Suicide is an important public health problem and ranks among the top 10 causes of death for individuals of all ages and major depressive disorders (MDD) appeared to confer greater risk for suicide [1, 2]. Suicidal behavior is commonly considered to result from an interaction of genetic, neurobiological, and psychosocial factors. Genetic risk factors are estimated to account for approximately 30% to 40% of the variance in suicidal behavior, however the precise mechanism of the genetic contribution are unknown .
Dysregulation of brain serotonin contributes to many psychiatric disorders. Furthermore, abnormal serotonergic function has frequently been reported in individuals who commit or attempt suicide and is one of the most replicated findings in modern biological psychiatry . For example, low levels of serotonin (5-hydroxytryptamine, 5-HT) have also been observed in suicide victims and 5-HT could play a role in the predisposition to suicide . Tryptophan hydroxylase (TPH), the rate limiting enzyme in the biosynthesis of 5-HT neurotransmission, is a major candidate for genetic association studies in many psychiatric disorders, including suicide [6, 7]. Two genes coding TPH (TPH1 and TPH2) have been differentiated. The human TPH2 gene is located on chromosome 12q15, comprises 11 exons, and covers a region of about 93.5 kilobases (gene accession number: NM_173353). TPH2, rather than TPH1, is preferentially expressed in the brain . TPH2 is neuron-specific and expressed predominantly in serotonergic neurons of the raphe nuclei and in the peripheral myenteric neurons in the gut [9, 10]. The genetic polymorphisms affecting TPH2 gene expression might result in the alteration of physiological processes related to 5-HT. 5-HT is involved in the dysfunction of numerous psychiatric disorders and behavioral traits, such as MDD, suicide, or depression.
To date, nearly five hundred SNPs have been identified in human TPH2, most of them located in non-coding regions of the gene. However, a few functional polymorphisms have been reported. A functional (C1473G) SNP in mouse TPH2 that results in the substitution of Pro447 with Arg447 and leads to decreased serotonin levels in PC12 cells provides direct evidence for TPH2 controls brain serotonin synthesis . Zill et al provides evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MDD and might be a hint on the repeatedly discussed duality of the serotonergic system . The human TPH2 promoter polymorphism rs11178997 impacts on TPH2 expression, which might have implications for the development and function of the serotonergic system in the brain . The TPH2 gene and its 5' upstream region variants (SNPs: rs4448731 and rs4641527) may be involved in the predisposition to suicide in MDD . The core promoter of human TPH2 was localized to the region between -107 and +7, and the segment of +8 to +53 within the 5'-UTR was found to exert a potent inhibitory effect on gene expression at both transcriptional and post-transcriptional levels . The TPH2 C2755A polymorphism may represent a population-specific risk factor for peripartum major depression and anxiety disorder, perhaps by interacting with hormones in Chinese . These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders. Understanding the mechanisms of TPH2 gene polymorphism in suicide attempters may shed light on the neurobiology of the vulnerability to suicidal behavior and reveal potential targets of preventive and therapeutic actions.
In the current study, we investigated another TPH2 polymorphism named rs7305115 at approximately 1077 bp from the 7 exon. To our knowledge, its functionality has not been studied so far. Therefore, the purpose of the present study was to detect possible association between rs7305115 polymorphisms of TPH2 gene and suicide behavior in MDD patients. We performed association and linkage disequilibrium studies on 215 MDD who committed suicide and 215 control MDD patients without suicide behavior. It could be an attempt to examine the association between different components-genetic, environmental, neurobiological, and behavioral of a complex, multivariate and heterogeneous phenomenon.