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Genetics of suicide


The concept that genetic factors contribute to the complex trait of suicidal behaviour has stimulated much work aimed at identifying susceptibility genes. So far molecular genetic studies focused on the serotonergic pathway as the intent to die and the lethality of suicide acts were related to the serotonergic system. Two genes have so far emerged as being involved in the vulnerability for suicidality: first, the intronic polymorphisms (A218C or A779C) of the tryptophan hydroxylase 1 (TPH1) gene, which was suggested as a quantitative risk factor for suicidal behaviour; second, the insertion/deletion polymorphism of the serotonin transporter gene (5-HTTLPR), which does not seem to be involved in general suicidal behaviour, but in violent and repeated suicide attempts. The data have further shown that the MAOA gene, which is consistently associated with impulsive-aggressive personality traits, is not related to suicide but might induce violent methods in subjects with other suicide risk factors. Predominantly negative were the findings with any type of the serotonin receptors and inconsistent with catecholamine-synthesizing and -metabolizing enzymes or with the dopaminergic receptors. This paper reviews the status of current knowledge in this area, points to the weakness of the investigations and presents new approaches beyond the serotonergic system.


Suicide is a significant public health issue and a major cause of death throughout the world. Although the epidemiological data vary from country to country with the highest annual rates in a group of Eastern European countries, which share similar historical and socio-cultural characteristics, such as Estonia, Latvia, Lithuania, Finland and Hungary and to a lesser extent the Russian Federation; the WHO estimates that suicide accounts for almost 2% of the deaths in the world.1 There is a relatively consistent predominance of completed suicide rates in males over those in females with the exception of China, where suicide rates are higher in females.2, 3 Attempted suicide is more frequent than completed suicide with a lifetime prevalence of about 3.5% and it is usually estimated that up to 10% of suicide attempters will commit suicide within 10 years.4 Although there is a clear tendency towards an increase in suicide rates with age (for both men and women), numerically more suicides are committed by younger people and recent evidence suggests that suicide rates of young people are increasing in many geographical areas.5 Several explanations have been considered for national and regional variations, including climate, religion, social and political systems, but a more likely scenario is that the genetic contributions to suicide will be represented by small size effects of many gene variants associated with processes involved in suicidal behaviour, and by interaction of these genetic factors with environmental factors.3, 6

Defining the phenotype

Suicidal behaviour includes a wide spectrum and refers to the occurrence of suicide attempts that range from fatal acts (completed suicide) over highly lethal, but failed suicide attempts (where high intention and planning are evident and survival is fortuitous) to low lethality, usually impulsive attempts triggered by a social crisis which contain a strong element of an appeal for help.7 Suicidal ideation, which comprises suicidal thoughts or threats devoid of action, is more common than suicide attempts and completed suicide and its prevalence varies widely, being almost twice in females compared to males. It was further found that suicidal ideations are almost always associated with a psychiatric disorder.8, 9 Although the exact clinical definition of suicidal behaviour remains unsatisfactory and is a source of confusion, the phenomenon of suicidality is often viewed as occurring on a continuum of increasing severity from ideation over attempts to completed suicide10 and may be classified according to the intent to die, method and lethality (violent or non-violent), cognitive impairments (impulsivity, aggressiveness), or mitigating circumstances.11 The method of suicide is not randomly distributed. For example, violent methods, assessed with a higher level of lifetime aggression and a higher level of impulsivity, are more often applied by males than by females. In addition, violent methods were often associated with lifetime substance abuse or dependence and psychotic disorders.12

Clinical correlates of suicidal behaviour

Several arguments suggest that suicidal behaviour is a disorder on its own, although psychiatric disturbances are major contributing factors and about 90% of suicide attempters have a psychiatric disorder according to the Diagnostic and Statistical Manual of Mental Disorder.7 The majority of all suicides occur in relation to mood disorders, but also other psychiatric disturbances such as schizophrenia, alcoholism and drug abuse are similarly related to suicide5 (for review see Mann13). Other clinical features that increase the liability for suicidal behaviour include personality traits, hopelessness, a history of physical or sexual abuse during childhood, a history of head injury or neurological disorder, and cigarette smoking.13, 14 However, although the presence of a psychopathology is a strong predictor for suicide, only a minority of people with these diagnoses commit suicide. Thus, a psychiatric diagnosis might be a necessary, but insufficient, risk factor for suicide, indicating a predisposition that is independent of the main psychiatric disorders.13, 15

Especially impulsive-aggressive traits, neuroticism and anxiety-related traits, as well as anger-related traits were proposed as intermediary phenotypes and risk factors for suicidal behaviour.14 These traits seem to be independent from the role of associated axis I disorders, particularly major depression and may be part of a developmental cascade that increases suicide risk among a subset of patients.15 Further, as personality traits themselves are partly under genetic control, it was suggested that they may contribute to the familial loading of suicide attempts and completions.14, 15 On the other hand, it was proposed that impulsive-aggressive personality disorders and alcohol abuse/dependence were two independent predictors of suicide in major depression, and impulsive and depressive behaviours seem to underlie these risk factors.12

Family studies in suicidal behaviour

It is long known that suicidal behaviour runs within families and that this familial transmission cannot solely be explained by the transmission of psychiatric disorders alone, as the highest suicide rates were not observed in the biological relatives of patients with affective disorders, who by themselves have a strong genetically driven vulnerability.16 Although various biological, psychological, sociological and economic factors contribute to the complex aetiology of suicidal behaviour, evidence for a genetic liability is convincing since many years. Twin studies have shown that monozygotic twins have a significantly higher concordance rate for completed and attempted suicide than dizygotic twins.17 This finding was replicated in a large Australian twin study, in which the risk of a serious suicide attempt by a monozygotic twin was 17-fold increased if the co-twin made a serious suicide attempt.18 Also adoption studies supported the genetic component, as among the biological relatives of an adoptee who committed suicide, the rate of suicide is elevated about six times compared to the biological relatives of non-suicidal adopted persons (for review see Brent and Mann16). From these data it was estimated that 43% of the variability in suicidal behaviour may be explained by genetics, while the remaining 57% may be explained by environmental factors.17, 19, 20

The heritability of suicide and suicidal behaviour seems to be determined through at least two components: the heritable liability to psychiatric disorders, and the heritable liability to impulsive aggression or other personality traits. And thus the concordance of both liability factors results in the highest risk for suicidal behaviour.16

The neurochemistry of suicidal behaviour

Post-mortem brain analyses gave interesting data on the serotonergic, noradrenergic and dopaminergic neurotransmitter systems and the cellular morphology of suicide victims. Especially, the serotonergic abnormalities, which are related to a variety of psychopathological dimensions such as anxiety, depressed mood, impulsivity and aggression, were the focus of many investigations. The initial, seminal finding by Asberg21 that a low cerebrospinal fluid (CSF) 5-HIAA concentration could be related to the incidence of violent suicidal acts, was repeatedly replicated in higher lethality attempted suicides.21, 22 A low brain serotonin (5-HT) turnover rate was repeatedly found in impulsive violent offenders, especially when being intoxicated.23

Post-mortem studies with brains of suicide victims revealed evidence for reduced serotonin transporter sites in the prefrontal cortex, hypothalamus, occipital cortex and brainstem.24 In an autoradiographic study this abnormality could be localized to the ventromedial prefrontal cortex.25 Alterations were also observed on the receptor level, as postsynaptic 5-HT1A and 5-HT2A receptors were found to be upregulated in prefrontal cortex and this increase was suggested as being a compensatory mechanism to the low activity of the serotonergic neurons (for review see Mann13). It is interesting to note that the 5-HT1A upregulation seems to be localized to the ventral prefrontal cortex, a region that is involved in behavioural and cognitive inhibition,25 and low serotonergic input might contribute to impaired inhibition, creating a greater propensity to act on suicidal or aggressive feelings.13 These post-mortem findings are underlined by a challenge investigation with fenfluramine, which induces an increase in prolactin secretion in healthy people, but in suicide attempters with a higher degree of lethality, the increase is more blunted.26 As prolactin secretion is an indicator of central serotonergic function, the results of Malone et al. suggest some dysfunction in the serotonergic system in suicide attempters. Although some of the results are not consistent and/or discussed as being related more to major depression than to suicide,27 these results suggest that the serotonergic activity is decreased in suicidal behaviour.

Only few post-mortem studies covered alterations of the noradrenergic or dopaminergic systems. The main findings were decreased noradrenalin (NA) levels in brainstem and increased alpha2-adrenergic receptor densities, suggested as being upregulated due to the NA deficit.28 The results with tyrosine hydroxylase (TH), the rate-limiting enzyme for NA and dopamine (DA) synthesis were divergent, as both increased29 and decreased immunoreactivity were observed.30 However, increased TH and alpha2-adrenergic receptor densities could be indicative of noradrenergic depletion compensatory to increased NA release. This hypothesis is important with regard to the relation between the noradrenergic system and stress response, as severe anxiety or agitation are associated with noradrenergic overactivity, higher suicide risk and overactivity of the hypothalamic-pituitary-adrenal (HPA) axis.13

Results with the dopaminergic system are even scarce. Overall, no alterations were found for mRNA levels of the D1 and D2 receptor in the caudate nuclei of suicide victims31 and similarly not for D4 receptor binding.32 A recent in vivo investigation of homovanillinic acid (HVA), the main DA metabolite, in CSF of depressed suicide attempters demonstrated reduced HVA levels in attempters, but not in depressed non-attempters33 thus suggesting a relation of DA to suicide but not to depression.

On the basis of the neurobiological findings, genetic studies have been carried out since about a decade in order to elucidate the genetic contribution to the vulnerability of suicidal behaviour. As there is convincing evidence that a serotonergic dysfunction is involved in the biological susceptibility to suicide, especially in high-lethality suicide, the majority of the studies were performed with candidate genes of the serotonin pathway. However, also newer aspects deviant from the classical paradigms will be reviewed here.

Tryptophan hydroxylase

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), converting the amino-acid tryptophan to 5-hydroxytryptophan (5-HTP) which is further decarboxylated into 5-HT. Thus, TPH is a critical component for the amount of 5-HT available in the synaptic cleft and the TPH gene was among the first candidate genes for association studies of suicidality. In the meantime, two different TPH isoforms have been identified, referred to as TPH1 and TPH2, the genes for both being located on different chromosomes, chromosome 11 and 12, respectively.34 It is further known that TPH2 is expressed in brain but not in peripheral tissues in mice34 and in men,35 and the TPH2 is thus considered as the brain-specific enzyme, whereas TPH1 is responsible for peripheral serotonin generation.36 At present it is not completely clarified whether TPH1 is also expressed solely in the periphery in humans, as both TPH1 and TPH2 mRNA could be identified in various human brain regions, although TPH2 mRNA levels were about fourfold higher than that of TPH1 in the raphe nuclei.37

The data concerning the enzyme TPH as a presynaptic marker in post-mortem brains of suicide victims were unequivocal for a long time. Ono et al.38 found no overall difference in TPH immunoreactivity between suicide and control brains. Later on, Bonkale et al.39 studied TPH immunoreactivity in specific subnuclei of the dorsal raphe and again observed no differences between depressed suicide victims and controls. In contrast, a recent investigation by Boldrini et al.40 found TPH immunoreactivity to be higher in dorsal raphe nucleus of suicide victims and proposed a compensatory mechanism to alleviate the cortical serotonin deficit. Two recent studies investigated the TPH2 mRNA either by in situ hybridization or quantitative real-time PCR. Bach-Mizrachi et al.41 reported higher levels of TPH2 mRNA in drug-free suicides throughout the entire extent of the rostrocaudal axis of the dorsal raphe nucleus and explained their findings as homeostatic response to deficient brain serotonergic transmission. Investigating prefrontal cortex a greater amount of TPH2 mRNA was found, this however did not differ significantly between suicides and controls.42 In evaluating these discrepant results one has to acknowledge that different areas were investigated in the different studies and that the studies that have been carried out before the identification of TPH2 did not distinguish between the two isoforms of the enzyme.

All together the discovery of TPH2 was supposed to explain all the previously puzzling data in the past 30 years about divergent protein/mRNA ratios and biochemical characteristics of TPH from peripheral sources and from CNS.

The TPH1 gene

The TPH1 gene is located on chromosome 11p15.3–p14 and has two common polymorphisms in intron 7 consisting of an A to C substitution at nucleotides 779 (A779C) and at 218 (A218C) which are in tight, but not complete, linkage disequilibrium. Although the AA genotype of the TPH1 A218C polymorphism was associated with higher TPH immunoreactivity in 28 post-mortem brain samples than the other genotypes,38 both variants are supposed not to alter the amino-acid sequence or the TPH gene transcription.43 Further, four common variants have been identified in the promoter region, as the T-7180G, C-7065T, A-6526G, and G-5806T polymorphisms, and a significant association was observed between the A-6526G variant and suicidality in 167 Finnish offenders.44

Originally the A779C polymorphism was classified as U and L (upper and lower band) and Nielsen et al.45 were the first who reported an association between the UU genotype and higher CSF 5-HIAA concentration in a group of violent alcoholic offenders, whereas the LL genotype had the lowest 5-HIAA levels. Further, a significant association of the TPH1 A779C polymorphism emerged with a history of violent suicide attempts, as only two of the 36 suicide attempters had the UU genotype in contrast to 10 out of 34 probands who never attempted suicide.45 This finding was replicated by the same group in an extended study with 804 Finnish alcoholic offenders, controls, and their relatives, altogether a sample that included 369 sib pairs. Again the L-allele showed significant evidence for linkage to suicidality in affected sib pairs (P=0.006), severe suicide attempts in unaffected sib pairs (P=0.01), alcoholism in unaffected sib pairs (P=0.002) and to the Karolinska Scales of Personality socialization score (P=0.002).46 The authors concluded that the A779C variant of the TPH1 gene might predispose to suicidality but this association was discussed as being relevant mainly among impulsive offenders, as they are phenotypically more extreme.23, 46 These studies were extended by Roy et al.,47 who observed an excess of the TPH 779C allele (L-allele) in 24 surviving Swedish co-twins of monozygotic twin suicide victims. However, a contradictory result emerged from a subsequent study, as the less common A779 allele (U-allele) was more frequent in depressed suicide attempters.48

Many studies followed these first reports and most of them investigated the A218C polymorphism. The majority of studies were carried out in the frame of association studies with depressed, bipolar, schizophrenic or alcoholic patients. Although the numbers of patients within the diagnostic categories seemed to be sufficient, those with suicidal attempts were small in most studies. Nevertheless, Mann et al.,48 found an excess of the A218 allele in suicide attempters among patients with depressive disorder in American Caucasians. Similarly, in a multicentre study investigating a large cohort of patients from several European countries, Souery et al.49 observed the CC genotype of the A218C polymorphisms less frequently in unipolar patients with a history of suicide attempts, but not in bipolar patients. Investigating seven polymorphisms spanning the entire gene in 231 individuals who attempted suicide, significant associations were found between violent suicide attempt and variants in introns 7, 8 and 9 (which are in complete linkage disequilibrium) and in the 3-non-coding region that encodes for the catalytic part of the enzyme.50 Turecki et al.51 focused on polymorphisms in the promoter region (A-6526G and G-5806T) which were investigated together with the intron 7 A218C variant in 101 suicide completers from the French-Canadian population. In contrast to the fact that the single loci were not associated with suicide, a haplotype analysis revealed that one haplotype (−6526G −59061T 218C) was significantly more frequent among violent suicide victims than in normal controls (χ2=11.3, df=2, P=0.0008; OR=2, CI:1.3–3.6).

Concerning the relation between personality traits and the TPH1 gene it is noteworthy that two independent studies observed a relation between the A779 allele and aggressive disposition in healthy individuals without psychopathology. In both studies, investigating probands of American52 and German descent53 the U-allele scored significantly higher on measures of aggression, irritability and anger-related traits.

However, the positive results could not be replicated in all studies and the list of negative findings is long. Post-mortem analyses with DNA derived from suicide victims yielded negative results for 47 depressed Caucasians suicide victims,54 35 depressed suicide victims of Canadian origin55 and for 160 deceased males of Slavic origin.56 Two groups investigated the TPH1 polymorphism in Japanese suicide victims, but both failed to demonstrate an association between suicide and the A-6526G and A218C polymorphism.57, 58 Also studies with Caucasians suicide attempters of different diagnostic categories yielded negative results between suicide attempts in unipolar and bipolar patients54, 59, 60 or alcohol-dependent patients,61 although some of the studies identified an association between the A218C polymorphism and the disorder in question. A case–control family-based study in Ashkenazi and non-Ashkenazi Jewish adolescents again revealed no significant allelic association with the A218C polymorphism.62 Interestingly and in contradiction to the findings with suicide victims of the Japanese population, 218C homozygotes were overrepresented in Korean schizophrenic patients with suicidal behaviour.63 Tsai et al.64 have observed an association between the 218C homozygotes and suicidal attempts in Chinese patients with major depression but not with bipolar disorder. However, Kunugi et al.65 could not relate both the A218C and A779C polymorphisms to a history of suicidality among Japanese unipolar or bipolar patients, thus being in agreement with the findings in completed suicide.

Owing to the discrepancy of the results together with the small numbers of patients, the diagnostic heterogeneity with either committed suicide as clear-cut act or a history of suicidal attempts, and finally due to the use of the different markers the impact of the TPH1 gene on suicidal behaviour remains still ambiguous. Almost all studies lacked in statistical power, ethnic heterogeneity and variations in the sampling strategy, in particular for controls. Three meta-analyses were carried out in the recent years to pool results from individual studies and in order to test, whether the TPH1 gene intron 7 polymorphisms affect the vulnerability for suicidal behaviour. Lalovic and Turecki66 have selected 17 studies for the analysis and carried out two meta-analyses. One compared suicide attempters or completers (n=1290) with 2295 healthy controls; the other compared suicide attempters (n=625) with non-attempters (n=1475), but none of these analyses provided evidence for association (OR=1.14, 95%CI 0.97–1.34 for the first; and OR=0.96, 5%CI 0.77–1.2 for the second study). Also the combined results from both analyses showed no overall association between suicidal behaviour and the intron 7 A218C polymorphism of the TPH gene.

A subsequent meta-analysis by Rujescu et al.67 observed no significant differences in genotype or allele frequencies for 147 suicide attempters with violent or non-violent means, but a weak yet highly significant association was observed in a meta-analysis including these data together with those of seven studies investigating the A218C polymorphism (OR=1.33; 95%CI 1.17–1.5, P=0.00002) in Caucasian suicide attempters. This association could be replicated by a further, more refined meta-analysis by Bellivier et al.68 The authors assessed the heterogeneity due to variations in genetic background together with the polymorphisms studied and nine studies fulfilled the inclusion criteria. Thus by improving the quality of the sample, the authors found a significant association between the A218C polymorphism and suicidal behaviour using the fixed effect method (OR=1.62; 95% CI 1.26–2.07) and the random effect method (OR=1.61; 95% CI 1.11–2.35). Even after removing two studies, which deviated from the calculated global effect (one positive and one negative), the meta-analysis revealed a significant association and suggested that the A-allele has a dose-dependent effect on the risk of suicidal behaviour, at least in the Caucasian population.

The THP2 gene

The identification of the brain-specific, second isoform TPH2 gene,36 being located on chromosome 12q15, promised a step forward in investigating the genetic contribution to suicidality, as this isoform apparently plays a more important role in the synthesis of brain serotonin and thus might be a better candidate gene. However, so far the number of studies using TPH2 as candidate gene is rare. Zill et al.69 from our group carried out a SNP, haplotype and linkage disequilibrium study with 263 German suicide victims with 10 SNPs defining a 28-kbp gene region in the TPH2 gene, across which linkage disequilibrium is high. We observed significant association between one SNP and suicide (P=0.001, global P=0.01). Additional haplotype analyses produced support for association (P<0.0001, global P=0.0001). Although a subsequent study could not demonstrate the influence of a polymorphism in the promoter region (T–473A) and a marker in intron 1 (hCV245410)70 on suicidal behaviour in schizophrenic patients,71 there was a recent supportive evidence for TPH2 haplotype linkage to anxiety/depression phenotypes and suicide attempts in two populations.72 Zhou et al.72 investigated different markers in the 5′-promoter and 3′-untranslated region and a 15-locus panel spanning 106 kbp of the TPH2 gene in 1798 cases and controls of four ethnic groups for association with suicide attempt, anxiety, major depression and CSF 5-HIAA as neurochemical intermediate phenotype. They identified a haplotype block of 52 kbp in size, which increased in frequency in suicide attempters in Finnish whites and African Americans and which was further associated with the CSF 5-HIAA concentration. Moreover, this haplotype resembles that investigated by Zill et al.69 Although the functional consequences of these polymorphisms are unknown and although the data on the TPH2 gene are really limited, the TPH2 gene deserves further evaluation as candidate gene for suicidal behaviour.

The serotonin transporter

The serotonin transporter (5-HTT) is terminating the 5-HT action via uptake of this neurotransmitter from the synaptic cleft and thus the density of 5-HTT sites is regarded as an important index of 5-HT function. The human 5-HTT gene, being located on chromosome 17, has a common polymorphism (5-HTTLPR) in the 5′-regulatory region due to a 44-bp deletion which results in either the S- (short) or L- (long) allele.73, 74 The presence of the S-allele was associated with reduced transcriptional activity and lower level of gene expression, lower levels of 5-HT uptake in transformed lymphoblastoma cell lines and with anxiety-related traits.74 In a comprehensive study, Mann and co-workers investigated a possible relation between the 5-HTTLPR and 5-HTT binding in prefrontal cortex, assayed by quantitative autoradiography in 159 post-mortem brain samples. Although they could replicate the finding of reduced 5-HTT binding in prefrontal cortex in major depression and suicide, they observed no relation between 5-HTTLPR genotypes and 5-HTT binding.75 A study of our group with 72 controls and 72 alcoholics has shown that also in periphery, using platelets as peripheral model for the central serotonergic system, no relation between 5-HTT binding (3[H]-paroxetine sites) and the 5-HTTLPR genotypes were found, neither in healthy controls nor in alcoholic patients.76

Despite these still open questions about the function of the insertion/deletion polymorphism it was hypothesized that the short form of the 5-HTT gene might be associated with impulsive aggression and suicidal behaviour. We have carried out a study using genomic DNA from 58 Caucasian suicide victims and found an association of the S-allele and completed, mainly violent, suicide (OR=2.08; 95%CI 1.3–3.2; P=0.001).77 This finding could be replicated in a subsequent study with 51 Caucasian depressed, violent suicide attempters,78 but not with suicide victims from an isolated Canadian79 or American population.75

In agreement with our results, an association was found between the S-allele and violent suicide attempts of Caucasian bipolar80 and schizophrenic patients,81 although in the latter study there was no correlation between the genotypes and impulsivity, assessed with the BIS (Barratt's Impulsivity Scale). Moreover, the association between the S-allele and suicidal behaviour seems to be independent of clinical diagnosis, demographic or socio-cultural parameters. Campi-Azevedo et al.82 carried out a study in depressed and schizophrenic patients of the Brazilian population, which is very heterogeneous, and they found that the S-allele carriers are overrepresented among persons who committed suicide and moreover these patients attempted suicide more frequently and had higher lethality scores.

The relation between the S-allele and violent suicide methods was underlined in a study by Courtet et al.83 who clearly demonstrated that the frequency of the SS and SL genotypes was not increased in patients with non-violent suicide attempts. The same authors have published a follow-up study with 103 patients and found that patients who reattempted suicide during a 1-year follow-up period had a significantly higher frequency of the S-allele and the SS genotype.84 As it is known that patients are at high risk for reattempt and for completed suicide within the first year following a suicide attempt, these authors proposed that the presence of at least one S-allele might be an important predictor for subsequent suicide attempts.

The relation of the S-allele of the 5-HTTLPR and some personality traits was not only shown in suicidal behaviour but also in alcohol- or heroin-dependent persons. Sander et al.85 found that antisocial alcoholics carrying the SS genotype exhibited significantly lower scores on harm avoidance and higher novelty-seeking scores. Similarly, the SS genotype was more frequent among a group of violent heroin-dependent persons compared with addicted individuals without aggressive behaviour86 and was further associated with an increased availability to experiment illegal drugs, particularly in subjects with more aggressiveness.87

Gender-specific associations of the 5-HTTLPR and suicide were proposed in a study enrolling 180 Spanish suicide attempters (121 women and 59 men) by Baca-Garcia et al. The S-individuals (SS or SL) were significantly overrepresented among female attempters and especially in those who had unsuccessfully tried to commit suicide.88 In contrast, in a sample of 100 French Caucasian alcohol-dependent patients (48 men, 52 women), the presence of the S-allele was related to a lifetime risk of suicide attempts, but only in male subjects.89 Previous association studies also observed a overrepresentation of the S-allele in suicide attempters in a sample of French90 or German alcoholic patients;91 however, females were underrepresented in both studies and thus the results were not analysed as a function of gender. An explanation for this discrepant data and the gender-specific effect might be that intermediate links between alcohol dependence and suicidal behaviour may involve different genetic factors in men and women. A recent study investigating the 5-HTTLPR in the continuum between compulsivity and impulsivity in females observed that the frequency of S-individuals (either homo- or heterozygotic) was low in patients with OCD, intermediate in non-impulsive controls and higher (82%) in impulsive suicide attempters92 and thus it was suggested that genetic variants may be related more likely to behavioural dimensions instead of to specific psychiatric disorders.

In contrast to these positive findings a variety of studies did not observe an association of the 5-HTTLPR with suicidality, neither in post-mortem studies75 nor in studies investigating DNA of suicide attempters from Caucasian,93, 94 Chinese95, 96 or Jewish Ashkeanzi origin.97 Even an increased frequency of the low-activity L-allele was observed within a patient group with increased hopelessness and suicide ideation.98 Du et al.99 found in a very small sample of 24 probands that the L-allele was more frequent in suicide victims, and these authors observed more instead of less 5-HTT binding sites in platelets of S-allele carriers.

Also the relation between familial suicidal behaviour and the history of suicide attempts have been investigated and has yielded discrepant results. One study found an association between suicidal family history and suicide attempts in 237 probands with major depression or schizophrenia as well as first- and second-degree relatives, but no association to the 5-HTTLPR genotype.100 Another study found a relationship between family history of suicidality and the SS genotype.101

Despite the many discrepant results there is still an ongoing interest on genetic variants of 5-HTT as possible indicator for suicidality. Two meta-analyses were carried out in order to unravel the importance of the 5-HTTLPR in suicidal behaviour. The analysis of Anguelova et al.102 reviewed 12 studies with 1599 subjects and found evidence for a significant association of the S-allele with suicidal behaviour. This result was robust and remained significant following sensitivity analysis. A more recent meta-analysis by Lin and Tsai analysed the cumulative data from primary literature in order to determine conclusively the hypothesized role of the 5-HTTLPR. The authors have performed three meta-analyses comparing the 5-HTTLPR between suicidal subjects and controls, between suicide attempters and non-attempters of the same psychiatric diagnoses and finally between violent or non-violent suicidal subjects compared to normal controls. The authors found no association between the 5-HTTLPR and suicidal behaviour. However, comparing the suicide attempters with non-attempters within one diagnostic category, persons with at least one S-allele were more frequent among suicide attempters (P=0.004). A further finding was that the S-allele was associated with violent suicide (P=0.001), but not with non-violent suicide.103 In summarizing all the studies with inadequate number of patients and controls, this study provides significant evidence supporting the role of the 5-HTTLPR S-allele with suicidal behaviour, especially with violent suicide.

Based on the identification of variable-number-tandem-repeats in intron 2 (VNTR-2) of the 5-HTT gene some studies were carried out with this variant to identify a possible liability to suicidality. No association was observed to bipolar disorder or suicidality in a Canadian family study104 and in Canadian suicide attempters.105 Similar negative findings were derived for Chinese mood disorder patients with suicidal history106 or psychotic patients with suicidal behaviour.95 Using DNA of Croatian suicide victims there was also no association between suicide and the VNTR-2 variants. However, a combined analysis of the 5-HTTLPR and VNTR-2 provided evidence towards an increase of 5-HTTLPR L-allele and VNTR-2 allele 10 in the suicide victim group, which was however of low significance.107

Serotonin receptors

The 5-HT2A receptor

There is considerable evidence that the density of the 5-HT2A receptor is upregulated in parietal cortical regions of depressed suicide victims (for review see Mann13) and it was suggested that this increase may be at least partly be regulated genetically.108 The importance of 5-HT2A receptor upregulation as marker for suicidality was further underlined by a recent investigation showing that in suicide brains the lifetime aggression scores correlated positively with 3H-ketanserin binding in all investigated prefrontal Brodman areas.109 Further, several studies with platelets of suicide attempters showed an upregulation of 5-HT2A receptor as a peripheral marker for suicidality,110, 111 although a critical review claimed that methodological flaws limited the validity of platelets as biological model.112

The 5-HT2A receptor gene is located on chromosome 13q14–q21 and according to the current SNP databases more than 200 single-nucleotide polymorphisms (SNPs) are identified spanning the gene;113 only a small number of them have been investigated as candidates in psychiatric disorders, most notably the T102C and A-1438G variants. However, the genetic findings of associations between 5-HT2A receptor gene variants and suicide have been controversial. Du et al.114 reported an association of the 5-HT2A receptor 102C-allele with suicidal ideation in 78 Canadian patients with major depression (χ2=8,5; df=1; P=0.005). They found that patients with the CC genotype had significantly higher scores in HAMD item 3 score (indication of suicidal behaviour) than TC or TT genotypes and concluded that the 5-HT2A receptor 102C allele might confer increased risk for suicidality independently of psychiatric diagnosis. In this context it is remarkable that in an earlier study, genotyping DNA from 24 suicide victims, these authors found no association between the 5-HT2A receptor 102C allele and suicidality.99 A similar positive finding was obtained in a sample of Spanish depressed patients, where significant differences in both allele and genotype distribution were observed between 126 non-suicide and 33 suicide attempters.115 Moreover, 5-HT2A 102C allele carriers had more than five times the risk for attempting suicide than non-carriers (OR=5.5; 95% CI 1.18–35.2).

In the light of the findings of Du et al.,114 several studies have been carried out among different diagnostic groups and different ethnicities. However, no associations were found with suicidal behaviour in the Caucasian population comprising alcoholics with suicidal ideation and previous suicide attempts,116 schizophrenics with suicidal ideation117 or suicide attempts.118, 119 Results were also negative in the Jewish97 or Brazilian120 population. Similarly, investigating the closely linked A-1438G polymorphism, no convincing association was found in the Caucasian121 and Japanese patients with suicidality.122

As completed suicides are more homogeneous in terms of higher lethality and are thought to be more influenced by serotonergic mechanisms than attempted suicides,7 we and others examined whether one of the 5-HT2A receptor polymorphisms was associated with completed suicides, irrespective of the underlying clinical diagnosis. Neither the A-1438G nor the T102C polymorphism were associated with completed suicide in 151 Japanese,123 131 Caucasian124 or 68 Australian suicide victims.125 However, one has to take into account that in none of these studies a psychological autopsy was available, and therefore no information about the proportion of depressed patients in these samples.

A recent systematic review and meta-analysis of suicide association studies, enrolling suicide attempt or completion but not ideation, found no association with the 5-HT2A T102C variants.102 One of the explanations for the conflicting finding might be the size of the sample in both positive studies and/or ethnic stratification. Considering all data published since 1996, it becomes obvious that small but albeit important ethnic differences between Caucasian and non-Caucasian probands exist; as in Chinese and Japanese population, the frequency of the T-allele is slightly higher than in the European sample.124 Thus, one reason for the discrepant result might be the fact that the sample of Du et al. consisted of French Canadians who might have a different ethnic background than the other samples. However, overall there is little proof that the 5-HT2A receptor gene is involved in liability to suicidality.

Other serotonergic receptors

Negative feedback inhibition of raphe neurons is mediated by somatodentritic 5-HT1A autoreceptors and it is known that several antidepressants desensitize raphe 5-HT1A autoreceptors thereby resulting in enhanced serotonergic transmission.126 Conversely, post-mortem brains from depressed suicide victims displayed increased 5-HT1A receptor density in the raphe nuclei but not at postsynaptic sites, which is a further hint towards a decreased serotonergic activity.127 Although it is not established as to whether this upregulation is associated with depression or with suicide, the 5-HT1A receptor gene became a candidate for vulnerability studies in suicide.

Huang et al. have genotyped almost 700 psychiatric subjects for a common polymorphism (C–1019G) within the promoter region of the 5-HT1A receptor gene. Data were related to psychopathology and diagnoses, and associations in genotypes and allele frequencies were observed for substance abuse disorder, schizophrenia and panic attacks, but not for suicidal behaviour.128 Recently, this polymorphism was investigated in suicide completers and patients with major depression in separate cohorts (all Canadian Caucasian), and in both groups the homozygous −1019G allele was found to be enriched, in the suicide groups even fourfold as compared to controls.129 According to the hypothesis and model of these authors, this polymorphism prevents binding of the transcriptional repressor NUDR, thereby resulting in enhanced 5-HT1A receptor expression and affecting the serotonergic system in limbic and cortical areas.129, 130, 131 Two further structural polymorphisms in the 5-HT1A receptor gene which lead to an exchange of amino acids, the Pro161Leu and Gly272Asp variants, were not associated with suicide in Japanese suicide victims.132

Using a mice knockout model being deficient for the 5-HT1B receptor it was suggested that aggressive behaviour might be mediated via this receptor thus making the 5-HT1B receptor gene a candidate for evaluating the liability to suicidality. Two common polymorphisms were identified in the human gene (chromosome 6q13–15), a silent C to T substitution at nucleotide 129 and a silent G to C substitution at nucleotide 861; it was shown that the G861C polymorphism and a closely linked short tandem repeat locus D6S284 are involved in the control of aggression and impulsivity, as in Finnish, as well as Southwestern American Indians antisocial alcoholics had a significantly higher 861C allele frequency.133 This finding is supported by a study with German alcoholics, where a lower frequency of the 861C allele was observed in alcohol-dependent patients with antisocial personality traits and conduct disorder.134 However, no association was found with suicide, depression, alcoholism or pathological aggression in a large sample of 696 unrelated American psychiatric subjects135 and in German suicide attempters.136 Similarly negative were the results in a study combining 245 German and 118 Slavic suicide victims137 and in suicide victims of Japanese origin.138 Further polymorphisms in the coding and in the promoter region were identified, as the common A–161T polymorphism in the promoter region139 but two subsequent studies did not find an association to attempted suicide and aggression in Chinese schizophrenics140 or in Chinese depressives.141

The other serotonin receptors gained so far less attention and investigations with the 5-HT2C receptor,142 the 5-HT6 receptor143 or a combined investigation of seven serotonergic receptor genes revealed no hints of being involved in suicidality.144

This constantly negative finding on the serotonin receptors other than the two positive findings with the 5-HT2A receptor gene, demonstrates that they seem not to have an impact on the liability for suicidality. Despite these discrepant results, it cannot be ruled out that a locus predisposing to antisocial alcoholism may be linked to the 5-HT1B receptor, thus making it worthwhile to be investigated further as a candidate for suicidal behaviour as elevated impulsive aggression is one of the most prominent characteristics of violent suicide.

Genes involved in transmitter synthesis and degradation

Tyrosine hydroxylase

Central monoamines are important modulators of mood and behaviour and a deficit in both serotonin and NA play an important role in the pathophysiology of stress and the response to stress reactions.145 Thus, tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of adrenaline, NA and DA might be an interesting candidate for genetic suicide research. Nevertheless, there was so far not much interest in this gene, as only one study investigated the tetranucleotide repeat polymorphism within the first intron of this gene.146 Persson et al. genotyped Swedish suicide attempters of different diagnostic categories but found no overall differences in the allele frequencies when all suicide attempters were compared to controls. However, they observed a significant higher incidence of the TH-K3 allele (252 bp) among attempted suicide in patients with adjustment disorders147 and it was proposed that this allele might reflect predisposition for a common phenotype with altered vulnerability for psychiatric disorders.

Monoamine oxidase A

Monoamine oxidase A (MAOA) is a mitochondrial membrane enzyme that is involved in human behaviour due to its key role in the metabolism of biological amines.148 The general idea underlying the investigation of MAOA activity in relation to violent behaviour is that low MAO activity results in elevated levels of serotonin, NA, and DA in the brain, manifesting as mood disorder and/or aggressive behaviour.13 Several finding with peripheral tissues underlined its importance, as low platelet MAO activity has been connected with personality traits like impulsiveness, sensation seeking, monotony avoidance and increased psychiatric morbidity149 which all seem to predispose for violent behaviour and increased risk for antisocial and criminal acts.150

Interest in the MAOA gene as a putative candidate for suicide research is derived from the first exciting study by Brunner et al. who showed that a point mutation in the MAOA gene observed in a Dutch kindred was associated with violent behaviour and a phenotype bearing some resemblance to the manic syndrome.151 Although this mutation is rare, the report emphasized that a variant within the MAOA gene might be a liability factor for aggressive behaviour and finally for suicidality.

A number of polymorphisms have been described for the MAOA gene. A 30-bp repeated sequence being located 1.2 kbp upstream of the MAOA coding sequences and being present in 3, 3.5, 4 or 5 copies has been shown to affect the transcriptional activity of the gene. Alleles with 3.5 or 4 copies of this 30-bp tandem repeat (uVNTR) are transcribed 2–10 times more efficiently than those with three or five copies of the repeat.152 Further, two restriction fragment length polymorphisms (EcoRV and Fnu4HI) were identified with a 30-fold difference in enzyme activity.153

This 30-bp VNTR has attracted much interest in psychiatric studies. Manuk et al.154 reported that healthy men carrying the high activity alleles (3.5 and 4 copies) expressed a lower CNS serotonergic responsiveness in the fenfluramine challenge test and more impulsive aggression. Although a subsequent study could not replicate the impact of this functional polymorphism on the expression of personality traits,155 an influence of this polymorphism on the serotonin metabolism with altered CSF 5-HIAA concentrations could be shown in female156 and male157 volunteers. Further, some studies showed associations with bipolar disorder and major depression but also to aggression and impulsivity in antisocial alcoholism (for review see Hattori et al.158).

Concerning suicide the results are not convincing as no association was identified for the MAOA uVNTR variant and only a weak association (P=0.016) of the Fnu4HI locus with a history of suicide attempts in female bipolar patients, but not in males.159 Further studies failed to find an association between suicidality and the MAO uVNTR in heroin-dependent subjects of Italian descent,160 in Japanese unipolar and bipolar patients159, 161, 162 or Japanese suicide victims.162 Only in the study by Du et al.163 a positive result with the MAOA gene was observed. This Canadian group investigated a restriction fragment length polymorphism at position 1460 (EcoRV) in post-mortem brain samples from 44 depressed suicide victims and differences in genotype/allelic distributions were found for the male group (n=33), but not for females.

A recent study by Courtet et al.164 investigated the uVNTR and a dinucleotide repeat in intron 2, which both are in linkage disequilibrium in 738 West European Caucasians with previous suicide attempts. In agreement with the previous studies, there was no overall association between the MAOA variants and suicidality; however, the frequency of the high activity alleles was higher in men who had attempted violent suicide than in men who had used non-violent means (OR 2.17, 95%CI 1.08–4.35). Although at present there seems to be no relation between the MAOA gene and the vulnerability for suicidality, especially the finding by Courtet et al.164 strengthens the hypothesis that an excess of high-activity MAOA gene promoter alleles may influence the methods used in suicide attempts.

Catechol-O-methyltransferase (COMT)

As there is some evidence that NA and DA are contributing to aggressive behaviour and suicidality,165 COMT, the major catecholamine-degrading enzyme is of potential interest as candidate genes for suicidal behaviour. The COMT gene has a functional common genetic polymorphism that is responsible for substantial variability in COMT enzymatic activity. At position 158, a valine (Val) is replaced by methionine (Met) and the Val allele is associated with a relatively high activity (H-allele), whereas the Met allele is associated with relatively low activity (L-allele).166 Although there is presently no evidence about an association between this polymorphism and core diagnoses in psychiatry, it was shown that the clinical phenotype within different diagnostic categories might be influenced by this variant. Thus, across different ethnic groups it was shown that schizophrenic patients with the Met allele had a higher propensity for violence.167, 168, 169 Although early studies were unable to identify an association between the low-activity allele and suicidal behaviour or violence,98, 170 some studies have shown the low-activity allele being more frequent in Finnish and Amercian Caucasian suicide attempters171 and in male Japanese suicide completers.172 A recent study investigating families with at least one member having bipolar disorder and suicidal ideas or attempts, observed no association to the COMT variants, but one has to take into account that females comprised >60% of the sample and that the association might be more pronounced in males.173

The dopaminergic and noradrenergic system

The interest in the DA system, including DA receptors and the DA transporter, derives from the involvement of this system in several psychiatric disorders, especially in alcoholism and its relationship to the reward syndrome which is mediated via the DA D2 receptors.174 A deficiency or absence of DA D2 receptors then predispose individuals to a higher risk for multiple addictive, impulsive or compulsive behaviours175 and a polymorphism in the D2 receptor gene (TaqI) was repeatedly investigated as risk for addictive behaviour, however, with inconsistent results (for review see Noble176). A recent study investigated an insertion/deletion polymorphism within the promoter region of the DA D2 receptor at position −141 (−141C Ins/Del), where one of two cytosines is deleted upstream of exon 1 in the 5′-regulatory region, and this deletion shows a lower transcription activity.177 In a large sample of more than 1000 chronic alcoholic patients of German descent, Putzhammer et al.178 found that the D2 −141C Ins/Del was related according to a phenotype–genotype strategy, for example, patients suffering from severe withdrawal symptoms, seizure or delirium, family history positive alcoholics, and alcoholics with an antisocial personality disorder. They observed −141C Del allele to be significantly in excess in alcoholics with positive family history and in alcoholics with suicidality, although there was no association to the entire group of alcoholics. From these results it might be concluded that the DA D2 receptor might confer a risk to suicidality in patients with high familial loading for alcoholism.

Further, there was an extended discussion about an association between the risk-taking behaviour and the length of the DA D4 receptor (DRD4) gene exon III repeat alleles (for review see Kluger179). However, most studies revealed negative results, either with Israeli suicidal patients,180 or with Swedish suicide attempters.181

Sequeira et al.182 followed the concept of catecholaminergic participation in the etiology of suicidality and studied genetic variations at four loci of the alpha-2-adrenergic receptor gene in Canadian suicide victims, three in the promoter region and one functional variant (N251K) which leads to an amino-acid exchange, and found that the 251K allele was only present in suicide victims, although only in three suicide cases.

Search for new candidate genes and miscellaneous results

Despite the studies that followed the original concepts and hypotheses of serotonergic dysfunction, several recent studies expanded the research to identify new mechanisms and candidate genes. Thus, under the assumption that anxiety and stress response are involved in suicidal behaviour,13 several mechanism modulating these effects are gaining importance. Especially the effects of cannabinoids on anxiety-related responses, which involve endocannabinoid receptors (CB1) and further corticotropin-releasing hormone (CRH), γ-aminobutyric acid (GABA) as main inhibitory transmitter, and the neuropeptide cholecystokinin (CCK)183 were in the focus of recent investigations. The importance of the endogen cannabinoid system may be underlined by recent data showing an upregulation of CB1 receptors together with a concomitant increase of the receptor-mediated [35S]GTPgammaS binding in prefrontal cortex of depressed suicide victims.184 However, so far no studies are available investigating CB1 receptor polymorphisms in relation to suicidal behaviour.

Concerning the association between GABA and suicidality, Baca-Garcia et al.,185 who investigated a dinucleotide repeat (CA)n polymorphism of the α3 subunit of the GABA receptor (GABRA3) gene in 184 Spanish suicide attempters yielded a negative result.

A further study observed an association between Japanese suicide victims and a common polymorphism in the cholecystokinin (CCK) gene promoter (G-196A) in males, but not in females.186

Neurotrophins might play a role in the etiology of mood disorders and suicidal behaviour, as a significant reduction of BDNF mRNA levels was shown in prefrontal cortex and hippocampus of suicide subjects.187 The common Val66Met polymorphism of the BDNF gene was investigated in Chinese unipolar and bipolar patients, but no relation between the disorder or a history of suicide attempts were observed.188 A further study comprised a missense polymorphism (S205L) of the low-affinity neurotrophin receptor gene (p75NTR) which found a positive result in Japanese suicide attempters.189 The possible involvement of 14-3-3 epsilon, which is related to neurogenesis, was identified as possible candidate gene, as it was upregulated using DNA microarrays with brains of suicide victims.190 These authors investigated several SNPs within this gene and found a haplotype associated with completed suicide thus suggesting that a dysregulation of neurogenesis might be involved in suicide.190

This latter study clearly eliminated the possibility that microarray analysis provides the opportunity to study thousands of genes at once and may thus give a ‘snapshot’ about the brain gene activity before completing suicide.191 Thus, microarray analysis is especially useful to identify new candidate genes and to gain new insight into the biological mechanism of suicide beyond the serotonergic system. Despite the fact that there are several methodological pitfalls, as post-mortem delay and the quality of the mRNA preparation, microarray analysis has become a standard tool in many areas of biomedical research.192


As there is abundant evidence that the serotonergic transmission plays a pivotal role in individual differences in mood, impulsiveness and aggression, and that intent to die and lethality are correlated positively with abnormalities in the serotonergic system, it is no surprise that molecular genetic studies in suicide research focus on serotonergic genes. In the last decade, a growing number of molecular genetic studies have been carried out to identify candidate genes that may be involved in the pathophysiological mechanisms of suicidal behaviour. Despite tremendous effort and a plenty of investigations, only two genes, one coding for the tryptophan hydroxylase 1 (TPH1 A218C) and the other for the serotonin transporter (5-HTTLPR), were reliably suggestive to be involved in the vulnerability for suicidal behaviour.

In summarizing all findings with TPH1 it seems as to whether the intronic polymorphisms A779C and/or A218C are associated with suicidality via serotonergic dysfunction, (reflected by the low 5-HIAA), Courtet et al.10 suggested that TPH may be a quantitative risk factor, where a greater effect of the gene leads to more pronounced serotonergic dysfunction with higher levels of anger and more severe suicidal acts. Concerning the brain-specific TPH2 gene, the results published until now are promising attempts but far from being conclusive.

The S-allele of the serotonin transporter polymorphism (5-HTTLPR), which plays a role in mood disorders193 and in the response to antidepressive medication,194 was further shown to be involved in violent behaviour in subjects with type II alcoholism85 and aggressive behaviour in heroin addicts.86 These data, together with the results of the association studies in suicidal behaviour, favour the assumption that the serotonin transporter gene is not involved in suicidal behaviour in general, but in violent and repeated suicide attempts. In contrast to this, the data with the MAOA gene, which was repeatedly and consistently associated with impulsive-aggressive personality traits, do not propose a direct relation to suicidal behaviour, but it might orient an act towards violence in subjects with other suicide risk factors.10 Predominantly negative were the findings with any type of the serotonin receptors and not convincing for studies with catecholamine-synthesizing and -metabolising enzymes or with the dopaminergic receptors.

One has to concede that the majority of the studies were case–control association studies, which are hampered by many pitfalls.195 A major concern is that the sample size was often very small (below 50 cases) and thus could not provide enough statistical power to detect an effect of minor genes and ethnic stratification between cases and controls would hide spurious associations between a genetic marker and a disorder.

Further, the phenotypes investigated were different from study to study, as persons with suicidal ideation, suicide attempts and completed suicide were investigated. Especially for suicide ideation there is an ongoing discussion as to whether there is a similar genetic component as that demonstrated for suicide attempts and completed suicide. It was even proposed to exclude suicide ideation from the ‘biological’ spectrum of suicidal behaviour196 as the familial transmission of the risk of suicide was not linked to suicidal ideation.197 On the other hand, a study by Statham et al.18 proposed that genetic factors could also affect suicidal ideation, and he estimated that the heritability is 43% for suicidal thoughts. As a consequence of these discrepant findings it was suggested that the existence of a genetic component in suicidal ideation should be tested in separate studies, as even the neurobiological mechanisms might be different from those in suicide acts.10

Suicidal behaviour is a complex disorder and thus the predisposition towards suicide consists of numerous genetic factors, which manifest themselves as suicidal behaviour only when a certain threshold of predisposition is crossed.198 Further, genes interact not only among each other but also with environmental factors, but so far only little attention has been paid to this possible interplay. A positive example in this direction is the study by Caspi et al. who tested why stressful experiences lead to depression in some people but not in others, and the functional 5-HTTLPR was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the S-allele exhibited more depressive symptoms, diagnosable depression and suicidality to stressful life events than individuals being homozygous for the L-allele.199 In the majority of the studies only one single polymorphism in one gene was investigated, thus hardly being able to uncover an interaction between the different factors contributing to the liability for suicidality.

Despite these points of criticism there is no doubt that genetic variants remain one of the multiple factors implicated in the phenomenon of suicide and represent a serious risk factor, in particular when an individual is confronted with stress, such as negative life events and somatic disorders. Thus, further studies are needed to identify more robustly the susceptibility genes using well-characterized suicide phenotypes. Some genetic factors may be related to aggressiveness and impulsivity, which have their effects independently of, or additively to, a mental disorder198 and the link to impulsive-aggressive behaviour should be clarified.


  1. 1

    World Health Organization. World Health Report 2000. Health Systems: Improving Performance. World Health Organization: Geneva, 2000.

  2. 2

    Phillips MR, Li X, Zhang Y . Suicide rates in China, 1995–1999. Lancet 2002; 359: 835–840.

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Bertolote JM, Fleischmann A . Suicidal behavior prevention: WHO perspectives on research. Am J Med Genet C Semin Med Genet 2005; 133: 8–12.

    Google Scholar 

  4. 4

    Suominen K, Isometsa E, Suokas J, Haukka J, Achte K, Lonnqvist J . Completed suicide after a suicide attempt: a 37-year follow-up study. Am J Psychiatry 2004; 161: 562–563.

    PubMed  PubMed Central  Google Scholar 

  5. 5

    Fleischmann A, Bertolote JM, Belfer M, Beautrais A . Completed suicide and psychiatric diagnoses in young people: a critical examination of the evidence. Am J Orthopsychiatry 2005; 75: 676–683.

    PubMed  PubMed Central  Google Scholar 

  6. 6

    Marusic A . History and geography of suicide: could genetic risk factors account for the variation in suicide rates? Am J Med Genet C Semin Med Genet 2005; 133: 43–47.

    Google Scholar 

  7. 7

    Mann JJ . A current perspective of suicide and attempted suicide. Ann Intern Med 2002; 136: 302–311.

    PubMed  Google Scholar 

  8. 8

    Mann JJ, Apter A, Bertolote J, Beautrais A, Currier D, Haas A et al. Suicide prevention strategies: a systematic review. JAMA 2005; 294: 2064–2074.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Zimmerman M, Lish JD, Lush DT, Farber NJ, Plescia G, Kuzma MA . Suicidal ideation among urban medical outpatients. J Gen Intern Med 1995; 10: 573–576.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Courtet P, Jollant F, Castelnau D, Buresi C, Malafosse A . Suicidal behavior: relationship between phenotype and serotonergic genotype. Am J Med Genet C Semin Med Genet 2005; 133: 25–33.

    Google Scholar 

  11. 11

    Leboyer M, Slama F, Siever L, Bellivier F . Suicidal disorders: a nosological entity per se? Am J Med Genet C Semin Med Genet 2005; 133: 3–7.

    Google Scholar 

  12. 12

    Dumais A, Lesage AD, Alda M, Rouleau G, Dumont M, Chawky N et al. Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. Am J Psychiatry 2005; 162: 2116–2124.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Mann JJ . Neurobiology of suicidal behaviour. Nat Rev Neurosci 2003; 4: 819–828.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Baud P . Personality traits as intermediary phenotypes in suicidal behavior: genetic issues. Am J Med Genet C Semin Med Genet 2005; 133: 34–42.

    Google Scholar 

  15. 15

    Turecki G . Dissecting the suicide phenotype: the role of impulsive-aggressive behaviours. J Psychiatry Neurosci 2005; 30: 398–408.

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Brent DA, Mann JJ . Family genetic studies, suicide, and suicidal behavior. Am J Med Genet C Semin Med Genet 2005; 133C: 13–24.

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Roy A . Genetic and biologic risk factors for suicide in depressive disorders. Psychiatr Q 1993; 64: 345–358.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Statham DJ, Heath AC, Madden PA, Bucholz KK, Bierut L, Dinwiddie SH et al. Suicidal behaviour: an epidemiological and genetic study. Psychol Med 1998; 28: 839–855.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Roy A, Segal NL, Sarchiapone M . Attempted suicide among living co-twins of twin suicide victims. Am J Psychiatry 1995; 152: 1075–1076.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    McGuffin P, Marusic A, Farmer A . What can psychiatric genetics offer suicidology? Crisis 2001; 22: 61–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Asberg M, Traskman L, Thoren P . 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Arch Gen Psychiatry 1976; 33: 1193–1197.

    CAS  PubMed  Google Scholar 

  22. 22

    Mann JJ, Malone KM . Cerebrospinal fluid amines and higher-lethality suicide attempts in depressed inpatients. Biol Psychiatry 1997; 41: 162–171.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Virkkunen M, Goldman D, Nielsen DA, Linnoila M . Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence. J Psychiatry Neurosci 1995; 20: 271–275.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Mann JJ, Henteleff RA, Lagattuta TF, Perper JA, Li S, Arango V . Lower 3H-paroxetine binding in cerebral cortex of suicide victims is partly due to fewer high affinity, non-transporter sites. J Neural Transm 1996; 103: 1337–1350.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Arango V, Underwood MD, Gubbi AV, Mann JJ . Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res 1995; 688: 121–133.

    CAS  Google Scholar 

  26. 26

    Malone KM, Corbitt EM, Li S, Mann JJ . Prolactin response to fenfluramine and suicide attempt lethality in major depression. Br J Psychiatry 1996; 168: 324–329.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Meyer JH, McMain S, Kennedy SH, Korman L, Brown GM, DaSilva JN et al. Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am J Psychiatry 2003; 160: 90–99.

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Ordway GA, Widdowson PS, Smith KS, Halaris A . Agonist binding to alpha 2-adrenoceptors is elevated in the locus coeruleus from victims of suicide. J Neurochem 1994; 63: 617–624.

    CAS  PubMed  Google Scholar 

  29. 29

    Ordway GA, Smith KS, Haycock JW . Elevated tyrosine hydroxylase in the locus coeruleus of suicide victims. J Neurochem 1994; 62: 680–685.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Biegon A, Fieldust S . Reduced tyrosine hydroxylase immunoreactivity in locus coeruleus of suicide victims. Synapse 1992; 10: 79–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Hurd YL, Herman MM, Hyde TM, Bigelow LB, Weinberger DR, Kleinman JE . Prodynorphin mRNA expression is increased in the patch vs matrix compartment of the caudate nucleus in suicide subjects. Mol Psychiatry 1997; 2: 495–500.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Sumiyoshi T, Stockmeier CA, Overholser JC, Thompson PA, Meltzer HY . Dopamine D4 receptors and effects of guanine nucleotides on [3 H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major depression. Brain Res 1995; 681: 109–116.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Sher L, Mann JJ, Traskman-Bendz L, Winchel R, Huang YY, Fertuck E et al. Lower cerebrospinal fluid homovanillic acid levels in depressed suicide attempters. J Affect Disord 2006; 190: 83–89.

    Google Scholar 

  34. 34

    Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003; 299: 76.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Zill P, Buttner A, Eisenmenger W, Bondy B, Ackenheil M . Regional mRNA expression of a second tryptophan hydroxylase isoform in postmortem tissue samples of two human brains. Eur Neuropsychopharmacol 2004; 14: 282–284.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Walther DJ, Bader M . A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 2003; 66: 1673–1680.

    CAS  PubMed  Google Scholar 

  37. 37

    Zill P, Buttner A, Eisenmenger W, Moller HJ, Ackenheil M, Bondy B . Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: A post-mortem study. J Psychiatr Res 2005; July 13 [Epub ahead of print].

  38. 38

    Ono H, Shirakawa O, Kitamura N, Hashimoto T, Nishiguchi N, Nishimura A et al. Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls. Mol Psychiatry 2002; 7: 1127–1132.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Bonkale WL, Murdock S, Janosky JE, Austin MC . Normal levels of tryptophan hydroxylase immunoreactivity in the dorsal raphe of depressed suicide victims. J Neurochem 2004; 88: 958–964.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Boldrini M, Underwood MD, Mann JJ, Arango V . More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides. Brain Res 2005; 1041: 19–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Bach-Mizrachi H, Underwood MD, Kassir SA, Bakalian MJ, Sibille E, Tamir H et al. Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology 2005; September 28 [Epub ahead of print].

  42. 42

    De Luca V, Likhodi O, Van Tol HH, Kennedy JL, Wong DF . Gene expression of tryptophan hydroxylase 2 in post-mortem brain of suicide subjects. Int J Neuropsychopharmacol 2005; 8: 1–5.

    Google Scholar 

  43. 43

    Nielsen DA, Dean M, Goldman D . Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. Am J Hum Genet 1992; 51: 1366–1371.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Rotondo A, Schuebel K, Bergen A, Aragon R, Virkkunen M, Linnoila M et al. Identification of four variants in the tryptophan hydroxylase promoter and association to behavior. Mol Psychiatry 1999; 4: 360–368.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M . Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch Gen Psychiatry 1994; 51: 34–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Nielsen DA, Virkkunen M, Lappalainen J, Eggert M, Brown GL, Long JC et al. A tryptophan hydroxylase gene marker for suicidality and alcoholism. Arch Gen Psychiatry 1998; 55: 593–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Roy A, Rylander G, Forslund K, Asberg M, Mazzanti CM, Goldman D et al. Excess tryptophan hydroxylase 17 779C allele in surviving cotwins of monozygotic twin suicide victims. Neuropsychobiology 2001; 43: 233–236.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J . Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients. Am J Psychiatry 1997; 154: 1451–1453.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Souery D, Van GS, Massat I, Blairy S, Adolfsson R, Blackwood D et al. Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study. Biol Psychiatry 2001; 49: 405–409.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Abbar M, Courtet P, Bellivier F, Leboyer M, Boulenger JP, Castelhau D et al. Suicide attempts and the tryptophan hydroxylase gene. Mol Psychiatry 2001; 6: 268–273.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Turecki G, Zhu D, Tzenova J, Lesage AD, Seguin M, Tousignant M et al. TPH and suicidal behaviour: a study in suicide completers. Mol Psychiatry 2001; 6: 98–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Manuck SB, Flory JD, Ferrell RE, Dent KM, Mann JJ, Muldoon MF . Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene. Biol Psychiatry 1999; 45: 603–614.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Rujescu D, Giegling I, Bondy B, Gietl A, Zill P, Moller HJ . Association of anger-related traits with SNPs in the TPH gene. Mol Psychiatry 2002; 7: 1023–1029.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Bennett PJ, McMahon WM, Watabe J, Achilles J, Bacon M, Coon H et al. Tryptophan hydroxylase polymorphisms in suicide victims. Psychiatr Genet 2000; 10: 13–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Du L, Faludi G, Palkovits M, Bakish D, Hrdina PD . Tryptophan hydroxylase gene 218A/C polymorphism is not associated with depressed suicide. Int J Neuropsychopharmacol 2000; 3: 215–220.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Stefulj J, Kubat M, Balija M, Skavic J, Jernej B . Variability of the tryptophan hydroxylase gene: study in victims of violent suicide. Psychiatry Res 2005; 134: 67–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Ono H, Shirakawa O, Nishiguchi N, Nishimura A, Nushida H, Ueno Y et al. Tryptophan hydroxylase gene polymorphisms are not associated with suicide. Am J Med Genet 2000; 96: 861–863.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Ohtani M, Shindo S, Yoshioka N . Polymorphisms of the tryptophan hydroxylase gene and serotonin 1A receptor gene in suicide victims among Japanese. Tohoku J Exp Med 2004; 202: 123–133.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Bellivier F, Leboyer M, Courtet P, Buresi C, Beaufils B, Samolyk D et al. Association between the tryptophan hydroxylase gene and manic-depressive illness. Arch Gen Psychiatry 1998; 55: 33–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC . No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder. Am J Med Genet 1998; 81: 245–247.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Koller G, Engel RR, Preuss UW, Karakesisoglou A, Zill P, Bondy B et al. Tryptophan hydroxylase gene 1 polymorphisms are not associated with suicide attempts in alcohol-dependent individuals. Addict Biol 2005; 10: 269–273.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Zalsman G, Frisch A, King RA, Pauls DL, Grice DE, Gelernter J et al. Case control and family-based studies of tryptophan hydroxylase gene A218C polymorphism and suicidality in adolescents. Am J Med Genet 2001; 105: 451–457.

    CAS  PubMed  Google Scholar 

  63. 63

    Paik I, Toh K, Kim J, Lee C . TPH gene may be associated with suicidal behavior, but not with schizophrenia in the Korean population. Hum Hered 2000; 50: 365–369.

    CAS  Google Scholar 

  64. 64

    Tsai SJ, Hong CJ, Wang YC . Tryptophan hydroxylase gene polymorphism (A218C) and suicidal behaviors. Neuroreport 1999; 10: 3773–3775.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Kunugi H, Ishida S, Kato T, Sakai T, Tatsumi M, Hirose T et al. No evidence for an association of polymorphisms of the tryptophan hydroxylase gene with affective disorders or attempted suicide among Japanese patients. Am J Psychiatry 1999; 156: 774–776.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Lalovic A, Turecki G . Meta-analysis of the association between tryptophan hydroxylase and suicidal behavior. Am J Med Genet 2002; 114: 533–540.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Rujescu D, Giegling I, Sato T, Hartmann AM, Moller HJ . Genetic variations in tryptophan hydroxylase in suicidal behavior: analysis and meta-analysis. Biol Psychiatry 2003; 54: 465–473.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Bellivier F, Chaste P, Malafosse A . Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2004; 124: 87–91.

    Google Scholar 

  69. 69

    Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M . Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 2004; 56: 581–586.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Kennedy MA, Miller AL, Rogers G, Luty S, Mulder R, Joyce P . Polymorphic variants and association analysis of TPH2, brain tryptophan hydroxylase. Neuropsychiatr Genet 2003; 122B: 69.

    Google Scholar 

  71. 71

    De Luca V, Voineskos D, Wong GW, Shinkai T, Rothe C, Strauss J et al. Promoter polymorphism of second tryptophan hydroxylase isoform (TPH2) in schizophrenia and suicidality. Psychiatry Res 2005; 134: 195–198.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Zhou Z, Roy A, Lipsky R, Kuchipudi K, Zhu G, Taubman J et al. Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 2005; 62: 1109–1118.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 2621–2624.

    CAS  Google Scholar 

  74. 74

    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region [see comments]. Science 1996; 274: 1527–1531.

    CAS  Google Scholar 

  75. 75

    Mann JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM et al. A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide (see comments). Arch Gen Psychiatry 2000; 57: 729–738.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Preuss UW, Soyka M, Bahlmann M, Wenzel K, Behrens S, de Jonge S et al. Serotonin transporter gene regulatory region polymorphism (5-HTTLPR), [3H]paroxetine binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity. Psychiatry Res 2000; 96: 51–61.

    CAS  Google Scholar 

  77. 77

    Bondy B, Erfurth A, de Jonge S, Kruger M, Meyer H . Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide. Mol Psychiatry 2000; 5: 193–195.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Courtet P, Baud P, Abbar M, Boulenger JP, Castelnau D, Mouthon D et al. Association between violent suicidal behaviour and the low activity allele of the serotonin transporter gene. Mol Psychiatry 2001; 6: 338–341.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Fitch D, Lesage A, Seguin M, Trousignant M, Bankelfat C, Rouleau GA et al. Suicide and the serotonin transporter gene. Mol Psychiatry 2001; 6: 127–128.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Bellivier F, Szoke A, Henry C, Lacoste J, Bottos C, Nosten-Bertrand M et al. Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders. Biol Psychiatry 2000; 48: 319–322.

    CAS  Google Scholar 

  81. 81

    Bayle FJ, Leroy S, Gourion D, Millet B, Olie JP, Poirier MF et al. 5HTTLPR polymorphism in schizophrenic patients: further support for association with violent suicide attempts. Am J Med Genet B Neuropsychiatr Genet 2003; 119: 13–17.

    Google Scholar 

  82. 82

    Campi-Azevedo AC, Boson W, De ML, Romano-Silva MA, Correa H . Association of the serotonin transporter promoter polymorphism with suicidal behavior. Mol Psychiatry 2003; 8: 899–900.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Courtet P, Buresi C, Abbar M, Baud P, Boulenger JP, Castelnau D et al. No association between non-violent suicidal behavior and the serotonin transporter promoter polymorphism. Am J Med Genet 2003; 116B: 72–76.

    PubMed  PubMed Central  Google Scholar 

  84. 84

    Courtet P, Picot MC, Bellivier F, Torres S, Jollant F, Michelon C et al. Serotonin transporter gene may be involved in short-term risk of subsequent suicide attempts. Biol Psychiatry 2004; 55: 46–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Sander T, Harms H, Dufeu P, Kuhn S, Hoehe M, Lesch KP et al. Serotonin transporter gene variants in alcohol-dependent subjects with dissocial personality disorder. Biol Psychiatry 1998; 43: 908–912.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Gerra G, Garofano L, Santoro G, Bosari S, Pellegrini C, Zaimovic A et al. Association between low-activity serotonin transporter genotype and heroin dependence: behavioral and personality correlates. Am J Med Genet B Neuropsychiatr Genet 2004; 126: 37–42.

    Google Scholar 

  87. 87

    Gerra G, Garofano L, Castaldini L, Rovetto F, Zaimovic A, Moi G et al. Serotonin transporter promoter polymorphism genotype is associated with temperament, personality traits and illegal drugs use among adolescents. J Neural Transm 2005; 112: 1397–1410.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Baca-Garcia E, Vaquero C, az-Sastre C, Saiz-Ruiz J, Fernandez-Piqueras J, de LJ . A gender-specific association between the serotonin transporter gene and suicide attempts. Neuropsychopharmacology 2002; 26: 692–695.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Limosin F, Loze JY, Boni C, Hamon M, Ades J, Rouillon F et al. Male-specific association between the 5-HTTLPR S allele and suicide attempts in alcohol-dependent subjects. J Psychiatr Res 2005; 39: 179–182.

    PubMed  PubMed Central  Google Scholar 

  90. 90

    Gorwood P, Batel P, Ades J, Hamon M, Boni C . Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior. Biol Psychiatry 2000; 48: 259–264.

    CAS  Google Scholar 

  91. 91

    Preuss UW, Koller G, Soyka M, Bondy B . Association between suicide attempts and 5-HTTLPR-S-allele in alcohol-dependent and control subjects: further evidence from a German alcohol-dependent inpatient sample. Biol Psychiatry 2001; 50: 636–639.

    CAS  Google Scholar 

  92. 92

    Baca-Garcia E, Salgado BR, Segal HD, Lorenzo CV, Acosta MN, Romero MA et al. A pilot genetic study of the continuum between compulsivity and impulsivity in females: the serotonin transporter promoter polymorphism. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 713–717.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Rujescu D, Giegling I, Sato T, Moeller HJ . A polymorphism in the promoter of the serotonin transporter gene is not associated with suicidal behavior. Psychiatr Genet 2001; 11: 169–172.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Geijer T, Frisch A, Persson ML, Wasserman D, Rockah R, Michaelovsky E et al. Search for association between suicide attempt and serotonergic polymorphisms. Psychiatr Genet 2000; 10: 19–26.

    CAS  Google Scholar 

  95. 95

    Shen Y, Li H, Gu N, Tan Z, Tang J, Fan J et al. Relationship between suicidal behavior of psychotic inpatients and serotonin transporter gene in Han Chinese. Neurosci Lett 2004; 372: 94–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Chong SA, Lee WL, Tan CH, Tay AH, Chan AO, Tan EC . Attempted suicide and polymorphism of the serotonin transporter gene in Chinese patients with schizophrenia. Psychiatry Res 2000; 97: 101–106.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Zalsman G, Frisch A, Bromberg M, Gelernter J, Michaelovsky E, Campino A et al. Family-based association study of serotonin transporter promoter in suicidal adolescents: no association with suicidality but possible role in violence traits. Am J Med Genet 2001; 105: 239–245.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Russ MJ, Lachman HM, Kashdan T, Saito T, Bajmakovic-Kacila S . Analysis of catechol-O-methyltransferase and 5-hydroxytryptamine transporter polymorphisms in patients at risk for suicide. Psychiatry Res 2000; 93: 73–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Du L, Faludi G, Palkovits M, Demeter E, Bakish D, Lapierre YD et al. Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims. Biol Psychiatry 1999; 46/2: 201.

    Google Scholar 

  100. 100

    Correa H, Campi-Azevedo AC, De ML, Boson W, Viana MM, Guimaraes MM et al. Familial suicide behaviour: association with probands suicide attempt characteristics and 5-HTTLPR polymorphism. Acta Psychiatr Scand 2004; 110: 459–464.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Joiner Jr TE, Johnson F, Soderstrom K . Association between serotonin transporter gene polymorphism and family history of attempted and completed suicide. Suicide Life Threat Behav 2002; 32: 329–332.

    PubMed  PubMed Central  Google Scholar 

  102. 102

    Anguelova M, Benkelfat C, Turecki G . A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 2003; 8: 574–591.

    CAS  PubMed  Google Scholar 

  103. 103

    Lin PY, Tsai G . Association between serotonin transporter gene promoter polymorphism and suicide: results of a meta-analysis. Biol Psychiatry 2004; 55: 1023–1030.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    De Luca V, Zai G, Tharmalingam S, de BA, Wong G, Kennedy JL . Association study between the novel functional polymorphism of the serotonin transporter gene and suicidal behaviour in schizophrenia. Eur Neuropsychopharmacol 2005; November 3 [Epub ahead of print].

  105. 105

    de Lara CL, Dumais A, Rouleau G, Lesage A, Dumont M, Chawky N et al. STin2 variant and family history of suicide as significant predictors of suicide completion in major depression. Biol Psychiatry 2005; August 25 [Epub ahead of print].

  106. 106

    Yen FC, Hong CJ, Hou SJ, Wang JK, Tsai SJ . Association study of serotonin transporter gene VNTR polymorphism and mood disorders, onset age and suicide attempts in a Chinese sample. Neuropsychobiology 2003; 48: 5–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Hranilovic D, Stefulj J, Furac I, Kubat M, Balija M, Jernej B . Serotonin transporter gene promoter (5-HTTLPR) and intron 2 (VNTR) polymorphisms in Croatian suicide victims. Biol Psychiatry 2003; 54: 884–889.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Turecki G, Briere R, Dewar K, Antonetti T, Lesage AD, Seguin M et al. Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry 1999; 156: 1456–1458.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Oquendo MA, Russo SA, Underwood MD, Kassir SA, Ellis SP, Mann JJ et al. Higher postmortem prefrontal 5-HT(2A) receptor binding correlates with lifetime aggression in suicide. Biol Psychiatry 2005; Sep: 1.

    Google Scholar 

  110. 110

    Rao ML, Hawellek B, Papassotiropoulos A, Deister A, Frahnert C . Upregulation of the platelet Serotonin2A receptor and low blood serotonin in suicidal psychiatric patients. Neuropsychobiology 1998; 38: 84–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Alda M, Hrdina PD . Distribution of platelet 5-HT(2A) receptor densities in suicidal and non-suicidal depressives and control subjects. Psychiatry Res 2000; 94: 273–277.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Muller-Oerlinghausen B, Roggenbach J, Franke L . Serotonergic platelet markers of suicidal behavior – do they really exist? J Affect Disord 2004; 79: 13–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Norton N, Owen MJ . HTR2A: association and expression studies in neuropsychiatric genetics. Ann Med 2005; 37: 121–129.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Du L, Bakish D, Lapierre YD, Ravindran A, Hrdina P . Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder. Am J Med Genet Neuropsychiatric Genet 2000; 96: 56–60.

    CAS  Google Scholar 

  115. 115

    Arias B, Gasto C, Catalan R, Gutierrez B, Pintor L, Fananas L . The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients. Am J Med Genet 2001; 105: 801–804.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Preuss UW, Koller G, Bahlmann M, Soyka M, Bondy B . No association between suicidal behavior and 5-HT2A-T102C polymorphism in alcohol dependents. Am J Med Genet 2000; 96: 877–878.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Ertugrul A, Kennedy JL, Masellis M, Basile VS, Jayathilake K, Meltzer HY . No association of the T102C polymorphism of the serotonin 2A receptor gene (HTR2A) with suicidality in schizophrenia. Schizophr Res 2004; 69: 301–305.

    PubMed  PubMed Central  Google Scholar 

  118. 118

    Tan EC, Chong SA, Chan AO, Tan CH . No evidence for association of the T102C polymorphism in the serotonin type 2A receptor with suicidal behavior in schizophrenia. Am J Med Genet 2002; 114: 321–322.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Khait VD, Huang YY, Zalsman G, Oquendo MA, Brent DA, Harkavy-Friedman JM et al. Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects. Neuropsychopharmacology 2005; 30: 166–172.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Correa H, De ML, Boson W, Viana MM, Lima VF, Campi-Azevedo AC et al. Analysis of T102C 5HT2A polymorphism in Brazilian psychiatric inpatients: relationship with suicidal behavior. Cell Mol Neurobiol 2002; 22: 813–817.

    CAS  PubMed  Google Scholar 

  121. 121

    Bonnier B, Gorwood P, Hamon M, Sarfati Y, Boni C, Hardy-Bayle MC . Association of 5-HT(2A) receptor gene polymorphism with major affective disorders: the case of a subgroup of bipolar disorder with low suicide risk. Biol Psychiatry 2002; 51: 762–765.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Ohara K, Nagai M, Tsukamoto T, Tani K, Suzuki Y, Ohara K . 5-HT2A receptor gene promoter polymorphism – 1438G/A and mood disorders. Neuroreport 1998; 9: 1139–1141.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Ono H, Shirakawa O, Nishiguchi N, Nishimura A, Nushida H, Ueno Y et al. Serotonin 2A receptor gene polymorphism is not associated with completed suicide. J Psychiatr Res 2001; 35: 173–176.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Bondy B, Kuznik J, Baghai T, Schule C, Zwanzger P, Minov C et al. Lack of association of serotonin-2A receptor gene polymorphism (T102C) with suicidal ideation and suicide. Am J Med Genet Neuropsychiatr Genet 2000; 96/6: 835.

    Google Scholar 

  125. 125

    Crawford J, Sutherland GR, Goldney RD . No evidence for association of 5-HT2A receptor polymorphism with suicide. Am J Med Genet 2000; 96: 879–880.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Albert PR, Lembo P, Storring JM, Charest A, Saucier C . The 5-HT1A receptor: signaling, desensitization, and gene transcription. Neuropsychopharmacology 1996; 14: 19–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G . Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci 1998; 18: 7394–7401.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Huang YY, Battistuzzi C, Oquendo MA, Harkavy-Friedman J, Greenhill L, Zalsman G et al. Human 5-HT1A receptor C(−1019)G polymorphism and psychopathology. Int J Neuropsychopharmacol 2004; 7: 441–451.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003; 23: 8788–8799.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Albert PR, Lemonde S . 5-HT1A receptors, gene repression, and depression: guilt by association. Neuroscientist 2004; 10: 575–593.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Lemonde S, Du L, Bakish D, Hrdina P, Albert PR . Association of the C(−1019)G 5-HT1A functional promoter polymorphism with antidepressant response. Int J Neuropsychopharmacol 2004; 7: 501–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Nishiguchi N, Shirakawa O, Ono H, Nishimura A, Nushida H, Ueno Y et al. Lack of an association between 5-HT1A receptor gene structural polymorphisms and suicide victims. Am J Med Genet 2002; 114: 423–425.

    PubMed  PubMed Central  Google Scholar 

  133. 133

    Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry 1998; 55: 989–994.

    CAS  Google Scholar 

  134. 134

    Soyka M, Preuss UW, Koller G, Zill P, Bondy B . Association of 5-HT1B receptor gene and antisocial behavior in alcoholism. J Neural Transm 2004; 111: 101–109.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Huang YY, Grailhe R, Arango V, Hen R, Mann JJ . Relationship of psychopathology to the human serotonin1B genotype and receptor binding kinetics in postmortem brain tissue. Neuropsychopharmacology 1999; 21: 238–246.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Rujescu D, Giegling I, Sato T, Moller HJ . Lack of association between serotonin 5-HT1B receptor gene polymorphism and suicidal behavior. Am J Med Genet B Neuropsychiatr Genet 2003; 116: 69–71.

    Google Scholar 

  137. 137

    Stefulj J, Buttner A, Skavic J, Zill P, Balija M, Eisenmenger W et al. Serotonin 1B (5HT-1B) receptor polymorphism (G861C) in suicide victims: association studies in German and Slavic population. Am J Med Genet B Neuropsychiatr Genet 2004; 127: 48–50.

    Google Scholar 

  138. 138

    Nishiguchi N, Shirakawa O, Ono H, Nishimura A, Nushida H, Ueno Y et al. No evidence of an association between 5HT1B receptor gene polymorphism and suicide victims in a Japanese population. Am J Med Genet 2001; 105: 343–345.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Sanders AR, Duan J, Gejman PV . DNA variation and psychopharmacology of the human serotonin receptor 1B (HTR1B) gene. Pharmacogenomics 2002; 3: 745–762.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Hong CJ, Pan GM, Tsai SJ . Association study of onset age, attempted suicide, aggressive behavior, and schizophrenia with a serotonin 1B receptor (A-161T) genetic polymorphism. Neuropsychobiology 2004; 49: 1–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Tsai SJ, Hong CJ, Yu YW, Chen TJ, Wang YC, Lin WK . Association study of serotonin 1B receptor (A-161T) genetic polymorphism and suicidal behaviors and response to fluoxetine in major depressive disorder. Neuropsychobiology 2004; 50: 235–238.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Stefulj J, Buttner A, Kubat M, Zill P, Balija M, Eisenmenger W et al. 5HT-2C receptor polymorphism in suicide victims. Association studies in German and Slavic populations. Eur Arch Psychiatry Clin Neurosci 2004; 254: 224–227.

    PubMed  PubMed Central  Google Scholar 

  143. 143

    Okamura K, Shirakawa O, Nishiguchi N, Ono H, Nushida H, Ueno Y et al. Lack of an association between 5-HT receptor gene polymorphisms and suicide victims. Psychiatry Clin Neurosci 2005; 59: 345–349.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Turecki G, Sequeira A, Gingras Y, Seguin M, Lesage A, Tousignant M et al. Suicide and serotonin: study of variation at seven serotonin receptor genes in suicide completers. Am J Med Genet B Neuropsychiatr Genet 2003; 118: 36–40.

    Google Scholar 

  145. 145

    Charney DS . Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry 1998; 59 (Suppl 14): 11–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Polymeropoulos MH, Xiao H, Rath DS, Merril CR . Tetranucleotide repeat polymorphism at the human tyrosine hydroxylase gene (TH). Nucleic Acids Res 1991; 19: 3753.

    PubMed  PubMed Central  Google Scholar 

  147. 147

    Persson ML, Wasserman D, Geijer T, Jonsson EG, Terenius L . Tyrosine hydroxylase allelic distribution in suicide attempters. Psychiatry Res 1997; 72: 73–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Ma J, Yoshimura M, Yamashita E, Nakagawa A, Ito A, Tsukihara T . Structure of rat monoamine oxidase A and its specific recognitions for substrates and inhibitors. J Mol Biol 2004; 338: 103–114.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Schalling D, Asberg M, Edman G, Oreland L . Markers for vulnerability to psychopathology: temperament traits associated with platelet MAO activity. Acta Psychiatr Scand 1987; 76: 172–182.

    CAS  Google Scholar 

  150. 150

    Skondras M, Markianos M, Botsis A, Bistolaki E, Christodoulou G . Platelet monoamine oxidase activity and psychometric correlates in male violent offenders imprisoned for homicide or other violent acts. Eur Arch Psychiatry Clin Neurosci 2004; 254: 380–386.

    PubMed  PubMed Central  Google Scholar 

  151. 151

    Brunner HG, Nelen MR, van Zandvoort P, Abeling NG, van Gennip AH, Wolters EC et al. X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism [see comments]. Am J Hum Genet 1993; 52: 1032–1039.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Sabol SZ, Hu S, Hamer D . A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998; 103: 273–279.

    CAS  Google Scholar 

  153. 153

    Hotamisligil GS, Breakefield XO . Human monoamine oxidase A gene determines levels of enzyme activity. Am J Hum Genet 1991; 49: 383–392.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Manuck SB, Flory JD, Ferrell RE, Mann JJ, Muldoon MF . A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity. Psychiatry Res 2000; 95: 9–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Garpenstrand H, Norton N, Damberg M, Rylander G, Forslund K, Mattila-Evenden M et al. A regulatory monoamine oxidase a promoter polymorphism and personality traits. Neuropsychobiology 2002; 46: 190–193.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Jonsson EG, Norton N, Gustavsson JP, Oreland L, Owen MJ, Sedvall GC . A promoter polymorphism in the monoamine oxidase A gene and its relationships to monoamine metabolite concentrations in CSF of healthy volunteers. J Psychiatr Res 2000; 34: 239–244.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ et al. Serotonin-related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology 2003; 28: 533–541.

    CAS  Google Scholar 

  158. 158

    Hattori E, Liu C, Zhu H, Gershon ES . Genetic tests of biologic systems in affective disorders. Mol Psychiatry 2005; 10: 719–740.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Ho LW, Furlong RA, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC . Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder. Am J Med Genet 2000; 96: 36–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Gerra G, Garofano L, Bosari S, Pellegrini C, Zaimovic A, Moi G et al. Analysis of monoamine oxidase A (MAO-A) promoter polymorphism in male heroin-dependent subjects: behavioural and personality correlates. J Neural Transm 2004; 111: 611–621.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Kunugi H, Ishida S, Kato T, Tatsumi M, Sakai T, Hattori M et al. A functional polymorphism in the promoter region of monoamine oxidase-A gene and mood disorders. Mol Psychiatry 1999; 4: 393–395.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Ono H, Shirakawa O, Nishiguchi N, Nishimura A, Nushida H, Ueno Y et al. No evidence of an association between a functional monoamine oxidase a gene polymorphism and completed suicides. Am J Med Genet 2002; 114: 340–342.

    PubMed  PubMed Central  Google Scholar 

  163. 163

    Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD . High activity-related allele of MAO-A gene associated with depressed suicide in males. Neuroreport 2002; 13: 1195–1198.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Courtet P, Jollant F, Buresi C, Castelnau D, Mouthon D, Malafosse A . The monoamine oxidase A gene may influence the means used in suicide attempts. Psychiatr Genet 2005; 15: 189–193.

    PubMed  PubMed Central  Google Scholar 

  165. 165

    Ordway GA . Pathophysiology of the locus coeruleus in suicide. Ann NY Acad Sci 1997; 836: 233–252.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM . Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243–250.

    CAS  Google Scholar 

  167. 167

    Koen L, Kinnear CJ, Corfield VA, Emsley RA, Jordaan E, Keyter N et al. Violence in male patients with schizophrenia: risk markers in a South African population. Aust NZ J Psychiatry 2004; 38: 254–259.

    CAS  Google Scholar 

  168. 168

    Strous RD, Nolan KA, Lapidus R, Diaz L, Saito T, Lachman HM . Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study. Am J Med Genet B Neuropsychiatr Genet 2003; 120: 29–34.

    Google Scholar 

  169. 169

    Kotler M, Barak P, Cohen H, Averbuch IE, Grinshpoon A, Gritsenko I et al. Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol-O-methyltransferase (COMT) activity. Am J Med Genet 1999; 88: 628–633.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Liou YJ, Tsai SJ, Hong CJ, Wang YC, Lai IC . Association analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenic patients in Taiwan. Neuropsychobiology 2001; 43: 11–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Nolan KA, Volavka J, Czobor P, Cseh A, Lachman H, Saito T et al. Suicidal behavior in patients with schizophrenia is related to COMT polymorphism. Psychiatr Genet 2000; 10: 117–124.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Ono H, Shirakawa O, Nushida H, Ueno Y, Maeda K . Association between catechol-O-methyltransferase functional polymorphism and male suicide completers. Neuropsychopharmacology 2004; 29: 1374–1377.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    De Luca V, Tharmalingam S, Sicard T, Kennedy JL . Gene-gene interaction between MAOA and COMT in suicidal behavior. Neurosci Lett 2005; 383: 151–154.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Franken IH, Booij J, van den BW . The role of dopamine in human addiction: from reward to motivated attention. Eur J Pharmacol 2005; 526: 199–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Bowirrat A, Oscar-Berman M . Relationship between dopaminergic neurotransmission, alcoholism, and Reward Deficiency syndrome. Am J Med Genet B Neuropsychiatr Genet 2005; 132: 29–37.

    Google Scholar 

  176. 176

    Noble EP . D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet B Neuropsychiatr Genet 2003; 116: 103–125.

    Google Scholar 

  177. 177

    Arinami T, Gao M, Hamaguchi H, Toru M . A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet 1997; 6: 577–582.

    CAS  Google Scholar 

  178. 178

    Johann M, Putzhammer A, Eichhammer P, Wodarz N . Association of the −141C Del variant of the dopamine D2 receptor (DRD2) with positive family history and suicidality in German alcoholics. Am J Med Genet B Neuropsychiatr Genet 2005; 132: 46–49.

    Google Scholar 

  179. 179

    Kluger J . Medicating young minds. Time 2003; 162: 46–48, 58.

  180. 180

    Zalsman G, Frisch A, Lewis R, Michaelovsky E, Hermesh H, Sher L et al. DRD4 receptor gene exon III polymorphism in inpatient suicidal adolescents. J Neural Transm 2004; 111: 1593–1603.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181

    Persson ML, Geijer T, Wasserman D, Rockah R, Frisch A, Michaelovsky E et al. Lack of association between suicide attempt and a polymorphism at the dopamine receptor D4 locus. Psychiatr Genet 1999; 9: 97–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Sequeira A, Mamdani F, Lalovic A, Anguelova M, Lesage A, Seguin M et al. Alpha 2A adrenergic receptor gene and suicide. Psychiatry Res 2004; 125: 87–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Viveros MP, Marco EM, File SE . Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 2005; 81: 331–342.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB et al. Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Mol Psychiatry 2004; 9: 184–190.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

    Baca-Garcia E, Vaquero C, az-Sastre C, Garcia-Resa E, Saiz-Ruiz J, Fernandez-Piqueras J et al. Lack of association between the serotonin transporter promoter gene polymorphism and impulsivity or aggressive behavior among suicide attempters and healthy volunteers. Psychiatry Res 2004; 126: 99–106.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Shindo S, Yoshioka N . Polymorphisms of the cholecystokinin gene promoter region in suicide victims in Japan. Forensic Sci Int 2005; 150: 85–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN . Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 2003; 60: 804–815.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ . Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 2003; 48: 186–189.

    CAS  PubMed  Google Scholar 

  189. 189

    Kunugi H, Hashimoto R, Yoshida M, Tatsumi M, Kamijima K . A missense polymorphism (S205L) of the low-affinity neurotrophin receptor p75NTR gene is associated with depressive disorder and attempted suicide. Am J Med Genet B Neuropsychiatr Genet 2004; 129: 44–46.

    Google Scholar 

  190. 190

    Yanagi M, Shirakawa O, Kitamura N, Okamura K, Sakurai K, Nishiguchi N et al. Association of 14-3-3 epsilon gene haplotype with completed suicide in Japanese. J Hum Genet 2005; 50: 210–216.

    PubMed  PubMed Central  Google Scholar 

  191. 191

    Bunney WE, Bunney BG, Vawter MP, Tomita H, Li J, Evans SJ et al. Microarray technology: a review of new strategies to discover candidate vulnerability genes in psychiatric disorders. Am J Psychiatry 2003; 160: 657–666.

    PubMed  PubMed Central  Google Scholar 

  192. 192

    Gwadry FG, Sequeira A, Hoke G, Ffrench-Mullen JM, Turecki G . Molecular characterization of suicide by microarray analysis. Am J Med Genet C Semin Med Genet 2005; 133: 48–56.

    Google Scholar 

  193. 193

    Detera-Wadleigh SD, McMahon FJ . Genetic association studies in mood disorders: issues and promise. Int Rev Psychiatry 2004; 16: 301–310.

    PubMed  PubMed Central  Google Scholar 

  194. 194

    Serretti A, Artioli P . The pharmacogenomics of selective serotonin reuptake inhibitors. Pharmacogenomics J 2004; 4: 233–244.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    Mann JJ . Psychobiologic predictors of suicide. J Clin Psychiatry 1987; 48 (Suppl): 39–43.

    PubMed  PubMed Central  Google Scholar 

  197. 197

    Brent DA, Bridge J, Johnson BA, Connolly J . Suicidal behavior runs in families. A controlled family study of adolescent suicide victims. Arch Gen Psychiatry 1996; 53: 1145–1152.

    CAS  Google Scholar 

  198. 198

    Balazic J, Marusic A . The completed suicide as interplay of genes and environment. Forensic Sci Int 2005; 147 (Suppl): S1–S3.

    PubMed  PubMed Central  Google Scholar 

  199. 199

    Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386–389.

    CAS  PubMed  Google Scholar 

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A part of the work cited here was supported by the German Federal Research Ministry within the promotional emphasis Competence Nets in Medicine.

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Bondy, B., Buettner, A. & Zill, P. Genetics of suicide. Mol Psychiatry 11, 336–351 (2006).

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  • suicide
  • serotonin
  • genetics
  • polymorphism
  • association studies

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