Balkan Journal of Medical Genetics

The problem of suicide, both successful suicides and suicide attempts, is very real in a lot of countries. In Russia, the prevalence of suicide is 39.7/100,000 inhabitants per year (World Health Organization, 2001). Risk factors for suicide are composed of genetic and environmental influences. Evidence of genetic involvement comes from studies of family history of suicide, twin and adoptive studies, which has shown that genetic risk factors accounted for approximately 45% of variance in suicidal behavior [1]. Several lines of evidence suggest that a serotonergic dysfunction is involved in biological susceptibility to suicide. There is association between suicide attempts and low levels of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid. This association is reported to be independent of diagnosis. The transduction of serotonergic signals across the neural membrane is mediated by 5‑hydroxytryptamine (5-HT) receptors (HTRs). Alterations in binding kinetics of a number of serotonin receptor subtypes in the brains of suicide victims appear to be independent of psychiatric diagnosis. There is growing evidence suggesting that genes of different serotonin receptors, particularly the serotonin 2A (HTR2A) and 1B (HTR1B) receptors, may play important role in predisposition to suicidal behavior [2-4].

The HTR2A gene (13q14-q21) is a prime candidate as a source of serotonergic dysfunction. Elevation of the density of the serotonin 2A receptor has been demonstrated in the prefrontal cortex in post-mortem brains of suicide victims [4]. HTR2A receptors are also increased on platelets of suicidal patients [5]. Two common polymorphisms in almost complete linkage disequilibrium, a silent nucleotide exchange T102C in the coding region [6] and a base change A/G at position –1438 of the HTR2A upstream promoter region, have been described for HTR2A [7]. The A1438G polymorphism is within a regulatory region of the gene; it could influence the expression of the HTR2A gene and consequently, have an effect on the density of the receptor [8].

There is also evidence that functional variants in the HTR1B receptor gene may contribute to suicidal behavior [9,10]. The HTR1B functions both pre-synaptically as a 5-HT as well as post-synaptically [11]. Impulsive aggressive sexual behavior, and increased alcohol and cocaine intake are reported in some studies of transgenic mice lacking the HTR1B gene and receptor [12,13]. The intron-lacking HTR1B gene, localized to chromosome 6q13, contains two common polymorphisms involving a silent GgC substitution at nucleotide 861 (G861C), and a silent CgT substitution at nucleotide 129 (C129T) of the coding region [14,15]. These polymorphisms were in complete linkage disequilibrium with each other [16]. Huang et al. [16] also demonstrated that the 861C allele may be associated with decreased post-mortem human HTR1B binding in the brain. Lappalainen et al. [17] reported that patients with antisocial alcoholism had a higher C861 allele frequency. Later, New et al. [10] reported an association of the G861 allele to suicide attempts in US Caucasians with personality disorders. However, some authors reported that there was no association between the G861C polymorphism of the HTR1B gene and suicidal behavior [18-20]. Thus, it is still unclear whether the G861C polymorphism of the HTR1B gene is associated with suicide.