Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide

Abstract

There is abundant evidence that the serotonin (5-HT) system is modulating mood and several behavioural traits and that disturbances in the regulation of this system can be associated with severe behavioural malfunctions, as aggressive implusive and suicidal behaviour. 1 Recently a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was identified 2 and the presence of one or two short alleles was associated with anxiety-related personality traits 3 and several psychiatric disturbances, such as affective disorder 4 or severe alcohol dependence. 5 With respect to the importance of the 5-HT transporter in serotonergic transmission, we have genotyped the DNA of 58 Caucasian suicide victims (with unknown psychiatric diagnoses) and 110 healthy controls for the biallelic functional polymorphism in the 5-HTTLPR. We found a highly significant increased frequency of suicide victims being carriers of one or two short alleles (Fisher's Exact Test, two sided, P = 0.0003), which suggests that a genetically altered protein function within the serotonergic pathway might be involved in suicidality, independently from the clinical diagnosis. Molecular Psychiatry (2000) 5, 193-195. Disturbances in serotonergic (5-HT) neurotransmission are widely associated with impulsive, violent behaviour, depression and suicidality. 6 Evidence of a decreased serotonergic transmission in depression derives from the clinical observation that symptoms are relieved by drugs that either block 5-HT reuptake and metabolism or otherwise potentiate serotonergic activity. 7 Especially an inverse correlation between impulsive, externally directed aggressive behaviour and the concentration of the main 5-HT metabolite 5-hydroxyindolacetic acid (5-HIAA) in cerebrospinal fluid 8 as well as postmortem results on decreased concentration of serotonin and 5-HIAA in the brainstem of suicide victims 9 were part of the hypothesis that decreased serotonin-related neurotransmission is linked to the pathophysiology of depression and suicide. 10 Postmortem studies reported on altered serotonin transporter in brain samples from persons committing suicide. 11 However, the results of radioligand binding studies have been inconsistent, most probably because of the different ligands used. 12,13 Studies with peripheral models, eg decreased 5-HT concentration in platelets 14 or platelet paroxetine binding studies 15 completed the postmortem findings in patients with suicidality or violent behaviour.Suicide is a multiply determined act and suicidal behaviour might be triggered by several risk factors such as acute psychiatric illness, substance abuse, adverse life events or family crisis. 16 Additionally, there is mounting evidence that genetic factors may be included in the determinants of suicidal behaviour. Clinical studies, which revealed that the risk of suicidal behaviour is increased by the presence of familial suicidality, 16 are supported by recent molecular genetic studies on associations between suicidal behaviour and differe...

Genetics of suicide

“…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 Canadian 79 or American population. 75 In agreement with our results, an association was found between the S-allele and violent suicide attempts of Caucasian bipolar 80 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).…”

Serotonin Transporter: A Potential Substrate in the Biology of Suicide

“…This finding was supported by another group who found that subjects with the ll genotype had significantly higher scores on Beck's Hopelessness Scale and Beck's Scale for Suicide Ideation than subjects with either the ls or ss genotype (Russ et al, 2000). In contrast, three other groups of researchers observed an association between the s allele and violent suicidal behavior, while a fourth found a link between the s allele and the number of lifetime suicide attempts and lethality of the suicidal behavior (Bellivier et al, 2000;Bondy et al, 2000;Gorwood et al, 2000;Courtet et al, 2001).…”

“…Seven of these studies failed to demonstrate any link between suicidal behavior and SERT genotype or 5-HTTLPR allele frequency (Ohara et al, 1998;Chong et al, 2000;Geijer et al, 2000;Ho et al, 2000;Mann et al, 2000;Fitch et al, 2001;Rujescu et al, 2001). The remaining seven studies all found some association, albeit with differing results (Du et al, 1999;Bellivier et al, 2000;Bondy et al, 2000;Gorwood et al, 2000;Russ et al, 2000;Courtet et al, 2001;Baca-Garcia et al, 2002). One study demonstrated a higher frequency of the l allele in depressed suicide victims compared to nonsuicidal controls (Du et al, 1999).…”

“…Although these studies have yielded conflicting results, it is impressive that the four studies that found an association between suicidal behavior or lethality of the behavior and the s form of the 5-HTTLPR were uniform in identifying a subset of attempters or completers that had a similar characteristicFthe use of violent or highly lethal means (Bellivier et al, 2000;Bondy et al, 2000;Gorwood et al, 2000;Courtet et al, 2001). Only one study that distinguished between violent and nonviolent attempters failed to demonstrate any associations (Rujescu et al, 2001).…”

A Gender-Specific Association between the Serotonin Transporter Gene and Suicide Attempts

“…One very small study on completed suicide in depression showed an increase of L subjects (Du et al 1999). Three studies showed an increase of S subjects in attempters: one study in completed suicides (Bondy et al 2000); one study on violent suicide attempts in depressive patients (Bellivier et al 2000), and another on more lethal attempters in alcoholic patients (Gorwood et al 2000). No gender differences were explored in any of these studies.…”