in Positive and Negative Syndrome Scale (PANSS). CYP2D6 poor metabolism was significantly associated with greater clinical improvement in total PANSS and a trend was also found for MDR1 3435C>T to higher total PANSS scores in 3435T carriers. This study suggests the importance that genetic variability on pharmacokinetic factors may have in risperidone response and gives evidence for the need for further investigation in order to establish the actual predictive value and clinical utility that CYP2D6 genotyping might have in risperidone therapy management.

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.

New perspectives in glutamate and anxiety.

Anxiety and stress-related disorders, namely posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (ODC), social and specific phobias, and panic disorder, are a major public health issue. A growing body of evidence suggests that glutamatergic neurotransmission may be involved in the biological mechanisms underlying stress response and anxiety-related disorders. The glutamatergic system mediates the acquisition and extinction of fear-conditioning. Thus, new drugs targeting glutamatergic neurotransmission may be promising candidates for new pharmacological treatments. In particular, N-methyl-d-aspartate receptors (NMDAR) antagonists (AP5, AP7, CGP37849, CGP39551, LY235959, NPC17742, and MK-801), NMDAR partial agonists (DCS, ACPC), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) antagonists (topiramate), and several allosteric modulators targeting metabotropic glutamate receptors (mGluRs) mGluR1, mGluR2/3, and mGluR5, have shown anxiolytic-like effects in several animal and human studies. Several studies have suggested that polyamines (agmatine, putrescine, spermidine, and spermine) may be involved in the neurobiological mechanisms underlying stress-response and anxiety-related disorders. This could mainly be attributed to their ability to modulate ionotropic glutamate receptors, especially NR2B subunits. The aim of this review is to establish that glutamate neurotransmission and polyaminergic system play a fundamental role in the onset of anxiety-related disorders. This may open the way for new drugs that may help to treat these conditions.

CYP2D6 and the severity of suicide attempts.

AIM: Among people who die by suicide, an increased frequency of CYP2D6 active gene multiplication has been described. Therefore, the present study analyzed the relationship between the severity of the suicidal intent and CYP2D6 number of active genes among survivors. MATERIALS & METHODS: A group of 342 individuals were evaluated with Beck Suicide Intent Scale within 24 h of the failed attempt. 'Severe' suicide attempters were classified as those scoring above percentile 75 in the objective circumstances section of the Suicide Intent Scale Scale. A group of 377 healthy controls were also genotyped. results: A higher number of 'severe' suicide attempters carrying ≥2 active CYP2D6 genes as compared with the rest of the patients population (p < 0.01) or the healthy control group (p < 0.01) was found. CONCLUSION: Considering that 'severe' suicide attempters are more likely eventually to die by suicide, CYP2D6 genetic polymorphism might be of use as a biomarker of death by suicide, which is in agreement with previous findings.

Evaluating a newly developed pharmacogenetic array: screening in a Spanish population.

AIMS: How genes affect the response in a patient to a given medication is still poorly understood; the validation of biomarkers and technologies need to be performed. This study aims to determine the analytical characteristics of PHARMAChip(®), a newly developed pharmacogenetic array, and the Spanish population allelic and genotypic frequencies of the genetic variants included in this chip. MATERIALS & METHODS: The analytical characteristics of PHARMAChip assessed were sensitivity and specificity (for CYP2D6 and SLC6A4), accuracy (for SLC6A4) and genotyping rate: frequencies of the 90 pharmacogenetic variants of 36 genes were included in PHARMAChip. These were compared in 449 Spanish subjects with data reported in Caucasians. RESULTS & CONCLUSION: Sensitivity and specificity ranged from 96-100%, accuracy was 94.8% and genotyping success rate was 99.6%. PHARMAChip is an accurate, rapid and updatable tool, which may be especially useful for cytochrome P450 testing. The allelic and genotypic frequencies found in the Spanish subjects reinforce the need for establishing possible intraethnic differences among populations prior to performing this kind of study.

Rare genotype combination of the serotonin transporter gene associated with treatment response in severe personality disorder.

The insertion deletion (ins/del) polymorphism of the serotonin transporter gene (5-HTTLPR) has been associated with several psychiatric phenotypes and antidepressant's response. We investigated, in a large cohort of 5,608 controls and subjects suffering from various psychiatric disorders, the frequency of haplotypes and corresponding genotypes combining the 5-HTTLPR and the other serotonin transporter promoter functional variant (rs25531). We showed that rs25531 lies 18 bp 5' to the site where the 43 bp (and not 44 bp as previously described) ins/del defines the 14- and 16-repeat alleles. These polymorphisms should therefore be considered as four alleles instead of a triallelic unique locus. The very rare G-14/G-16 genotype was carried on by only three subjects. These are women with a history of suicide attempt with a psychiatric history strongly suggesting a borderline personality disorder. Two of them have shown a non-response to serotoninergic antidepressant. Interestingly, in one of them was observed a spectacular response after the introduction of bupropion. The genotyping droved our therapeutic approach, by preferring a dopaminergic over a serotoninergic agent. This study highlights the usefulness of studying very rare clinical cases as well as rare variants, in order to deal with the biological heterogeneity of spectral disorders. © 2010 Wiley-Liss, Inc.

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.

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.

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).