Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Effect of Tryptophan Hydroxylase-2 rs7305115 SNP on suicide attempts risk in major depression

Effect of Tryptophan Hydroxylase-2 rs7305115 SNP on suicide attempts risk in major depression Background: Suicide and major depressive disorders (MDD) are strongly associated, and genetic factors are responsible for at least part of the variability in suicide risk. We investigated whether variation at the tryptophan hydroxylase-2 (TPH2) gene rs7305115 SNP may predispose to suicide attempts in MDD. Methods: We genotyped TPH2 gene rs7305115 SNP in 215 MDD patients with suicide and matched MDD patients without suicide. Differences in behavioral and personality traits according to genotypic variation were investigated by logistic regression analysis. Results: There were no significant differences between MDD patients with suicide and controls in genotypic (AG and GG) frequencies for rs7305115 SNP, but the distribution of AA genotype differed significantly (14.4% vs. 29.3%, p < 0.001). The G-allele frequency was significantly higher in cases than control group (58.1% vs.45.6%, p < 0.001), but the A-allele carrier indicated a decreased trend in MDD with suicide behaviors than control group (41.9% vs.54.4%, p < 0.001). The multivariate logistic regression analysis indicated that TPH2 rs7305115 AA (OR 0.33, 95% CI 0.22-0.99), family history of suicide (OR 2.98, 95% CI 1.17-5.04), negative life events half year ago (OR 6.64, 95% CI 2.48-11.04) and hopelessness (OR 7.68, 95% CI 5.79-13.74) were significantly associated with the suicide behaviors in MDD patients. Conclusions: The study suggested that hopelessness, negative life events and family history of suicide were risk factors of attempted suicide in MDD while the TPH2 rs7305115A remained a significant protective predictor of suicide attempts. Background who commit or attempt suicide and is one of the most Suicide is an important public health problem and ranks replicated findings in modern biological psychiatry [4]. amongthe top 10causesofdeathfor individualsofall For example, low levels of serotonin (5-hydroxytrypta- ages and major depressive disorders (MDD) appeared to mine, 5-HT) have also been observed in suicide victims confer greater risk for suicide [1,2]. Suicidal behavior is and 5-HT could play a role in the predisposition to sui- commonly considered to result from an interaction of cide [5]. Tryptophan hydroxylase (TPH), the rate limiting genetic, neurobiological, and psychosocial factors. enzyme in the biosynthesis of 5-HT neurotransmission, Genetic risk factors are estimated to account for is a major candidate for genetic association studies in approximately 30% to 40% of the variance in suicidal many psychiatric disorders, including suicide [6,7]. Two behavior, however the precise mechanism of the genetic genes coding TPH (TPH1 and TPH2) have been differen- contribution are unknown [3]. tiated. The human TPH2 gene is located on chromosome Dysregulation of brain serotonin contributes to many 12q15, comprises 11 exons, and covers a region of about psychiatric disorders. Furthermore, abnormal serotoner- 93.5 kilobases (gene accession number: NM_173353). gic function has frequently been reported in individuals TPH2, rather than TPH1, is preferentially expressed in the brain [8]. TPH2 is neuron-specific and expressed pre- * Correspondence: hbzcs@126.com dominantly in serotonergic neurons of the raphe nuclei † Contributed equally and in the peripheral myenteric neurons in the gut Wuxi Psychiatric Hospital, Nanjing Medical University, Wuxi, China [9,10]. The genetic polymorphisms affecting TPH2 gene Full list of author information is available at the end of the article © 2010 Zhang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 2 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 expression might result in the alteration of physiological Materials and methods processes related to 5-HT. 5-HT is involved in the dys- Patients and controls function of numerous psychiatric disorders and beha- The sample investigated consisted of 430 unrelated vioral traits, such as MDD, suicide, or depression. MDD patients who were recruited from Mar 2004 to To date, nearly five hundred SNPs have been identi- May 2008 in the Han nationality of Shandong Province, fied in human TPH2, most of them located in non- China. All patients (184 males, 246 females) hospitalized coding regions of the gene. However, a few functional in psychiatric clinics in Shandong, China. Diagnosis of polymorphisms have been reported. A functional MDD should be confirmed by the Mini International (C1473G) SNP in mouse TPH2 that results in the sub- Neuropsychiatric Interview and by a minimum score of stitution of Pro447 with Arg447 and leads to decreased Hamilton Depression Rating Scale (HDRS) [17,18]. All serotonin levels in PC12 cells provides direct evidence cases met DSM-IV diagnostic criteria for MDD and for TPH2 controls brain serotonin synthesis [11]. Zill were severe enough to require follow-up in a specialized et al provides evidence for an involvement of genetic psychiatric outpatient clinic [19,20]. Axis I and Axis II variants of the TPH2 gene in the pathogenesis of psychopathologies were determined using the Structured MDD and might be a hint on the repeatedly discussed Clinical Interview for DSM-IV Axis I Disorders (SCID-I) duality of the serotonergic system [12]. The human and the Structured Clinical Interview for DSM-IV Per- TPH2 promoter polymorphism rs11178997 impacts on sonality Disorders (SCID-II), respectively. The SCID was TPH2 expression, which might have implications for administered to all patient subjects by experienced psy- the development and function of the serotonergic sys- chiatrists. By means of structured questionnaires, infor- teminthe brain[13]. TheTPH2geneand its 5 ’ mation on specific demographic and clinical variables, upstream region variants (SNPs: rs4448731 and such as family history of suicide and history of physical rs4641527) may be involved in the predisposition to or sexual abuse, was also obtained. suicide in MDD [14]. The core promoter of human Two hundred and fifteen MDD patients (defined as TPH2 was localized to the region between -107 and MDD+suicide group, 92 males, and 123 females) conse- +7, and the segment of +8 to +53 within the 5’-UTR cutively admitted to our psychiatric departments after a was found to exert a potent inhibitory effect on gene suicide were included in this study. The suicide patient expression at both transcriptional and post-transcrip- was defined as intentional self-harm to end one’s life tional levels [15]. The TPH2 C2755A polymorphism but not die as a result of his/her action(s). Individuals may represent a population-specific risk factor for were scored as positive for a history of suicide attempt peripartum major depression and anxiety disorder, per- only when medical records documented a severe haps by interacting with hormones in Chinese [16]. attempt, a relative or partner con- firmed the history, or These results may open up new research strategies for there was physical evidence confirming the history. We the analysis of the observed disturbances in the seroto- classified suicide methods as violent or nonviolent nergic system in patients suffering from several other according to the classification used in previous study psychiatric disorders. Understanding the mechanisms [21]. Drug overdose, carbon monoxide poisoning, and of TPH2 gene polymorphism in suicide attempters drowning were considered nonviolent. All other meth- may shed light on the neurobiology of the vulnerability ods were classified as violent. to suicidal behavior and reveal potential targets of pre- Two hundred and fifteen MDD control patients ventive and therapeutic actions. (defined as MDD-suicide group, 92 males, and 123 In the current study, we investigated another TPH2 females) without suicide attempt, which were closely polymorphism named rs7305115 at approximately matched with individual patients in the suicidal group 1077 bp from the 7 exon. To our knowledge, its func- in terms of age and gender, were selected for this study. tionality has not been studied so far. Therefore, the They met all the DSM-IV criteria for major depressive purpose of the present study was to detect possible disorder and had HDRS scored of over 18. They had no association between rs7305115 polymorphisms of previous history of suicide attempt or family history of TPH2 gene and suicide behavior in MDD patients. We suicide. The other exclusion criteria included evidence performed association and linkage disequilibrium stu- of alcohol or drug dependency, significant organic brain dies on 215 MDD who committed suicide and 215 disease, and clinically significant somatic disease. control MDD patients without suicide behavior. It All cases and control subjects were the Han popula- could be an attempt to examine the association tion and came from the same geographical area in east- between different components-genetic, environmental, ern China. The protocol of the study was in accordance neurobiological, and behavioral of a complex, multi- with the ethics standards of the committee on Human variate and heterogeneous phenomenon. Experimentation of Nanjing Medical University. Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 3 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 Genotyping Table 1 Demographic Characteristics of the MDD patients with suicide and MDD patients without suicide Venous blood was drawn and immediately frozen in ali- quots at -70°C or below until analyzed. For genotyping, MDD+suicide MDD-suicide p value genomic DNA was extracted from EDTA blood samples Sex (males/females) 92/123 92/123 by using a commercial DNA extract kit, Wizard Geno- Age 15 ~ 75 15 ~ 77 0.721 (years, mean ± SD) (33.4 ± 11.9) (33.6 ± 10.8) mic DNA purification kit (Promega, Madison, WI, Age of onset 14 ~ 75 15 ~ 76 0.565 USA). TPH2 rs7305115 SNP genotyping was performed (years, mean ± SD) (28.4 ± 10.3) (29.4 ± 10.7) by DNA sequencing. First, DNA was amplified by poly- Course of disease 2 weeks ~ 25 years 2 weeks ~ 29 years 0.935 merase chain reaction (PCR). PCR were carried out in (years, mean ± SD) (3.43 ± 4.52) (3.39 ± 4.54) 25 ul volumes containing 20 ng genomic DNA, 0.4 mM HDRS scores 51.19 ± 10.61 49.87 ± 10.49 0.079 primers, 50 mM KCL, 10 mM Tris/HCl (pH 8.3), HDRS, Hamilton depression rating scale for depression 0.025% Tween 20, 0.025 mg/ml BSA, 1.5 mM magne- sium chloride, 0.4 mM dNTP and 1 U Taq polymerase deep cuts. No statistically significant differences were with the following oligonucleotide primers: forward observed between the MDD+suicide and MDD-suicide 5 ’-ACCTGAGCCCACGAGACTTT-3 ’; reverse 5 ’- groups for age, age at onset, course of disease or HDRS TCGAGCCAGAGCTGGAATAT-3 ’. After an initial scores. denaturation step for 5 min at 94°C, 35 cycles of dena- turing at 94°C for 30 s, annealing at 55°C for 30 s and Genotypes and allele frequencies in the TPH2 extension of 72°C for 30 s were performed, followed by rs7305115 polymorphisms a final extension step of 72°C for 5 min. After it had A total of 430 unrelated, major depression patients with been amplified, the 312 bp PCR products was subjected and without suicide behaviors were genotyped for the to direct sequencing on an ABI 3700 automated DNA TPH2 rs7305115 polymorphisms. The distributions of sequencer using a Dye Terminator Cycle sequencing kit both TPH2 polymorphisms in MDD+suicide and MDD- (Applied Biosystems, Foster City, CA). suicide were in agreement with the Hardy-Weinberg equilibrium (HWE) applying the HWSIM computer pro- Statistical analysis gram http://krunch.med.yale.edu/hwsim. The distribu- The differences in genotype distributions between tions of genotypes for TPH2 rs7305115 polymorphisms patients and controls and the Hardy-Weinberg equili- did not deviate from HWE in MDD with or without sui- brium (HWE) of each marker were analyzed using a cide groups (Table 2). Homozygous genotypes were chi-square test. Differences in age and age of onset identified by the presence of GG and AA, but the AG between three groups were calculated with t-test. Allelic for heterozygous genotype (Figure 1). In the total and genotypic frequency distributions were compared between groups by chi-square tests for independence. The univariate and multivariate logistic regression ana- lyses were performed to evaluate the unique contribu- Table 2 Distribution of genotypes and allele frequencies tion of identified risk factors in the prediction of suicide of TPH2 rs7305115 polymorphism behaviors. Possible interactions between genetic variants MDD MDD- P value OR and other risk factors were also investigated using logis- +suicide suicide (95%CI) tic regression analyses. Odds ratio (OR) values and 95% (n = 215) (n = 215) confidence intervals (CI) were calculated. The results Genotype (N, %) < 0.001 – were considered nominally significant at the level of p < AA 31 (14.4%) 63 (29.3%) 0.05. The SPSS package (version 13.0 for Windows; AG 118 108 (54.9%) (50.2%) SPSS, Chicago, Illinois) was used for statistical analyses. GG 66 (30.7%) 44 (20.5%) Genotype (N, %) < 0.001 0.406 Results AA 31 (14.4%) 63 (29.3%) (0.251- Clinical characteristics of patients 0.657) The demographic and clinical characteristics of the AG+GG 184 152 patients are presented in Table 1. The study population (85.6%) (70.7%) consisted of 215 MDD+suicide (mean age ± SD, 33.4 ± Allele (N, %) < 0.001 0.603 11.9 years) and 215 matched MDD-suicide (mean age ± A 180 234 (0.461- SD, 33.6 ± 10.8 years). For MDD+suicide group, one (41.9%) (54.4%) 0.790) hundred and seventy-one patients (79.5%) suicided by G 250 196 (58.1%) (45.6%) drug overdose, hanging, drowning and 44 patients (20.5%) suicided by violent methods such as several MDD+suicide vs. MDD-suicide, Pearson chi-square test. Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 4 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 Figure 1 Schematic representation of TPH2 rs7305115 SNP. Arrows represent homozygous genotypes GG (A), AA (B) and heterozygous genotype AG (C) of TPH2 rs7305115 SNP investigated in this study. sample, there were no significant differences between impairment and hopelessness were associated with MDD+suicide and MDD-suicide in genotypic (AG and TPH2 rs7305115 genotypes among MDD+suicide (p = GG) frequencies for TPH2 rs7305115 polymorphisms. 0.035 and p = 0.032). The patients with AA genotype But the distribution of AA genotype differed signifi- indicated lower HDRS scores for cognitive impairment cantly between MDD-suicideand MDD+suicidegroups (mean ± SD, 7.90 ± 3.97) and hopelessness (mean ± SD, (29.3% vs.14.4%, p < 0.001). Meanwhile, the distribution 9.60 ± 2.12) factors than AG and GG groups in MDD of AA genotype was significantly lower than AG+GG with suicide behaviors. This suggested that the TPH2 group in MDD+suicide groups (14.4% vs. 85.6%, p < rs7305115 AA could be a significant protective predictor 0.001). The allele distributions of both A and G was sig- for suicide behaviors. nificant differences between MDD+suicide and MDD-suicide in our sample. The G-allele frequency in Table 3 Genotypes of TPH2 rs7305115 polymorphism MDD+suicide was higher than MDD-suicide (58.1% and HDRS scores in MDD+suicide group (scores, mean ± vs.45.6%, p < 0.001), but the A-allele carrier indicated a SD) decreased trend in MDD with suicide behaviors by com- Genotype P pared with MDD-suicide group (41.9% vs.54.4%, value p < 0.001). We suggested that the presence of the A- AA AG GG allele was a significant predictor for suicide behaviors Anxiety/ l2.83 ± 4.03 l2.11 ± 3.72 l2.01 ± 3.83 0.113 because of the low frequency of the AA genotype in Somatization MDD+suicide group. Loss of weight 1.81 ± 0.54 1.78 ± 0.54 1.55 ± 0.48 0.832 Cognitive 7.90 ± 3.97 10.05 ± 4.23 10.93 ± 3.82 0.035 impairment Genotypes of TPH2 rs7305115 polymorphism and Diurnal change 1.76 ± 1.27 1.67 ± 1.26 1.45 ± 0.97 0.223 HDRS scores in MDD+suicide group Slow movement 10.23 ± 2.41 9.15 ± 2.33 9.38 ± 2.75 0.468 We determined the genotypes of TPH2 rs7305115 poly- Sleep disorders 5.61 ± 0.66 5.24 ± 0.71 5.60 ± 0.85 0.176 morphism and HDRS scores in MDD+suicide group Hopelessness 9.60 ± 2.12 11.57 ± 1.80 11.29 ± 2.10 0.032 (Table 3). The TPH2 rs7305115 SNP was not associated HDRS scores in sum 49.80 ± 51.49 ± 52.28 ± 0.092 with HDRS scores in sum for MDD+suicide (p = 0.092). l0.57 l0.71 l0.83 But, we found that HDRS scores of cognitive Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 5 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 Predictors for the suicide behaviors in MDD patients p < 0.001) were at lower risk for suicide attempts. The To investigate the predictive power of AA genotype of TPH2 polymorphism emerged as a significant variable TPH2 rs7305115 polymorphisms, a univariate logistic that could reliably predict clinical suicide behaviors. regression analysis was performed to examine the pre- Significant risk factors were entered into a forward dictive effect of each factor on the risk for behaviors in selection multivariate logistic regression analysis. The MDD patients (Table 4). The 36 potential risk factors involvement of sixteen factors in MDD+suicide was ana- for MDD+suicide group were compared with those of lyzed using multiple logistic regression analysis. Using MDD-suicide group. Compared with the AG and GG this model, the degree of involvement of each factor for groups, the AA group (OR = 0.50, 95% CI = 0.31-0.82, suicide patients could be estimated (Table 5). On multi- variate analysis, the final model indicated that TPH2 rs7305115 AA (OR 0.33, 95% CI 0.22-0.99, P < 0.001), Table 4 Results from univariate logistic regression family history of suicide (OR 2.98, 95% CI 1.17-5.04, P < analysis i.e., OR, 95% CI, Wald statistic, and probability 0.001), negative life events half year ago (OR 6.64, 95% values for predictor variables of MDD suicide behaviors CI 2.48-11.04, P < 0.001) and hopelessness (OR 7.68, Variables OR 95% CI Wald P value 95% CI 5.79-13.74, P < 0.001) were significantly asso- Education under middle school 2.39 1.62-3.52 19.705 0.000 ciated with the suicide behaviors in MDD patients. The Married 0.20 0.12-0.32 46.600 0.000 TPH2 rs7305115A remained a significant protective pre- Age of onset (= ≥ 35 years) 0.79 0.54-1.17 1.407 0.236 dictor of suicide behaviors. Short course of diseases (= ≤ 1 year) 0.83 0.57-1.21 0.943 0.332 Further, we examined the interactions between TPH2 Employed 0.67 0.45-1.00 3.809 0.051 genotypes and the potential three factors on the risk for Family history of Mental illness 0.94 0.64-1.39 0.086 0.769 MDD+suicide group (Table 6). The results indicated Onset abruptly or subacute 1.13 0.76-1.68 0.366 0.545 that family history of suicide, negative life events half Predisposing factors 1.15 0.78-1.72 0.500 0.479 year ago and hopelessness were significantly associated Unhappy childhood 1.12 0.70-1.80 0.233 0.650 with TPH2 genotypes in MDD+suicide patients (p = Family history of suicide 2.58 1.47-4.54 11.328 0.001 0.006, p = 0.005, and p = 0.002, respectively). Physical disease 1.15 0.69-1.93 0.279 0.597 Monthly income (= < $40) 2.02 1.37-2.99 7.892 0.005 Discussion Smoking 1.64 1.02-2.65 4.164 0.041 Suicide receives increasing attention worldwide, with Drinking 1.64 1.07-2.53 5.178 0.023 many countries developing national strategies for pre- Introversion 1.90 1.25-2.87 9.155 0.002 vention. Rates of suicide vary greatly between countries, Economic pressure 2.58 1.64-4.05 17.434 0.000 with the greatest burdens in developing countries [22]. Unhappy a month ago 0.96 0.65-1.42 0.040 0.841 Most people who die by suicide have psychiatric disor- Unhappy a year ago 1.14 0.76-1.72 0.397 0.529 ders, notably mood, substance-related, anxiety, psycho- Unhappy after a year 0.87 0.60-1.31 0.362 0.547 tic, and personality disorders, with comorbidity being Friend suicide two weeks ago 1.11 0.46-2.66 0.050 0.823 common [23]. Risk for suicide may have genetic contri- Friend suicide a year ago 1.22 0.60-2.49 0.295 0.587 butions, however, specific genes or relevant DNA Negative life events half year ago 5.74 3.28- 43.365 0.000 sequence variations have not yet been identified [24]. 10.04 Therefore, it is a major research challenge to clarify the Family emotional support needed 0.43 0.26-0.72 10.587 0.001 relative heritability of the risk for suicide, in particular, Family emotional support gained 1.06 0.72-1.55 0.086 0.769 separately from the heritability of disorders or traits that Friends’ emotional support needed 0.38 0.24-0.60 16.025 0.000 are strongly associated with suicidal risk [25]. Friends’ emotional support gained 1.06 0.72-1.55 0.084 0.772 a The rate-limiting enzyme of serotonin biosynthesis, Depression (HDRS = ≥ 35) 1.58 1.07-2.34 5.227 0.020 a TPH2, is one of the most promising candidate genes for Hopelessness (HDRS = ≥ 6) 7.68 4.99- 93.755 0.000 psychiatric disorders [26]. In the present study, we 11.83 Anxiety/Somatization(HDRS = > 7) 0.84 0.56-1.27 0.706 0.401 Loss of weight in a week(= 0.5 kg) 0.93 0.64-1.36 0.149 0.699 a Table 5 Results from multivariate logistic regression Cognitive impairment(HDRS = > 12) 1.17 0.77-1.78 0.553 0.457 analysis for predictor variables of MDD+suicide group Diurnal change (HDRS = ≥ 1) 1.12 0.76-1.66 0.350 0.554 a Variables OR 95% CI Wald P value Slow movement (HDRS = ≥ 8) 1.12 1.77-4.64 0.340 0.560 TPH2 rs7305115 AA 0.33 0.22-0.99 12.861 0.000 Sleep disorders (HDRS = ≥ 2) 3.28 2.20-4.88 35.128 0.000 Family history of suicide 2.98 1.17-5.04 10.228 0.001 Anxiety (HAMA = ≥ 21) 4.12 2.54-6.68 35.622 0.000 Negative life events half year ago 6.64 2.48-11.04 41.145 0.000 TPH2 rs7305115 AA 0.50 0.31-0.82 13.941 0.000 Hopelessness (HDRS > = 6) 7.68 5.79-13.74 90.235 0.000 HDRS, Hamilton depression rating scale for depression; b a HAMA, Hamilton anxiety scale for anxiety HDRS, Hamilton depression rating scale for depression Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 6 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 Table 6 Association analysis of TPH2 genotypes and predictor variables in MDD+suicide group Genotype (N) P value AA (n = 31) AG (n = 118) GG (n = 66) Family history of suicide 0.006 Yes 5 45 33 No 26 73 33 Negative life events half year ago 0.005 Yes 10 51 42 No 21 67 24 Hopelessness 0.002 Yes 17 86 58 No 14 32 8 Pearson chi-square test. investigated TPH2 rs7305115 variants in a Han sample of Limitations suicide attempters, and compared them to non-suicidal A number of limitations may be relevant to these studies. depressed patients. We also investigated the association First, we only paid attention on a SNP maker of the TPH2 of polymorphisms with the life environment factors gene in the current study. More TPH2 marker will be among suicide patients. The issue of association of TPH2 examined for MDD patients with suicide behaviors in the SNPs with suicide-related behavior is a complex and con- future study. Further, we had no the detail mechanistic troversial one. Several studies have indicated possible explanation regarding the role of serotonin functioning in associations between various TPH2 polymorphisms and depression for TPH2 SNP. Further study is needed to elu- major depression, suicidal behavior [12,27]. In contrast, cidate its mechanism. Understanding why the vulnerability other studies failed to find associations between TPH2 to suicide differs among MDD patients could assist in polymorphisms and suicidality [28,29]. Nevertheless, we improved screening of high risk patients and treatment. foundanassociationofsuicidal behavior with the TPH2 rs7305115 SNP in the present study. Our data shows that Conclusions MDD+suicide patients have low frequencies of the In case-control association studies, our findings sug- rs7305115 A-allele and AA genotypes (OR = 0.50). gested that the rs7305115 SNP in the TPH2 gene could Studies indicated that a history of suicide attempt, a be a marker for the genetic susceptibility to suicide- psychiatric condition such as ongoing major depression, related traits in Chinese. The TPH SNP might influence alcohol or other substance use disorder, hopelessness, suicide-related traits in behaviorally extreme populations separation or loss, anger, and suicidal ideation have and included an independent high risk clinical sample, been implicated as predictors of suicidal behaviors suicide attempters. We suggested that TPH2 gene could [30,31]. The MDD patients with greater levels of hope- regulate serotonergic system and contribute to the vul- lessness also were prone to the multiple suicide attempts nerability to suicidal behavior. [32]. Our findings indicated that cognitive impairment and hopelessness were associated with TPH2 rs7305115 Abbreviations SNP among MDD+suicide patients. DSM: The Diagnostic and Statistical Manual of Mental Disorders; HDRS: The multivariate analysis indicated that four factors Hamilton Depression Rating Scale; SCID-I: Structured Clinical Interview for DSM-IV Axis I Disorders; SCID-II: Structured Clinical Interview for DSM-IV (TPH2, family history of suicide, negative life events half Personality Disorders; 5-HT: 5-hydroxytryptamine; TPH2: the tryptophan year ago and hopelessness) were significantly associated hydroxylase-2; MDD: major depressive disorders; HWE: Hardy-Weinberg with the suicide behaviors in MDD patients. The TPH2 equilibrium. rs7305115 AA remained a significant protective predic- Acknowledgements tor of suicide behaviors (OR = 0.33). The results sug- This research was supported by the “333 Project” of Jiangsu province, China gested that A®G mutation carriers of TPH2 rs7305115 (No. CA051001-6; WZD0605; CSZ00721) and Science and Technology Planning Project of Changzhou Municipality, China (No. CS2008214). SNP could be a higher risk of suicide attempts than AA homozygous genotype carriers in MDD patients. To Author details 1 2 identify the functional locus, it will be important to clo- Wuxi Psychiatric Hospital, Nanjing Medical University, Wuxi, China. Ankang Hospital, Jining, China. Clinical Oncology Laboratory, Changzhou Tumor sely evaluate the significance of sequence variants in Hospital, Medical College of Suzhou University, Changzhou, China. coding regions that could alter gene expression at the Department of Molecular Epidemiology, Shantou University Medical DNA or RNA levels. College, Shantou, China. Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 7 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 18. Williams JB: A structured interview guide for the Hamilton Depression Authors’ contributions Rating Scale. Arch Gen Psychiatry 1988, 45:742-747. JY, ZC, and CL carried out the molecular genetic studies, participated in the 19. Baca-Garcia E, Perez-Rodriguez MM, Basurte-Villamor I, Fernandez del sequence alignment and drafted the manuscript. QL, GW, GS, YC, YL, and KL Moral AL, Jimenez-Arriero MA, Gonzalez de Rivera JL, Saiz-Ruiz J, recruited the Subjects. CZ and GY participated in the design of the study Oquendo MA: Diagnostic stability of psychiatric disorders in clinical and performed the statistical analysis. YZ conceived of the study, and practice. Br J Psychiatry 2007, 190:210-216. participated in its design and coordination and helped to draft the 20. Spitzer RL, Wakefield JC: DSM-IV diagnostic criterion for clinical manuscript. All authors read and approved the final manuscript. significance: does it help solve the false positives problem? Am J Psychiatry 1999, 156:1856-1864. Competing interests 21. Denning DG, Conwell Y, King D, Cox C: Method choice, intent, and The authors declare that they have no competing interests. gender in completed suicide. Suicide Life Threat Behav 2000, 30:282-288. Received: 25 June 2010 Accepted: 25 August 2010 22. Wasserman D, Terenius L, Wasserman J, Sokolowski M: The 2009 Nobel Published: 25 August 2010 conference on the role of genetics in promoting suicide prevention and the mental health of the population. Mol Psychiatry 2010, 15:12-17. 23. Hawton K, van Heeringen K: Suicide. Lancet 2009, 373:1372-1381. References 24. Brezo J, Klempan T, Turecki G: The genetics of suicide: a critical review of 1. Li X, Xiao Z, Xiao S: Suicide among the elderly in mainland China. molecular studies. Psychiatr Clin North Am 2008, 31:179-203. Psychogeriatrics 2009, 9:62-66. 25. Bondy B, Buettner A, Zill P: Genetics of suicide. Mol Psychiatry 2006, 2. Witte TK, Timmons KA, Fink E, Smith AR, Joiner TE: Do major depressive 11:336-351. disorder and dysthymic disorder confer differential risk for suicide? J 26. Invernizzi RW: Role of TPH-2 in brain function: news from behavioral and Affect Disord 2009, 115:69-78. pharmacologic studies. J Neurosci Res 2007, 85:3030-3035. 3. Roy A, Sarchiopone M, Carli V: Gene-environment interaction and suicidal 27. Zhou Z, Roy A, Lipsky R, Kuchipudi K, Zhu G, Taubman J, Enoch MA, behavior. J Psychiatr Pract 2009, 15:282-288. Virkkunen M, Goldman D: Haplotype-based linkage of tryptophan 4. Arango V, Huang YY, Underwood MD, Mann JJ: Genetics of the hydroxylase 2 to suicide attempt, major depression, and cerebrospinal serotonergic system in suicidal behavior. J Psychiatr Res 2003, 37:375-386. fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 5. Anguelova M, Benkelfat C, Turecki G: A systematic review of association 2005, 62:1109-1118. studies investigating genes coding for serotonin receptors and the 28. De Luca V, Mueller DJ, Tharmalingam S, King N, Kennedy JL: Analysis of serotonin transporter: II. Suicidal behavior. Mol Psychiatry 2003, 8:646-653. the novel TPH2 gene in bipolar disorder and suicidality. Mol Psychiatry 6. Savelieva KV, Zhao S, Pogorelov VM, Rajan I, Yang Q, Cullinan E, 2004, 9:896-897. Lanthorn TH: Genetic disruption of both tryptophan hydroxylase genes 29. De Luca V, Voineskos D, Wong GW, Shinkai T, Rothe C, Strauss J, dramatically reduces serotonin and affects behavior in models sensitive Kennedy JL: Promoter polymorphism of second tryptophan hydroxylase to antidepressants. PLoS One 2008, 3:e3301. isoform (TPH2) in schizophrenia and suicidality. Psychiatry Res 2005, 7. Mann JJ: Role of the serotonergic system in the pathogenesis of major 134:195-198. depression and suicidal behavior. Neuropsychopharmacology 1999, 30. Oquendo MA, Galfalvy H, Russo S, Ellis SP, Grunebaum MF, Burke A, 21:99S-105S. Mann JJ: Prospective study of clinical predictors of suicidal acts after a 8. Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M: major depressive episode in patients with major depressive disorder or Synthesis of serotonin by a second tryptophan hydroxylase isoform. bipolar disorder. Am J Psychiatry 2004, 161:1433-1441. Science 2003, 299:76. 31. Beevers CG, Miller IW: Perfectionism, cognitive bias, and hopelessness as 9. Patel PD, Pontrello C, Burke S: Robust and tissue-specific expression of prospective predictors of suicidal ideation. Suicide Life Threat Behav 2004, TPH2 versus TPH1 in rat raphe and pineal gland. Biol Psychiatry 2004, 34:126-137. 55:428-433. 32. Esposito C, Spirito A, Boergers J, Donaldson D: Affective, behavioral, and 10. Cote F, Thevenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA, Bayard E, cognitive functioning in adolescents with multiple suicide attempts. Hanoun N, Saurini F, Lechat P, et al: Disruption of the nonneuronal tph1 Suicide Life Threat Behav 2003, 33:389-399. gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci USA 2003, 100:13525-13530. doi:10.1186/1744-9081-6-49 11. Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG: Cite this article as: Zhang et al.: Effect of Tryptophan Hydroxylase-2 Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science rs7305115 SNP on suicide attempts risk in major depression. Behavioral 2004, 305:217. and Brain Functions 2010 6:49. 12. Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R, Moller HJ, Bondy B, Ackenheil M: SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 2004, 9:1030-1036. 13. Scheuch K, Lautenschlager M, Grohmann M, Stahlberg S, Kirchheiner J, Zill P, Heinz A, Walther DJ, Priller J: Characterization of a functional promoter polymorphism of the human tryptophan hydroxylase 2 gene in serotonergic raphe neurons. Biol Psychiatry 2007, 62:1288-1294. 14. Lopez de Lara C, Brezo J, Rouleau G, Lesage A, Dumont M, Alda M, Benkelfat C, Turecki G: Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression. Biol Psychiatry 2007, 62:72-80. Submit your next manuscript to BioMed Central 15. Chen GL, Vallender EJ, Miller GM: Functional characterization of the and take full advantage of: human TPH2 5’ regulatory region: untranslated region and polymorphisms modulate gene expression in vitro. Hum Genet 2008, 122:645-657. • Convenient online submission 16. Lin YM, Ko HC, Chang FM, Yeh TL, Sun HS: Population-specific functional • Thorough peer review variant of the TPH2 gene 2755C > A polymorphism contributes risk association to major depression and anxiety in Chinese peripartum • No space constraints or color figure charges women. Arch Womens Ment Health 2009, 12:401-408. • Immediate publication on acceptance 17. Leung CM, Wing YK, Kwong PK, Lo A, Shum K: Validation of the Chinese- • Inclusion in PubMed, CAS, Scopus and Google Scholar Cantonese version of the hospital anxiety and depression scale and comparison with the Hamilton Rating Scale of Depression. Acta Psychiatr • Research which is freely available for redistribution Scand 1999, 100:456-461. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Effect of Tryptophan Hydroxylase-2 rs7305115 SNP on suicide attempts risk in major depression

Loading next page...
 
/lp/springer-journals/effect-of-tryptophan-hydroxylase-2-rs7305115-snp-on-suicide-attempts-Hml45H71Xg
Publisher
Springer Journals
Copyright
Copyright © 2010 by Zhang et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
eISSN
1744-9081
DOI
10.1186/1744-9081-6-49
pmid
20738857
Publisher site
See Article on Publisher Site

Abstract

Background: Suicide and major depressive disorders (MDD) are strongly associated, and genetic factors are responsible for at least part of the variability in suicide risk. We investigated whether variation at the tryptophan hydroxylase-2 (TPH2) gene rs7305115 SNP may predispose to suicide attempts in MDD. Methods: We genotyped TPH2 gene rs7305115 SNP in 215 MDD patients with suicide and matched MDD patients without suicide. Differences in behavioral and personality traits according to genotypic variation were investigated by logistic regression analysis. Results: There were no significant differences between MDD patients with suicide and controls in genotypic (AG and GG) frequencies for rs7305115 SNP, but the distribution of AA genotype differed significantly (14.4% vs. 29.3%, p < 0.001). The G-allele frequency was significantly higher in cases than control group (58.1% vs.45.6%, p < 0.001), but the A-allele carrier indicated a decreased trend in MDD with suicide behaviors than control group (41.9% vs.54.4%, p < 0.001). The multivariate logistic regression analysis indicated that TPH2 rs7305115 AA (OR 0.33, 95% CI 0.22-0.99), family history of suicide (OR 2.98, 95% CI 1.17-5.04), negative life events half year ago (OR 6.64, 95% CI 2.48-11.04) and hopelessness (OR 7.68, 95% CI 5.79-13.74) were significantly associated with the suicide behaviors in MDD patients. Conclusions: The study suggested that hopelessness, negative life events and family history of suicide were risk factors of attempted suicide in MDD while the TPH2 rs7305115A remained a significant protective predictor of suicide attempts. Background who commit or attempt suicide and is one of the most Suicide is an important public health problem and ranks replicated findings in modern biological psychiatry [4]. amongthe top 10causesofdeathfor individualsofall For example, low levels of serotonin (5-hydroxytrypta- ages and major depressive disorders (MDD) appeared to mine, 5-HT) have also been observed in suicide victims confer greater risk for suicide [1,2]. Suicidal behavior is and 5-HT could play a role in the predisposition to sui- commonly considered to result from an interaction of cide [5]. Tryptophan hydroxylase (TPH), the rate limiting genetic, neurobiological, and psychosocial factors. enzyme in the biosynthesis of 5-HT neurotransmission, Genetic risk factors are estimated to account for is a major candidate for genetic association studies in approximately 30% to 40% of the variance in suicidal many psychiatric disorders, including suicide [6,7]. Two behavior, however the precise mechanism of the genetic genes coding TPH (TPH1 and TPH2) have been differen- contribution are unknown [3]. tiated. The human TPH2 gene is located on chromosome Dysregulation of brain serotonin contributes to many 12q15, comprises 11 exons, and covers a region of about psychiatric disorders. Furthermore, abnormal serotoner- 93.5 kilobases (gene accession number: NM_173353). gic function has frequently been reported in individuals TPH2, rather than TPH1, is preferentially expressed in the brain [8]. TPH2 is neuron-specific and expressed pre- * Correspondence: hbzcs@126.com dominantly in serotonergic neurons of the raphe nuclei † Contributed equally and in the peripheral myenteric neurons in the gut Wuxi Psychiatric Hospital, Nanjing Medical University, Wuxi, China [9,10]. The genetic polymorphisms affecting TPH2 gene Full list of author information is available at the end of the article © 2010 Zhang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 2 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 expression might result in the alteration of physiological Materials and methods processes related to 5-HT. 5-HT is involved in the dys- Patients and controls function of numerous psychiatric disorders and beha- The sample investigated consisted of 430 unrelated vioral traits, such as MDD, suicide, or depression. MDD patients who were recruited from Mar 2004 to To date, nearly five hundred SNPs have been identi- May 2008 in the Han nationality of Shandong Province, fied in human TPH2, most of them located in non- China. All patients (184 males, 246 females) hospitalized coding regions of the gene. However, a few functional in psychiatric clinics in Shandong, China. Diagnosis of polymorphisms have been reported. A functional MDD should be confirmed by the Mini International (C1473G) SNP in mouse TPH2 that results in the sub- Neuropsychiatric Interview and by a minimum score of stitution of Pro447 with Arg447 and leads to decreased Hamilton Depression Rating Scale (HDRS) [17,18]. All serotonin levels in PC12 cells provides direct evidence cases met DSM-IV diagnostic criteria for MDD and for TPH2 controls brain serotonin synthesis [11]. Zill were severe enough to require follow-up in a specialized et al provides evidence for an involvement of genetic psychiatric outpatient clinic [19,20]. Axis I and Axis II variants of the TPH2 gene in the pathogenesis of psychopathologies were determined using the Structured MDD and might be a hint on the repeatedly discussed Clinical Interview for DSM-IV Axis I Disorders (SCID-I) duality of the serotonergic system [12]. The human and the Structured Clinical Interview for DSM-IV Per- TPH2 promoter polymorphism rs11178997 impacts on sonality Disorders (SCID-II), respectively. The SCID was TPH2 expression, which might have implications for administered to all patient subjects by experienced psy- the development and function of the serotonergic sys- chiatrists. By means of structured questionnaires, infor- teminthe brain[13]. TheTPH2geneand its 5 ’ mation on specific demographic and clinical variables, upstream region variants (SNPs: rs4448731 and such as family history of suicide and history of physical rs4641527) may be involved in the predisposition to or sexual abuse, was also obtained. suicide in MDD [14]. The core promoter of human Two hundred and fifteen MDD patients (defined as TPH2 was localized to the region between -107 and MDD+suicide group, 92 males, and 123 females) conse- +7, and the segment of +8 to +53 within the 5’-UTR cutively admitted to our psychiatric departments after a was found to exert a potent inhibitory effect on gene suicide were included in this study. The suicide patient expression at both transcriptional and post-transcrip- was defined as intentional self-harm to end one’s life tional levels [15]. The TPH2 C2755A polymorphism but not die as a result of his/her action(s). Individuals may represent a population-specific risk factor for were scored as positive for a history of suicide attempt peripartum major depression and anxiety disorder, per- only when medical records documented a severe haps by interacting with hormones in Chinese [16]. attempt, a relative or partner con- firmed the history, or These results may open up new research strategies for there was physical evidence confirming the history. We the analysis of the observed disturbances in the seroto- classified suicide methods as violent or nonviolent nergic system in patients suffering from several other according to the classification used in previous study psychiatric disorders. Understanding the mechanisms [21]. Drug overdose, carbon monoxide poisoning, and of TPH2 gene polymorphism in suicide attempters drowning were considered nonviolent. All other meth- may shed light on the neurobiology of the vulnerability ods were classified as violent. to suicidal behavior and reveal potential targets of pre- Two hundred and fifteen MDD control patients ventive and therapeutic actions. (defined as MDD-suicide group, 92 males, and 123 In the current study, we investigated another TPH2 females) without suicide attempt, which were closely polymorphism named rs7305115 at approximately matched with individual patients in the suicidal group 1077 bp from the 7 exon. To our knowledge, its func- in terms of age and gender, were selected for this study. tionality has not been studied so far. Therefore, the They met all the DSM-IV criteria for major depressive purpose of the present study was to detect possible disorder and had HDRS scored of over 18. They had no association between rs7305115 polymorphisms of previous history of suicide attempt or family history of TPH2 gene and suicide behavior in MDD patients. We suicide. The other exclusion criteria included evidence performed association and linkage disequilibrium stu- of alcohol or drug dependency, significant organic brain dies on 215 MDD who committed suicide and 215 disease, and clinically significant somatic disease. control MDD patients without suicide behavior. It All cases and control subjects were the Han popula- could be an attempt to examine the association tion and came from the same geographical area in east- between different components-genetic, environmental, ern China. The protocol of the study was in accordance neurobiological, and behavioral of a complex, multi- with the ethics standards of the committee on Human variate and heterogeneous phenomenon. Experimentation of Nanjing Medical University. Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 3 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 Genotyping Table 1 Demographic Characteristics of the MDD patients with suicide and MDD patients without suicide Venous blood was drawn and immediately frozen in ali- quots at -70°C or below until analyzed. For genotyping, MDD+suicide MDD-suicide p value genomic DNA was extracted from EDTA blood samples Sex (males/females) 92/123 92/123 by using a commercial DNA extract kit, Wizard Geno- Age 15 ~ 75 15 ~ 77 0.721 (years, mean ± SD) (33.4 ± 11.9) (33.6 ± 10.8) mic DNA purification kit (Promega, Madison, WI, Age of onset 14 ~ 75 15 ~ 76 0.565 USA). TPH2 rs7305115 SNP genotyping was performed (years, mean ± SD) (28.4 ± 10.3) (29.4 ± 10.7) by DNA sequencing. First, DNA was amplified by poly- Course of disease 2 weeks ~ 25 years 2 weeks ~ 29 years 0.935 merase chain reaction (PCR). PCR were carried out in (years, mean ± SD) (3.43 ± 4.52) (3.39 ± 4.54) 25 ul volumes containing 20 ng genomic DNA, 0.4 mM HDRS scores 51.19 ± 10.61 49.87 ± 10.49 0.079 primers, 50 mM KCL, 10 mM Tris/HCl (pH 8.3), HDRS, Hamilton depression rating scale for depression 0.025% Tween 20, 0.025 mg/ml BSA, 1.5 mM magne- sium chloride, 0.4 mM dNTP and 1 U Taq polymerase deep cuts. No statistically significant differences were with the following oligonucleotide primers: forward observed between the MDD+suicide and MDD-suicide 5 ’-ACCTGAGCCCACGAGACTTT-3 ’; reverse 5 ’- groups for age, age at onset, course of disease or HDRS TCGAGCCAGAGCTGGAATAT-3 ’. After an initial scores. denaturation step for 5 min at 94°C, 35 cycles of dena- turing at 94°C for 30 s, annealing at 55°C for 30 s and Genotypes and allele frequencies in the TPH2 extension of 72°C for 30 s were performed, followed by rs7305115 polymorphisms a final extension step of 72°C for 5 min. After it had A total of 430 unrelated, major depression patients with been amplified, the 312 bp PCR products was subjected and without suicide behaviors were genotyped for the to direct sequencing on an ABI 3700 automated DNA TPH2 rs7305115 polymorphisms. The distributions of sequencer using a Dye Terminator Cycle sequencing kit both TPH2 polymorphisms in MDD+suicide and MDD- (Applied Biosystems, Foster City, CA). suicide were in agreement with the Hardy-Weinberg equilibrium (HWE) applying the HWSIM computer pro- Statistical analysis gram http://krunch.med.yale.edu/hwsim. The distribu- The differences in genotype distributions between tions of genotypes for TPH2 rs7305115 polymorphisms patients and controls and the Hardy-Weinberg equili- did not deviate from HWE in MDD with or without sui- brium (HWE) of each marker were analyzed using a cide groups (Table 2). Homozygous genotypes were chi-square test. Differences in age and age of onset identified by the presence of GG and AA, but the AG between three groups were calculated with t-test. Allelic for heterozygous genotype (Figure 1). In the total and genotypic frequency distributions were compared between groups by chi-square tests for independence. The univariate and multivariate logistic regression ana- lyses were performed to evaluate the unique contribu- Table 2 Distribution of genotypes and allele frequencies tion of identified risk factors in the prediction of suicide of TPH2 rs7305115 polymorphism behaviors. Possible interactions between genetic variants MDD MDD- P value OR and other risk factors were also investigated using logis- +suicide suicide (95%CI) tic regression analyses. Odds ratio (OR) values and 95% (n = 215) (n = 215) confidence intervals (CI) were calculated. The results Genotype (N, %) < 0.001 – were considered nominally significant at the level of p < AA 31 (14.4%) 63 (29.3%) 0.05. The SPSS package (version 13.0 for Windows; AG 118 108 (54.9%) (50.2%) SPSS, Chicago, Illinois) was used for statistical analyses. GG 66 (30.7%) 44 (20.5%) Genotype (N, %) < 0.001 0.406 Results AA 31 (14.4%) 63 (29.3%) (0.251- Clinical characteristics of patients 0.657) The demographic and clinical characteristics of the AG+GG 184 152 patients are presented in Table 1. The study population (85.6%) (70.7%) consisted of 215 MDD+suicide (mean age ± SD, 33.4 ± Allele (N, %) < 0.001 0.603 11.9 years) and 215 matched MDD-suicide (mean age ± A 180 234 (0.461- SD, 33.6 ± 10.8 years). For MDD+suicide group, one (41.9%) (54.4%) 0.790) hundred and seventy-one patients (79.5%) suicided by G 250 196 (58.1%) (45.6%) drug overdose, hanging, drowning and 44 patients (20.5%) suicided by violent methods such as several MDD+suicide vs. MDD-suicide, Pearson chi-square test. Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 4 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 Figure 1 Schematic representation of TPH2 rs7305115 SNP. Arrows represent homozygous genotypes GG (A), AA (B) and heterozygous genotype AG (C) of TPH2 rs7305115 SNP investigated in this study. sample, there were no significant differences between impairment and hopelessness were associated with MDD+suicide and MDD-suicide in genotypic (AG and TPH2 rs7305115 genotypes among MDD+suicide (p = GG) frequencies for TPH2 rs7305115 polymorphisms. 0.035 and p = 0.032). The patients with AA genotype But the distribution of AA genotype differed signifi- indicated lower HDRS scores for cognitive impairment cantly between MDD-suicideand MDD+suicidegroups (mean ± SD, 7.90 ± 3.97) and hopelessness (mean ± SD, (29.3% vs.14.4%, p < 0.001). Meanwhile, the distribution 9.60 ± 2.12) factors than AG and GG groups in MDD of AA genotype was significantly lower than AG+GG with suicide behaviors. This suggested that the TPH2 group in MDD+suicide groups (14.4% vs. 85.6%, p < rs7305115 AA could be a significant protective predictor 0.001). The allele distributions of both A and G was sig- for suicide behaviors. nificant differences between MDD+suicide and MDD-suicide in our sample. The G-allele frequency in Table 3 Genotypes of TPH2 rs7305115 polymorphism MDD+suicide was higher than MDD-suicide (58.1% and HDRS scores in MDD+suicide group (scores, mean ± vs.45.6%, p < 0.001), but the A-allele carrier indicated a SD) decreased trend in MDD with suicide behaviors by com- Genotype P pared with MDD-suicide group (41.9% vs.54.4%, value p < 0.001). We suggested that the presence of the A- AA AG GG allele was a significant predictor for suicide behaviors Anxiety/ l2.83 ± 4.03 l2.11 ± 3.72 l2.01 ± 3.83 0.113 because of the low frequency of the AA genotype in Somatization MDD+suicide group. Loss of weight 1.81 ± 0.54 1.78 ± 0.54 1.55 ± 0.48 0.832 Cognitive 7.90 ± 3.97 10.05 ± 4.23 10.93 ± 3.82 0.035 impairment Genotypes of TPH2 rs7305115 polymorphism and Diurnal change 1.76 ± 1.27 1.67 ± 1.26 1.45 ± 0.97 0.223 HDRS scores in MDD+suicide group Slow movement 10.23 ± 2.41 9.15 ± 2.33 9.38 ± 2.75 0.468 We determined the genotypes of TPH2 rs7305115 poly- Sleep disorders 5.61 ± 0.66 5.24 ± 0.71 5.60 ± 0.85 0.176 morphism and HDRS scores in MDD+suicide group Hopelessness 9.60 ± 2.12 11.57 ± 1.80 11.29 ± 2.10 0.032 (Table 3). The TPH2 rs7305115 SNP was not associated HDRS scores in sum 49.80 ± 51.49 ± 52.28 ± 0.092 with HDRS scores in sum for MDD+suicide (p = 0.092). l0.57 l0.71 l0.83 But, we found that HDRS scores of cognitive Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 5 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 Predictors for the suicide behaviors in MDD patients p < 0.001) were at lower risk for suicide attempts. The To investigate the predictive power of AA genotype of TPH2 polymorphism emerged as a significant variable TPH2 rs7305115 polymorphisms, a univariate logistic that could reliably predict clinical suicide behaviors. regression analysis was performed to examine the pre- Significant risk factors were entered into a forward dictive effect of each factor on the risk for behaviors in selection multivariate logistic regression analysis. The MDD patients (Table 4). The 36 potential risk factors involvement of sixteen factors in MDD+suicide was ana- for MDD+suicide group were compared with those of lyzed using multiple logistic regression analysis. Using MDD-suicide group. Compared with the AG and GG this model, the degree of involvement of each factor for groups, the AA group (OR = 0.50, 95% CI = 0.31-0.82, suicide patients could be estimated (Table 5). On multi- variate analysis, the final model indicated that TPH2 rs7305115 AA (OR 0.33, 95% CI 0.22-0.99, P < 0.001), Table 4 Results from univariate logistic regression family history of suicide (OR 2.98, 95% CI 1.17-5.04, P < analysis i.e., OR, 95% CI, Wald statistic, and probability 0.001), negative life events half year ago (OR 6.64, 95% values for predictor variables of MDD suicide behaviors CI 2.48-11.04, P < 0.001) and hopelessness (OR 7.68, Variables OR 95% CI Wald P value 95% CI 5.79-13.74, P < 0.001) were significantly asso- Education under middle school 2.39 1.62-3.52 19.705 0.000 ciated with the suicide behaviors in MDD patients. The Married 0.20 0.12-0.32 46.600 0.000 TPH2 rs7305115A remained a significant protective pre- Age of onset (= ≥ 35 years) 0.79 0.54-1.17 1.407 0.236 dictor of suicide behaviors. Short course of diseases (= ≤ 1 year) 0.83 0.57-1.21 0.943 0.332 Further, we examined the interactions between TPH2 Employed 0.67 0.45-1.00 3.809 0.051 genotypes and the potential three factors on the risk for Family history of Mental illness 0.94 0.64-1.39 0.086 0.769 MDD+suicide group (Table 6). The results indicated Onset abruptly or subacute 1.13 0.76-1.68 0.366 0.545 that family history of suicide, negative life events half Predisposing factors 1.15 0.78-1.72 0.500 0.479 year ago and hopelessness were significantly associated Unhappy childhood 1.12 0.70-1.80 0.233 0.650 with TPH2 genotypes in MDD+suicide patients (p = Family history of suicide 2.58 1.47-4.54 11.328 0.001 0.006, p = 0.005, and p = 0.002, respectively). Physical disease 1.15 0.69-1.93 0.279 0.597 Monthly income (= < $40) 2.02 1.37-2.99 7.892 0.005 Discussion Smoking 1.64 1.02-2.65 4.164 0.041 Suicide receives increasing attention worldwide, with Drinking 1.64 1.07-2.53 5.178 0.023 many countries developing national strategies for pre- Introversion 1.90 1.25-2.87 9.155 0.002 vention. Rates of suicide vary greatly between countries, Economic pressure 2.58 1.64-4.05 17.434 0.000 with the greatest burdens in developing countries [22]. Unhappy a month ago 0.96 0.65-1.42 0.040 0.841 Most people who die by suicide have psychiatric disor- Unhappy a year ago 1.14 0.76-1.72 0.397 0.529 ders, notably mood, substance-related, anxiety, psycho- Unhappy after a year 0.87 0.60-1.31 0.362 0.547 tic, and personality disorders, with comorbidity being Friend suicide two weeks ago 1.11 0.46-2.66 0.050 0.823 common [23]. Risk for suicide may have genetic contri- Friend suicide a year ago 1.22 0.60-2.49 0.295 0.587 butions, however, specific genes or relevant DNA Negative life events half year ago 5.74 3.28- 43.365 0.000 sequence variations have not yet been identified [24]. 10.04 Therefore, it is a major research challenge to clarify the Family emotional support needed 0.43 0.26-0.72 10.587 0.001 relative heritability of the risk for suicide, in particular, Family emotional support gained 1.06 0.72-1.55 0.086 0.769 separately from the heritability of disorders or traits that Friends’ emotional support needed 0.38 0.24-0.60 16.025 0.000 are strongly associated with suicidal risk [25]. Friends’ emotional support gained 1.06 0.72-1.55 0.084 0.772 a The rate-limiting enzyme of serotonin biosynthesis, Depression (HDRS = ≥ 35) 1.58 1.07-2.34 5.227 0.020 a TPH2, is one of the most promising candidate genes for Hopelessness (HDRS = ≥ 6) 7.68 4.99- 93.755 0.000 psychiatric disorders [26]. In the present study, we 11.83 Anxiety/Somatization(HDRS = > 7) 0.84 0.56-1.27 0.706 0.401 Loss of weight in a week(= 0.5 kg) 0.93 0.64-1.36 0.149 0.699 a Table 5 Results from multivariate logistic regression Cognitive impairment(HDRS = > 12) 1.17 0.77-1.78 0.553 0.457 analysis for predictor variables of MDD+suicide group Diurnal change (HDRS = ≥ 1) 1.12 0.76-1.66 0.350 0.554 a Variables OR 95% CI Wald P value Slow movement (HDRS = ≥ 8) 1.12 1.77-4.64 0.340 0.560 TPH2 rs7305115 AA 0.33 0.22-0.99 12.861 0.000 Sleep disorders (HDRS = ≥ 2) 3.28 2.20-4.88 35.128 0.000 Family history of suicide 2.98 1.17-5.04 10.228 0.001 Anxiety (HAMA = ≥ 21) 4.12 2.54-6.68 35.622 0.000 Negative life events half year ago 6.64 2.48-11.04 41.145 0.000 TPH2 rs7305115 AA 0.50 0.31-0.82 13.941 0.000 Hopelessness (HDRS > = 6) 7.68 5.79-13.74 90.235 0.000 HDRS, Hamilton depression rating scale for depression; b a HAMA, Hamilton anxiety scale for anxiety HDRS, Hamilton depression rating scale for depression Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 6 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 Table 6 Association analysis of TPH2 genotypes and predictor variables in MDD+suicide group Genotype (N) P value AA (n = 31) AG (n = 118) GG (n = 66) Family history of suicide 0.006 Yes 5 45 33 No 26 73 33 Negative life events half year ago 0.005 Yes 10 51 42 No 21 67 24 Hopelessness 0.002 Yes 17 86 58 No 14 32 8 Pearson chi-square test. investigated TPH2 rs7305115 variants in a Han sample of Limitations suicide attempters, and compared them to non-suicidal A number of limitations may be relevant to these studies. depressed patients. We also investigated the association First, we only paid attention on a SNP maker of the TPH2 of polymorphisms with the life environment factors gene in the current study. More TPH2 marker will be among suicide patients. The issue of association of TPH2 examined for MDD patients with suicide behaviors in the SNPs with suicide-related behavior is a complex and con- future study. Further, we had no the detail mechanistic troversial one. Several studies have indicated possible explanation regarding the role of serotonin functioning in associations between various TPH2 polymorphisms and depression for TPH2 SNP. Further study is needed to elu- major depression, suicidal behavior [12,27]. In contrast, cidate its mechanism. Understanding why the vulnerability other studies failed to find associations between TPH2 to suicide differs among MDD patients could assist in polymorphisms and suicidality [28,29]. Nevertheless, we improved screening of high risk patients and treatment. foundanassociationofsuicidal behavior with the TPH2 rs7305115 SNP in the present study. Our data shows that Conclusions MDD+suicide patients have low frequencies of the In case-control association studies, our findings sug- rs7305115 A-allele and AA genotypes (OR = 0.50). gested that the rs7305115 SNP in the TPH2 gene could Studies indicated that a history of suicide attempt, a be a marker for the genetic susceptibility to suicide- psychiatric condition such as ongoing major depression, related traits in Chinese. The TPH SNP might influence alcohol or other substance use disorder, hopelessness, suicide-related traits in behaviorally extreme populations separation or loss, anger, and suicidal ideation have and included an independent high risk clinical sample, been implicated as predictors of suicidal behaviors suicide attempters. We suggested that TPH2 gene could [30,31]. The MDD patients with greater levels of hope- regulate serotonergic system and contribute to the vul- lessness also were prone to the multiple suicide attempts nerability to suicidal behavior. [32]. Our findings indicated that cognitive impairment and hopelessness were associated with TPH2 rs7305115 Abbreviations SNP among MDD+suicide patients. DSM: The Diagnostic and Statistical Manual of Mental Disorders; HDRS: The multivariate analysis indicated that four factors Hamilton Depression Rating Scale; SCID-I: Structured Clinical Interview for DSM-IV Axis I Disorders; SCID-II: Structured Clinical Interview for DSM-IV (TPH2, family history of suicide, negative life events half Personality Disorders; 5-HT: 5-hydroxytryptamine; TPH2: the tryptophan year ago and hopelessness) were significantly associated hydroxylase-2; MDD: major depressive disorders; HWE: Hardy-Weinberg with the suicide behaviors in MDD patients. The TPH2 equilibrium. rs7305115 AA remained a significant protective predic- Acknowledgements tor of suicide behaviors (OR = 0.33). The results sug- This research was supported by the “333 Project” of Jiangsu province, China gested that A®G mutation carriers of TPH2 rs7305115 (No. CA051001-6; WZD0605; CSZ00721) and Science and Technology Planning Project of Changzhou Municipality, China (No. CS2008214). SNP could be a higher risk of suicide attempts than AA homozygous genotype carriers in MDD patients. To Author details 1 2 identify the functional locus, it will be important to clo- Wuxi Psychiatric Hospital, Nanjing Medical University, Wuxi, China. Ankang Hospital, Jining, China. Clinical Oncology Laboratory, Changzhou Tumor sely evaluate the significance of sequence variants in Hospital, Medical College of Suzhou University, Changzhou, China. coding regions that could alter gene expression at the Department of Molecular Epidemiology, Shantou University Medical DNA or RNA levels. College, Shantou, China. Zhang et al. Behavioral and Brain Functions 2010, 6:49 Page 7 of 7 http://www.behavioralandbrainfunctions.com/content/6/1/49 18. Williams JB: A structured interview guide for the Hamilton Depression Authors’ contributions Rating Scale. Arch Gen Psychiatry 1988, 45:742-747. JY, ZC, and CL carried out the molecular genetic studies, participated in the 19. Baca-Garcia E, Perez-Rodriguez MM, Basurte-Villamor I, Fernandez del sequence alignment and drafted the manuscript. QL, GW, GS, YC, YL, and KL Moral AL, Jimenez-Arriero MA, Gonzalez de Rivera JL, Saiz-Ruiz J, recruited the Subjects. CZ and GY participated in the design of the study Oquendo MA: Diagnostic stability of psychiatric disorders in clinical and performed the statistical analysis. YZ conceived of the study, and practice. Br J Psychiatry 2007, 190:210-216. participated in its design and coordination and helped to draft the 20. Spitzer RL, Wakefield JC: DSM-IV diagnostic criterion for clinical manuscript. All authors read and approved the final manuscript. significance: does it help solve the false positives problem? Am J Psychiatry 1999, 156:1856-1864. Competing interests 21. Denning DG, Conwell Y, King D, Cox C: Method choice, intent, and The authors declare that they have no competing interests. gender in completed suicide. Suicide Life Threat Behav 2000, 30:282-288. Received: 25 June 2010 Accepted: 25 August 2010 22. Wasserman D, Terenius L, Wasserman J, Sokolowski M: The 2009 Nobel Published: 25 August 2010 conference on the role of genetics in promoting suicide prevention and the mental health of the population. Mol Psychiatry 2010, 15:12-17. 23. Hawton K, van Heeringen K: Suicide. Lancet 2009, 373:1372-1381. References 24. Brezo J, Klempan T, Turecki G: The genetics of suicide: a critical review of 1. Li X, Xiao Z, Xiao S: Suicide among the elderly in mainland China. molecular studies. Psychiatr Clin North Am 2008, 31:179-203. Psychogeriatrics 2009, 9:62-66. 25. Bondy B, Buettner A, Zill P: Genetics of suicide. Mol Psychiatry 2006, 2. Witte TK, Timmons KA, Fink E, Smith AR, Joiner TE: Do major depressive 11:336-351. disorder and dysthymic disorder confer differential risk for suicide? J 26. Invernizzi RW: Role of TPH-2 in brain function: news from behavioral and Affect Disord 2009, 115:69-78. pharmacologic studies. J Neurosci Res 2007, 85:3030-3035. 3. Roy A, Sarchiopone M, Carli V: Gene-environment interaction and suicidal 27. Zhou Z, Roy A, Lipsky R, Kuchipudi K, Zhu G, Taubman J, Enoch MA, behavior. J Psychiatr Pract 2009, 15:282-288. Virkkunen M, Goldman D: Haplotype-based linkage of tryptophan 4. Arango V, Huang YY, Underwood MD, Mann JJ: Genetics of the hydroxylase 2 to suicide attempt, major depression, and cerebrospinal serotonergic system in suicidal behavior. J Psychiatr Res 2003, 37:375-386. fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 5. Anguelova M, Benkelfat C, Turecki G: A systematic review of association 2005, 62:1109-1118. studies investigating genes coding for serotonin receptors and the 28. De Luca V, Mueller DJ, Tharmalingam S, King N, Kennedy JL: Analysis of serotonin transporter: II. Suicidal behavior. Mol Psychiatry 2003, 8:646-653. the novel TPH2 gene in bipolar disorder and suicidality. Mol Psychiatry 6. Savelieva KV, Zhao S, Pogorelov VM, Rajan I, Yang Q, Cullinan E, 2004, 9:896-897. Lanthorn TH: Genetic disruption of both tryptophan hydroxylase genes 29. De Luca V, Voineskos D, Wong GW, Shinkai T, Rothe C, Strauss J, dramatically reduces serotonin and affects behavior in models sensitive Kennedy JL: Promoter polymorphism of second tryptophan hydroxylase to antidepressants. PLoS One 2008, 3:e3301. isoform (TPH2) in schizophrenia and suicidality. Psychiatry Res 2005, 7. Mann JJ: Role of the serotonergic system in the pathogenesis of major 134:195-198. depression and suicidal behavior. Neuropsychopharmacology 1999, 30. Oquendo MA, Galfalvy H, Russo S, Ellis SP, Grunebaum MF, Burke A, 21:99S-105S. Mann JJ: Prospective study of clinical predictors of suicidal acts after a 8. Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M: major depressive episode in patients with major depressive disorder or Synthesis of serotonin by a second tryptophan hydroxylase isoform. bipolar disorder. Am J Psychiatry 2004, 161:1433-1441. Science 2003, 299:76. 31. Beevers CG, Miller IW: Perfectionism, cognitive bias, and hopelessness as 9. Patel PD, Pontrello C, Burke S: Robust and tissue-specific expression of prospective predictors of suicidal ideation. Suicide Life Threat Behav 2004, TPH2 versus TPH1 in rat raphe and pineal gland. Biol Psychiatry 2004, 34:126-137. 55:428-433. 32. Esposito C, Spirito A, Boergers J, Donaldson D: Affective, behavioral, and 10. Cote F, Thevenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA, Bayard E, cognitive functioning in adolescents with multiple suicide attempts. Hanoun N, Saurini F, Lechat P, et al: Disruption of the nonneuronal tph1 Suicide Life Threat Behav 2003, 33:389-399. gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci USA 2003, 100:13525-13530. doi:10.1186/1744-9081-6-49 11. Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG: Cite this article as: Zhang et al.: Effect of Tryptophan Hydroxylase-2 Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science rs7305115 SNP on suicide attempts risk in major depression. Behavioral 2004, 305:217. and Brain Functions 2010 6:49. 12. Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R, Moller HJ, Bondy B, Ackenheil M: SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 2004, 9:1030-1036. 13. Scheuch K, Lautenschlager M, Grohmann M, Stahlberg S, Kirchheiner J, Zill P, Heinz A, Walther DJ, Priller J: Characterization of a functional promoter polymorphism of the human tryptophan hydroxylase 2 gene in serotonergic raphe neurons. Biol Psychiatry 2007, 62:1288-1294. 14. Lopez de Lara C, Brezo J, Rouleau G, Lesage A, Dumont M, Alda M, Benkelfat C, Turecki G: Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression. Biol Psychiatry 2007, 62:72-80. Submit your next manuscript to BioMed Central 15. Chen GL, Vallender EJ, Miller GM: Functional characterization of the and take full advantage of: human TPH2 5’ regulatory region: untranslated region and polymorphisms modulate gene expression in vitro. Hum Genet 2008, 122:645-657. • Convenient online submission 16. Lin YM, Ko HC, Chang FM, Yeh TL, Sun HS: Population-specific functional • Thorough peer review variant of the TPH2 gene 2755C > A polymorphism contributes risk association to major depression and anxiety in Chinese peripartum • No space constraints or color figure charges women. Arch Womens Ment Health 2009, 12:401-408. • Immediate publication on acceptance 17. Leung CM, Wing YK, Kwong PK, Lo A, Shum K: Validation of the Chinese- • Inclusion in PubMed, CAS, Scopus and Google Scholar Cantonese version of the hospital anxiety and depression scale and comparison with the Hamilton Rating Scale of Depression. Acta Psychiatr • Research which is freely available for redistribution Scand 1999, 100:456-461. Submit your manuscript at www.biomedcentral.com/submit

Journal

Behavioral and Brain FunctionsSpringer Journals

Published: Aug 25, 2010

References