Association between TPH1 polymorphisms and the risk of suicide behavior: An updated meta-analysis of 18,398 individuals

Objectives: We aimed to examine the association of TPH1 polymorphisms with the risk of suicide behavior (SB).

Design: Systematic review and meta-analysis.

Method: All relevant studies that evaluated the association between the A218C (rs1800532), A779C (rs1799913) and A6526G (rs4537731) polymorphisms and the susceptibility to SB published up to September 2021 were identified through a comprehensive systematic search in PubMed, Scopus, EBSCO and Science Direct electronic databases. The association between TPH1 gene polymorphisms and SB was evaluated using inherence models by odds ratio (OR) and 95% confidence interval (CI). Subgroup analyses, heterogeneity analyses, and publication bias were also tested in this meta-analysis.

Results: The meta-analysis for TPH1 A218C revealed an increased risk of SB in the dominant model (OR = 1.11, 95%CI 1.01–1.22). We also observed a positive association in the allelic (OR = 1.13, 95%CI 1.05–1.21), homozygous (OR = 1.22, 95%CI 1.06–1.40), heterozygous (OR = 1.21, 95%CI 1.08–1.37) and dominant (OR = 1.21, 95%CI 1.09–1.34) inherence models with the suicide attempt. Additionally, in the heterozygous (OR = 0.84, 95%CI 0.73–0.97) and dominant (OR = 0.79, 95%CI 0.68–0.91) inherence models we detected an association with completed suicide. Based on ethnicity, an association of SB in the European population also was observed (OR = 1.29, 95%CI 1.12–1.51). However, for both A779C and A6526G polymorphisms we did not find evidence of an association with SB.

Conclusion: This meta-analysis suggests that the A218C polymorphism of TPH1 gene could be a possible risk factor of SB. Future large-scale studies are required to analyze the molecular mechanisms by which affect the susceptibility of developing suicide behavior.

Introduction

Human behavior is governed by a complex interplay of numerous biological, genetic, psychological, cultural, social and family determinants. In particular, suicide behavior (SB) ranges from suicide ideation to suicide attempts and completed suicide and constitutes a multifactorial public health issue. The understanding of the genetic system that causes vulnerability to develop SB is largely incomplete, as its etiology is complex and diverse; however, epidemiological studies show that suicide behavior is partly heritable and polygenic (1, 2).

Serotonin, also known as 5-hydroxytryptamine (5-HT), is produced by generating 5-hydroxytryptophan out of tryptophan and the downstream decarboxylation using aromatic amino acid decarboxylase (3). Tryptophan hydroxylase (TPH) is the rate limiting enzyme in the biosynthesis of serotonin. Serotonin is synthesized in the central nervous system (CNS) as well as gastrointestinal system, and it is produced by TPH, which can be present in two isoforms, TPH1 and TPH2 (4, 5).

The serotonergic system is implicated in the etiology and pathogenesis of several psychiatric disorders. Serotonergic pathways associated with mood disorders and SB include the inflammatory processes related to serotonin processing (6). The neuroimmunological kynurenine pathway has been implicated in major depressive disorder and suicide in adults. Kynurenine is formed from its precursor, tryptophan, if kynurenine levels are associated with tryptophan concentrations, these pathways are argued to have the ability to influence levels of serotonin. It has been reported that the kynurenine production is higher among individuals with a history of suicide attempts (1, 7).

The TPH1 gene has been extensively studied as a candidate for suicide behavior due to its role in serotonergic neurotransmission (1, 8). This gene is located on chromosome 11p15.3-p14 and has two common polymorphisms in intron 7 consisting of A for C substitution at nucleotides 779 (A779C; rs1799913) and at 218 (A218C; rs1800532), plus one polymorphism in the promoter region consisting of A for G substitution at nucleotides 6526 (A6526G; rs4537731). These polymorphisms have been associated with suicide for they may influence the level of serotonin metabolites and their functionality (9, 10).

Although one meta-analysis (10) has already addressed the issue of the association between the TPH1 polymorphisms and (11) SB, the sample sizes used were relatively small. Also, in the las years, the TPH1 polymorphisms have been attracting attention and more studies have explored the association of TPH1 polymorphisms and suicide behavior. Therefore, it is important to summarize the results from more studies to further validate the association of TPH1 polymorphisms with the risk of suicide behavior. In this study, a systematic review and updated meta-analysis was performed on all eligible case-control studies to estimate the overall SB risk associated with three polymorphisms of TPH1 gene: A218C, A779C and A6526G. Additionally, we conducted subgroup analyses stratified by ethnicity and diagnostic. The results of this meta-analysis can provide an opportunity to unveil the role that the TPH1 gene plays in the susceptibility to suicide.

Materials and methods

The search strategy follows the PRISMA (http://www.prisma-statement.org/) reporting guidelines.

Search strategy

The following terms were used for searching potential studies: (“suicide” OR “suicidal”) AND (“TPH1” OR “tryptophan hydroxylase 1”). We searched for articles were searched in PubMed, Scopus, EBSCO and Science Direct databases, dated up to September 2021. To find other potential studies, we examined the references of the eligible studies. The process of the study selection in the preset work is detailed in a flow diagram; Figure 1.

FIGURE 1

Figure 1. The flow diagram of study selection.

Eligible inclusion/exclusion criteria

The criteria applied for eligible studies were: 1- studies that evaluated the association between TPH1 A218C, A779C and A6526G polymorphisms and suicide risk, 2- cases-controls designs studies, 3- individuals with a suicidal behavior which identified by a specialist; we included all the suicidal behavior spectrum (attempt, ideation and completed suicide) addressed in the published studies, 4- sufficient data available to obtain genotypic frequencies to calculate odds ratio (OR) and 95% confidence interval (95%CI), 5- articles published in English. These data were not always available for all studies, but when needed, we contacted the authors to clarify the information not included in the papers. Reviews, meta-analysis, duplicates, case reports, book chapters, and animal studies were all excluded.

Data collection

The relevant data from each study were extracted by to reviewers (Hernandez-Díaz and Castillo-Avila) using standardized and structured forms. The following data were extracted: first author, year of publication, country, main outcome, criteria diagnostic, source of DNA, genotyping method, ethnicity, gender, sample size, genotype distribution for the cases and controls. Once encountering discrepancies, other authors re-checked the original articles until an agreement was achieved by all of them.

Assessment of methodological quality

The Newcastle-Ottawa Scale (NOS) was used to examine the quality of each study. Quality scores range from 0 to 9, and higher scores mean better quality of the study. Studies scoring six o higher were considered as high-quality studies. The qualities of the includes studies were evaluated by the same two investigators. Disagreements were resolved through discussion by a third investigator (Gonzalez-Castro).

Statistical analysis

The relationship between TPH1 gene polymorphism and SB risk was determined by calculating OR and 95%CI. To measure this association, we evaluated the effect by five genetic models: allelic (A vs. C), dominant (AA + AC vs. CC), recessive (AA vs. AC + CC), heterozygous (AC vs. CC) and homozygous (AA vs. CC).

Z-test was used to determine the significance of the OR (P < 0.05 was considered statistically significant). Cochrane Q-test and I² test was conducted to assess the between studies heterogeneity. Significant heterogeneity was defined with a P-value < 0.05 and I² ≥ 50% and a random effect model (DerSimonian–Laird) was used in this case. Otherwise, a fixed effect model (Mantel–Haenszel) was applied. Subgroup analysis was used to further identify the factors influencing heterogeneity. Publication bias was assessed by funnel diagram that produces a diagram according to its OR and the standard error of each study, moreover, Egger's test was calculated (P < 0.05 was considered statistically significant). The data were analyzed using Comprehensive Meta-Analysis (CMA) software v.2.

Results

Literature search and study characteristics

A total of 441 potentially relevant studies emerged from the first search in PubMed, EBSCO, Science Direct, Scopus and manual searching. After excluding 351 unrelated publications, we screened 90 publications for eligibility of inclusion. Finally, thirty-six studies met the selection criteria and were finally enrolled for pooled analyses (11–47). The PRISMA flow diagram used for study selection process is summarized in Figure 1.

There were 6,214 cases and 12,184 controls in these 36 studies, 16 studies were conducted in European populations, 13 in Asian populations, 5 in American populations, 1 in Turkish and 1 in mixed populations (USA and Italy). In terms of the SB type, some studies evaluated suicide attempt (n = 27), suicide ideation (n = 1), and completed suicide (n = 8). The age of the individuals studied ranged from 17.4 to 65 years old. There were statistically significant deviations from the HWE in the control groups (n = 3); therefore, these studies were excluded from the meta-analysis.

According to the Newcastle–Ottawa scale, the quality score of each included study was >6, indicating good quality overall. Tables 1, 2 displays the main characteristics and quality assessment results of the eligible studies.

TABLE 1

Table 1. The characteristics of included studies in this meta-analysis for A218C polymorphism.

TABLE 2

Table 2. The characteristics of included studies in this meta-analysis for A779C and A6528G polymorphisms.

TPH1 A218C polymorphism and the risk of SB

Twenty-seven studies (4,917cases and 7,098 controls) assessed the relationship between TPH1 A218C polymorphism and the risk of suicide behavior (12, 14, 19–43, 45–47). The integrated analyses demonstrated that the AA/AC genotypes of A218C polymorphism was significantly associated with an increased risk of SB compared with the CC genotype (OR = 1.11, 95%CI 1.01–1.22; P = 0.026, Q test = 0.212, I² = 19.90) (Figure 2A).

FIGURE 2

Figure 2. Meta-analysis of the association between A218C polymorphism and suicide behavior risk. (A) Forest plot of overall analysis in dominant comparison. (B) Funnel plot of overall analysis in dominant comparison.

Subgroup analyses were then performed based on ethnicity and diagnostic in order to investigate sources of heterogeneity (Table 3). We observed a positive association in the allelic (OR = 1.13, 95%CI 1.05–1.21; P = 0.000, Q test = 0.233, I² = 19.72), homozygous (OR = 1.22, 95%CI 1.06–1.40; n = 0.004, Q test = 0.117, I² = 30.77), heterozygous (OR = 1.21, 95%CI 1.08–1.37; P = 0.001, Q test = 0.186, I² = 23.60) and dominant (OR = 1.21, 95%CI 1.09–1.34; P = 0.000, Q test = 0.175, I² = 24.71) inherence models with the suicide attempt; while a decreased risk of completed suicide was observed in the heterozygous model (OR = 0.84, 95%CI 0.73–0.97; P = 0.023, Q test = 0.153, I² = 33.09) and dominant model (OR = 0.79, 95%CI 0.68–0.91; P = 0.001, Q test = 0.317, I² = 14.38) (Figure 3A). In the subgroup analysis based on ethnicity, A218C was associated with increased SB risk in European populations according to the dominant model (OR = 1.29, 95%CI 1.12–1.51; P = 0.001, Q test = 0.117, I² = 43.22). However, no significant associations were found in Asian populations.

TABLE 3

Table 3. Integrated analyses for TPH1 gene polymorphisms and suicide behavior.

FIGURE 3

Figure 3. Meta-analysis of the association between A218C polymorphism and completed suicide risk. (A) Forest plot of subgroup analysis in dominant comparison. (B) Funnel plot of subgroup analysis in dominant comparison.

TPH1 A779C polymorphism and the risk of SB

Thirteen studies (1,893 cases and 3,103 controls) assessed relationship between TPH1 A779C polymorphism and the risk of suicide behavior (11, 14, 15, 24, 28–30, 32, 33, 35, 44, 46, 47). Overall, we did not observe an association between A779C polymorphisms of TPH1 gene in the allele frequencies or any genotype model with an overall SB risk (Table 3). Either in a subgroup analysis by ethnicity or by diagnostic, no significant SB risk was identified.

TPH1 A6526G polymorphism and the risk of SB

Three case–control studies with 516 patients and 441 controls were included in the present meta-analysis (20, 26, 35). The major outcomes in this study are summarized in Table 3. The TPH1 gene A6526G polymorphism was not significantly associated with suicide behavior under any genetic model.

Publication bias and sensitivity analysis

We estimated potential publication bias in this meta-analysis with funnel plots and Egger's test. Funnel plots were found to be overall symmetrical (Figures 2B, 3B) and the P values for Egger's test were >0.05 in all comparisons (Table 3). These results indicated that our quantitative pooled analysis results were not likely to be seriously influenced by publication biases. We carried out a sensitivity analysis to evaluate the influence of every study on the pooled OR by omitting an individual study at a time. The exclusion of any study did not alter the corresponding pooled OR; P-values demonstrated nonsignificant values ranging from 0.15 to 0.99.

Discussion

This meta-analysis, robustly estimated associations between gene polymorphisms in TPH1 gene and the risk of suicide behavior. Considerable evidence has shown that the TPH1 gene is a possible candidate involved in the etiology of suicide. Although one meta-analyses (10) has been conducted in the past 7 years evaluating the relationship between the TPH1 gene polymorphisms and SB, its findings were inconclusive. Hence, to resolve inconsistencies and to decrease heterogeneity, we performed an updated meta-analysis. Regarding the essential role of genetic factors in the pathogenesis of suicide behavior, we categorized our results according to ethnicity and diagnostic.

First, the pooled analyses results showed that the A218C polymorphism was significantly associated with the risk of SB. The A218C polymorphism was found to be associated with SB in Koreans and Caucasian populations; moreover, A218C has been associated with anger related traits (16, 21, 48). Subgroup analysis based on ethnicity rejected any association between A218C polymorphisms and the SB risk in Asian populations; nonetheless, a significant association between A218C polymorphism and SB susceptibility was detected in European populations. Many reasons might contribute to the conflicting results. First of all, environmental factors that individuals are exposed and different genetic backgrounds, which may have effects on suicide risk. Considering the polygenic effect on psychiatric disorders, the genetic factors that have impacted on the original diseases could share their contributions to suicide as well. In future, large number of case–control studies could provide more evidence for the role of this polymorphism with respect to susceptibility to SB. These findings are consistent with the results of Ono et al. (20), Liu et al. (35) and Abbar et al. (22).

The A218C polymorphism has also been associated with an increased risk of suicide attempt; nonetheless, a protective role was observed in individuals who completed suicide. This polymorphism is localized at intron 7, a site that is a potential GATA transcription factor-binding site. The GATA transcription binding factors allow the initiation of transcription (49). The A218C polymorphism could affect the transcription level of TPH1. The TPH is an initial enzyme in the TRYCATs pathway, and its low expression may lead to stopping the pathway.

The tryptophan (TRY) metabolism has two large pathways: the methoxyindole pathway and the kynurenine pathway. Regarding the available TRYs in the body, approximately 1~5% are synthesized as serotonin through the methoxyindole pathway and 95~99% of TRYs are metabolized through the kynurenine pathway and form tryptophan catabolites (TRYCATs) (50, 51). These TRYCATs are important metabolites that may contribute to the pathophysiology of psychiatric disorders such as anxiety and depression (52). TRYCATs potentiate or antagonize relationships with various neurotransmission systems (53). TRYCATs could influence SB by directly contributing to neuroprotective-neurodegenerative changes in the brain. Activation of the TRYCAT pathway leads to the production of a range of neuroactive, neuroprotective and neurotoxic TRYCATs. For example, quinolinic acid act as potent neurotoxin which inhibit ATP production by mitochondria, provoke disrupt neuron glial communication, induce apoptosis of glial cells and directly damage neurons. Other TRYCATS also possess neurotoxic or neuroprotective properties via pro-oxidant and antioxidant effects (54, 55).

Moreover, this polymorphism could also influence individual differences in anger-related personality traits. Individuals carrying the AA genotype have a reduced capacity of controlling anger expression when they experience this emotion. Conversely, the alternative genotypes (AC and CC) can be considered as “protective” against the tendency to lose control when experiencing anger (39). Therefore, we suggest that suicide attempt and completed suicide could be under genetic control and regulated through capacity to control anger.

The observed differences in susceptibility, between suicide attempt and completed suicide, are likely due to the overall genetic background that modifies the SB prone risk factors. Moreover, this discrepancy in SB risk may be explained by daily lifestyle, geographic climate, dietary habits, ethnic diversity and so on. However, these results should be illustrated prudently and need further confirmation by more trials.

Second, A779C and A6526G polymorphisms were not associated with the risk of suicide behavior. Still, we cannot ignore the interaction between TPH1 and other genes on SB susceptibility, such as TPH2. Therefore, it is necessary to systematically screen for functional variants within the TPH1 gene and other related genes in the SB pathogenesis.

In González-Castro (10) meta-analysis in 2014, our results indicated that the A218C polymorphism was associated with SB, which is consistent with the present study. In comparison with the previous meta-analyses, some advantages of the current study should be addressed. Our study updated the data on TPH1 polymorphism and the risk of SB and analyzed the role A6526G polymorphism on suicide behavior for the first time. Methodological issues were well explored (e.g., publication bias, sensitivity analysis, heterogeneity analysis) in the present work. Last but not least, the present work was carried out with five genetic models and sub-analyses by population and diagnostic subgroups were performed. Suicide attempt and completed suicide were not analyzed in previous meta-analyses.

The current meta-analysis also has some limitations. First, only articles published in English-language journals were included. Second, inter-gene and gene–environment interactions might also influence the accuracy of our outcomes. A lack of the original data restricted further evaluations of the potential inter-gene and gene–environment interactions. Related to, we recognized as a limitation that considerable percent of the studies were performed in some specific population (e.g. Croatian or German), this possible overlap of clinic center and sample population could introduce bias in the outcome. Therefore, the findings should be taken with caution. Finally, in the suicide ideation group, the number of relevant original documents was limited, there was not enough data to identify the relationship between TPH1 and suicide ideation. Moreover, the inclusion of the studies that dealt with only ideation may have increased the heterogeneity of the analyzed data.

Conclusion

The current meta-analysis gives a comprehensive analysis of the available information for the association between the TPH1 polymorphisms and suicide behavior. This meta-analysis revealed a significant association between the A218C polymorphism of TPH1 gene and SB. However, neither in overall population nor in subgroup analysis was found a significant association between A779C and A6526G polymorphisms and SB susceptibility. Therefore, the A218C polymorphism could be considered as one possible risk factor of SB. Further studies that investigate the relative contribution of TPH1 polymorphisms and the mechanisms by which they affect the pathogenesis of SB are required to corroborate these findings.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Author contributions

Conceptualization, investigation, methodology, validation, visualization, roles/writing—original draft, and writing—review and editing: YH-D, TG-C, CT-Z, RC-A, ML-N, MR-M, and AG-M. Data curation: YH-D, TG-C, CT-Z, and RC-A. Formal analysis and resources: TG-C, CT-Z, ML-N, and AG-M. Funding acquisition: YH-D, TG-C, CT-Z, and ML-N. Project administration: YH-D, TG-C, and CT-Z. Software: YH-D, TG-C, and CT-Z. Supervision: CT-Z, RC-A, ML-N, MR-M, and AG-M. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Sadkowski M, Dennis B, Clayden RC, Elsheikh W, Rangarajan S, Dejesus J, et al. The role of the serotonergic system in suicidal behavior. Neuropsychiatr Dis Treat. (2013) 9:1699–716. doi: 10.2147/NDT.S50300

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Mirkovic B, Laurent C, Podlipski MA, Frebourg T, Cohen D, Gerardin P. Genetic association studies of suicidal behavior: a review of the past 10 years, progress, limitations, and future directions. Front Psychiatry. (2016) 7:158. doi: 10.3389/fpsyt.2016.00158

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol. (2003) 66:1673–80. doi: 10.1016/S0006-2952(03)00556-2

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Nakamura K, Hasegawa H. Developmental role of tryptophan hydroxylase in the nervous system. Mol Neurobiol. (2007) 35:45–54. doi: 10.1007/BF02700623

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Swami T, Weber HC. Updates on the biology of serotonin and tryptophan hydroxylase. Curr Opin Endocrinol Diabetes Obes. (2018) 25:12–21. doi: 10.1097/MED.0000000000000383

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Bradley KA, Case JA, Khan O, Ricart T, Hanna A, Alonso CM, et al. The role of the kynurenine pathway in suicidality in adolescent major depressive disorder. Psychiatry Res. (2015) 227:206–12. doi: 10.1016/j.psychres.2015.03.031

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA, et al. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun. (2011) 25:1272–8. doi: 10.1016/j.bbi.2011.05.002

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Arango V, Huang YY, Underwood MD, Mann JJ. Genetics of the serotonergic system in suicidal behavior. J Psychiatr Res. (2003) 37:375–86. doi: 10.1016/S0022-3956(03)00048-7

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Jönsson EG, Goldman D, Spurlock G, Gustavsson JP, Nielsen DA, Linnoila M, et al. Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers. Eur Arch Psychiatry Clin Neurosci. (1997) 247:297–302. doi: 10.1007/BF02922258

PubMed Abstract | CrossRef Full Text | Google Scholar

10. González-Castro TB, Juárez-Rojop I, López-Narváez ML, Tovilla-Zárate CA. Association of TPH-1 and TPH-2 gene polymorphisms with suicidal behavior: a systematic review and meta-analysis. BMC Psychiatry. (2014) 14:196. doi: 10.1186/1471-244X-14-196

PubMed Abstract | CrossRef Full Text | Google Scholar

11. 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. doi: 10.1001/archpsyc.55.7.593

PubMed Abstract | CrossRef Full Text | Google Scholar

12. 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) 55:33–7. doi: 10.1001/archpsyc.55.1.33

PubMed Abstract | CrossRef Full Text | Google Scholar

13. New AS, Gelernter J, Yovell Y, Trestman RL, Nielsen DA, Silverman J, et al. Tryptophan hydroxylase genotype is associated with impulsive-aggression measures: a preliminary study. Am J Med Genet. (1998) 81:13–7. doi: 10.1002/(sici)1096-8628(19980207)81:1<13::aid-ajmg3>3.0.co;2-o

PubMed Abstract | CrossRef Full Text | Google Scholar

14. 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) 156:774–6.

PubMed Abstract | Google Scholar

15. 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) 4:360–8. doi: 10.1038/sj.mp.4000578

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Tsai SJ, Hong CJ, Wang YC. Tryptophan hydroxylase gene polymorphism (A218C) and suicidal behaviors. Neuroreport. (1999) 10:3773–5. doi: 10.1097/00001756-199912160-00010

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Bennett PJ, Mcmahon WM, Watabe J, Achilles J, Bacon M, Coon H, et al. Tryptophan hydroxylase polymorphisms in suicide victims. Psychiatr Genet. (2000) 10:13–7. doi: 10.1097/00041444-200010010-00003

PubMed Abstract | CrossRef Full Text | Google Scholar

18. 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) 3:215–20. doi: 10.1017/S1461145700001954

PubMed Abstract | CrossRef Full Text | Google Scholar

19. 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. doi: 10.1097/00041444-200010010-00004

PubMed Abstract | CrossRef Full Text | Google Scholar

20. 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) 96:861–3. doi: 10.1002/1096-8628(20001204)96:6<861::aid-ajmg34>3.0.co;2-p

PubMed Abstract | CrossRef Full Text | Google Scholar

21. 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) 50:365–9. doi: 10.1159/000022942

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Abbar M, Courtet P, Bellivier F, Leboyer M, Boulenger JP, Castelhau D, et al. Suicide attempts and the tryptophan hydroxylase gene. Mol Psychiatry. (2001) 6:268–73. doi: 10.1038/sj.mp.4000846

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Hong CJ, Tsai SJ, Wang YC. Association between tryptophan hydroxylase gene polymorphism (A218C) and schizophrenic disorders. Schizophr Res. (2001) 49:59–63. doi: 10.1016/S0920-9964(00)00039-6

PubMed Abstract | CrossRef Full Text | Google Scholar

24. 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) 43:233–6. doi: 10.1159/000054895

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Souery D, Van Gestel S, 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) 49:405–9. doi: 10.1016/S0006-3223(00)01043-X

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Turecki G, Zhu Z, Tzenova J, Lesage A, Séguin M, Tousignant M, et al. TPH and suicidal behavior: a study in suicide completers. Mol Psychiatry. (2001) 6:98–102. doi: 10.1038/sj.mp.4000816

PubMed Abstract | CrossRef Full Text | Google Scholar

27. 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) 105:451–7. doi: 10.1002/ajmg.1406

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Rujescu D, Giegling I, Bondy B, Gietl A, Zill P, Möller HJ. Association of anger-related traits with SNPs in the TPH gene. Mol Psychiatry. (2002) 7:1023–9. doi: 10.1038/sj.mp.4001128

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Pooley EC, Houston K, Hawton K, Harrison PJ. Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene (TPH A779C), but not with polymorphisms in five other serotonergic genes. Psychol Med. (2003) 33:775–83. doi: 10.1017/S0033291703007463

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Rujescu D, Giegling I, Sato T, Hartmann AM, Möller HJ. Genetic variations in tryptophan hydroxylase in suicidal behavior: analysis and meta-analysis. Biol Psychiatry. (2003) 54:465–73. doi: 10.1016/S0006-3223(02)01748-1

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Jernej B, Stefulj J, Hranilovic D, Balija M, Skavic J, Kubat M. Intronic polymorphism of tryptophan hydroxylase and serotonin transporter: indication for combined effect in predisposition to suicide. J Neural Transm. (2004) 111:733–8. doi: 10.1007/s00702-003-0114-7

PubMed Abstract | CrossRef Full Text | Google Scholar

32. 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) 202:123–33. doi: 10.1620/tjem.202.123

PubMed Abstract | CrossRef Full Text | Google Scholar

33. 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) 10:269–73. doi: 10.1080/13556210500235276

PubMed Abstract | CrossRef Full Text | Google Scholar

34. 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. doi: 10.1016/j.psychres.2004.04.011

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Liu X, Li H, Qin W, He G, Li D, Shen Y, et al. Association of TPH1 with suicidal behaviour and psychiatric disorders in the Chinese population. J Med Genet. (2006) 43:e4. doi: 10.1136/jmg.2004.029397

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Stefulj J, Kubat M, Balija M, Jernej B. TPH gene polymorphism and aging: indication of combined effect on the predisposition to violent suicide. Am J Med Genet B Neuropsychiatr Genet 141b. (2006) 139–41. doi: 10.1002/ajmg.b.30271

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Viana MM, De Marco LA, Boson WL, Romano-Silva MA, Corrêa H. Investigation of A218C tryptophan hydroxylase polymorphism: association with familial suicide behavior and proband's suicide attempt characteristics. Genes Brain Behav. (2006) 5:340–5. doi: 10.1111/j.1601-183X.2005.00171.x

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Yoon HK, Kim YK. Association between serotonin-related gene polymorphisms and suicidal behavior in depressive patients. Prog Neuropsychopharmacol Biol Psychiatry. (2008) 32:1293–7. doi: 10.1016/j.pnpbp.2008.04.004

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Baud P, Perroud N, Courtet P, Jaussent I, Relecom C, Jollant F, et al. Modulation of anger control in suicide attempters by TPH-1. Genes Brain Behav. (2009) 8:97–100. doi: 10.1111/j.1601-183X.2008.00451.x

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Wilson ST, Stanley B, Brent DA, Oquendo MA, Huang YY, Mann JJ. The tryptophan hydroxylase-1 A218C polymorphism is associated with diagnosis, but not suicidal behavior, in borderline personality disorder. Am J Med Genet B Neuropsychiatr Genet 150b. (2009) 202–8. doi: 10.1002/ajmg.b.30788

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Saetre P, Lundmark P, Wang A, Hansen T, Rasmussen HB, Djurovic S, et al. The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case-control study and meta-analysis. Am J Med Genet B Neuropsychiatr Genet. (2010) 153b:387–96. doi: 10.1002/ajmg.b.30991

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Buttenschøn HN, Flint TJ, Foldager L, Qin P, Christoffersen S, Hansen NF, et al. An association study of suicide and candidate genes in the serotonergic system. J Affect Disord. (2013) 148:291–8. doi: 10.1016/j.jad.2012.12.011

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Beden O, Senol E, Atay S, Ak H, Altintoprak AE, Kiyan GS, et al. TPH1 A218 allele is associated with suicidal behavior in Turkish population. Leg Med. (2016) 21:15–8. doi: 10.1016/j.legalmed.2016.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Pompili M, Gentile G, Scassellati C, Bonvicini C, Innamorati M, Erbuto D, et al. Genetic association analysis of serotonin and signal transduction pathways in suicide attempters from an Italian sample of psychiatric patients. Neurosci Lett. (2017) 656:94–102. doi: 10.1016/j.neulet.2017.07.020

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Choi HY, Kim GE, Kong KA, Lee YJ, Lim WJ, Park SH, et al. Psychological and genetic risk factors associated with suicidal behavior in Korean patients with mood disorders. J Affect Disord. (2018) 235:489–98. doi: 10.1016/j.jad.2018.04.059

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Lee SM, Lee S, Kang WS, Jahng GH, Park HJ, Kim SK, et al. Gray matter volume reductions were associated with TPH1 polymorphisms in depressive disorder patients with suicidal attempts. Psychiatry Investig. (2018) 15:1174–80. doi: 10.30773/pi.2018.11.01

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Pan YF, Zhang JY, Qiu HM, Yu PP, Liu ZZ, Liu BP, et al. Association of polymorphisms in HTR2A, TPH1, and TPH2 genes with attempted suicide in rural China. Psychiatr Genet. (2019) 29:79–85. doi: 10.1097/YPG.0000000000000221

PubMed Abstract | CrossRef Full Text | Google Scholar

48. 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) 124b:87–91. doi: 10.1002/ajmg.b.20015

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Lai TJ, Wu CY, Tsai HW, Lin YM, Sun HS. Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1) and association with bipolar affective disorder in Taiwan. BMC Med Genet. (2005) 6:14. doi: 10.1186/1471-2350-6-14

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Gál EM, Sherman AD. L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res. (1980) 5:223–39. doi: 10.1007/BF00964611

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Kim YK, Jeon SW. Neuroinflammation and the immune-kynurenine pathway in anxiety disorders. Curr Neuropharmacol. (2018) 16:574–82. doi: 10.2174/1570159X15666170913110426

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Kanchanatawan B, Sirivichayakul S, Carvalho AF, Anderson G, Galecki P, Maes M. Depressive, anxiety and hypomanic symptoms in schizophrenia may be driven by tryptophan catabolite (TRYCAT) patterning of IgA and IgM responses directed to TRYCATs. Prog Neuropsychopharmacol Biol Psychiatry. (2018) 80:205–16. doi: 10.1016/j.pnpbp.2017.06.033

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Morris G, Carvalho AF, Anderson G, Galecki P, Maes M. The many neuroprogressive actions of tryptophan catabolites (TRYCATs) that may be associated with the pathophysiology of neuro-immune disorders. Curr Pharm Des. (2016) 22:963–77. doi: 10.2174/1381612822666151215102420

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. (2011) 35:702–21. doi: 10.1016/j.pnpbp.2010.12.017

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Anderson G, Maes M. Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression. Prog Neuropsychopharmacol Biol Psychiatry. (2013) 42:5–19. doi: 10.1016/j.pnpbp.2012.06.014

PubMed Abstract | CrossRef Full Text | Google Scholar