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 (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
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
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.
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.
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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). https://doi.org/10.1038/sj.mp.4001803
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