TPH2基因单核苷酸多态性与双相情感障碍及其自杀行为的关系

目的 探讨色氨酸羟化酶2(TPH2)基因rs7305115单核苷酸多态性与双相情感障碍及自杀行为的关系.方法 提取205例双相情感障碍患者和225名健康对照者基因组DNA,采用聚合酶链反应(polymerase chain reaction PCR)扩增包括TPH2基因rs7305115位点的312bp基因组DNA片段,PCR产物直接测序.结果 在第7外显子周围未发现其它的单核苷酸多态性.双相情感障碍患者和健康对照者TPH2 rs7305115基因型和等位基因频率无统计学意义的差别(P>0.05),但患者组内有自杀行为的个体携带基因型AA的频率及等位基因A的频率均较低,两组比较差异有统计学意义(P<0.05).结论 TPH2基因rs7305115单核苷酸多态性与双相情感障碍无明显关联,与自杀行为有关联,其可能与双相情感障碍自杀行为易感性相关.

Abstract：

Objective To explore the relation among single nucleotide polymorphism of a novel tryptophan hydroxylase isoform (TPH2) gene rs7305115,bipolar disorder and suicidal behavior. Methods Specimens of peripheral blood were collected from 205 bipolar disorder and 225 controls. A novel tryptophan hydroxylase isoform (TPH2) gene rs7305115 in length 312bp was amplitied by Polvmerase chain reaction (PCR), and the product was analyzed by direct sequencing. Results We did not discover new single nucleotide polymorphism. Compared with Control Group,no significant difference of genotypes and alleles of TPH2 gene rs7305115 single nucleotide polymorphism had been found in patient group(P>0. 05). However,there existed significant differences between suicide behavior and non suicide behavior in bipolar disorder patient in genotypea of TPH2 gene rs7305115A/A. Suicide behavior of bipolar disorder patients in AA genotypes was much lower than non suicide behavior of bipolar disorder patients (P<0. 05). Con-clusion TPH2 gene rs7305115 single nucleotide polymorphism may have no association with the susceptibility of bipolar disorder, but associated with suicide behavior in bipolar disorder. A allele may be one of the risk factors for suicide behavior in bipolar disor-der.     

HTR2C and HTR1A gene variants in German and Italian suicide attempters and completers.

The serotonin 2C (HTR2C) and 1A (HTR1A) receptors have been involved in suicide-related behaviors. We studied gene variants of both receptors in suicide attempters and completers. The sample was composed of 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 Caucasian individuals who committed suicide, 312 German healthy subjects, 152 Italian suicide attempters (major depression n = 68 and bipolar disorder n = 84), and 131 Italian healthy volunteers. HTR2C (SNP: rs547536, rs2192372, rs6318, rs2428707, rs4272555, rs1801412) and HTR1A (SNP: rs1423691, rs878567, and rs6295) variants were analyzed in the German sample. HTR2C rs6318 and HTR1A rs6295 were analyzed in the Italian sample. Haplotype analysis in relation to suicidal behaviors did not reveal any significant association. Single markers and haplotypes were not or only marginally associated with other related features, such as violence of suicide attempt, family history for suicide attempt or State-Trait Anger Expression Inventory (STAXI) and Questionnaire for Measuring Factors of Aggression (FAF) scores. In conclusion, our study does not support the notion that HTR2C and HTR1A gene variants are major contributors to suicide-, anger-, or aggression-related behaviors in our sample.     

Bipolar pharmacotherapy and suicidal behavior Part 3: impact of antipsychotics

INTRODUCTION: Antipsychotics, particularly second generation agents, are widely used in bipolar disorder, but their effect on suicidal behavior in this population has not been systematically studied. METHODS: Retrospective chart review of 405 veterans with bipolar disorder followed for a mean of three years, with month-by-month systematic assessment of current pharmacotherapy and suicide completion, attempt or hospitalization for suicidality. Comparison of rates of suicidal events during mood stabilizer monotherapy, antipsychotic monotherapy, and combination of mood stabilizer and antipsychotic. RESULTS: Non-lethal suicide event rates were 9.4 times greater (chi2=28.29, p<.0001) during antipsychotic monotherapy and 3.5 times greater during mood stabilizer+antipsychotic (chi2=15.13, p=0.0001) than during mood stabilizer monotherapy. LIMITATIONS: Antipsychotics may have been prescribed because patients were at greater risk of suicidal behavior. First and second generation antipsychotics were not distinguished. CONCLUSIONS: Treatment of bipolar patients with antipsychotics is associated with an increase in non-lethal suicidal behavior. Thus, use of antipsychotics for bipolar patients requires careful monitoring for suicidal behavior. Further studies are urgently needed to better characterize this relationship.     

No association of the tryptophan hydroxylase gene with bipolar affective disorder,unipolar affective disorder,or suicidal behaviour in major affective disorder

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT). An association study in bipolar affective disorder I or unipolar major affective disorder was performed by using a Bfa I restriction site polymorphism within intron 7 of the tryptophan hydroxylase gene. A total of 118 bipolar, 125 unipolar, and 437 control subjects were used in the study (1:3.7 bipolar:control, 1:3.5 unipolar:control). There were no significant differences in TPH allele or genotype frequencies between the affective disorder and control groups. In addition, bipolar and/or unipolar subjects with or without a history of suicide attempts were compared for the TPH polymorphism. No significant differences were found between suicidal and nonsuicidal groups in major affective disorder, in contrast to a previous study suggesting an association of this polymorphism with a history of suicide attempts among alcoholic violent offenders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:245–247, 1998. © 1998 Wiley-Liss, Inc.     

Gene-gene interaction between MAOA and COMT in suicidal behavior

Several lines of evidence suggest that suicidal behavior is associated with altered noradrenergic neurotransmission. Noradrenaline (NA) is catabolized by monoamine oxidase A (MAOA) and cathecol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk for attempted suicide. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the Val 108/158 Met COMT polymorphism in 305 families with at least one member having bipolar disorder (BD). No association with history of suicide attempt was found either in the MAOA polymorphisms (VNTR:LRS = 1.90, d.f. = 1, p = 0.16; 941T > G:LRS = 1.39, d.f. = 1, p = 0.23), or with the Val 158 Met polymorphism (LRS = 1.61, d.f.=1, p = 0.20). When we performed the haplotype analysis for MAOA gene, we found no association between suicide attempt and haplotype distribution (LRS = 3.07, d.f. = 2, p = 0.21). As both genes are involved in degrading noradreanline, we also tested the hypothesis of epistasis between MAOA polymorphisms and Val158Met, however, no additive effect was found in conferring risk for suicide attempt. These findings suggest that MAOA and COMT genes may not influence suicidal behavior in patients with bipolar disorder.     

Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders

Variants of the functional polymorphism in the serotonin transporter (upstream regulatory region: 5-HTTLPR), the tryptophan hydroxylase (TPH), the monoamine oxidase A (MAO-A), and the dopamine receptor D4 (DRD4) genes have all been associated with mood disorders. The aim of this study was to test those hypotheses by using a family-based association approach. Both diagnoses and psychopathology were used for phenotype definitions. A total of 134 nuclear families with mood disorders, with probands affected by bipolar (n = 103) or major depressive (n = 58) disorders, were included in the study. All subjects were typed for the above-mentioned gene variants using polymerase chain reaction (PCR) technique. No significant transmission disequilibrium was found in the overall sample for any polymorphism. A separate analysis of bipolar subjects only, or the use of continuous psychopathologic traits as affectation status did not influence the observed results. Our study did not support the involvement of 5-HTTLPR, TPH, MAO-A, or DRD4 polymorphisms in mood disorders.     

TPH2基因单核苷酸多态性与单相抑郁及其自杀行为的关系

目的探讨色氨酸羟化酶2(TPH2)基因rs7305115单核苷酸多态性与单相抑郁及自杀行为的关系。方法提取197例单相抑郁患者和225名健康对照者基因组DNA,采用聚合酶链反应(polymerase chain reaction PCR)扩增包括TPH2基因rs7305115位点的312bp基因组DNA片段及PCR产物直接测序。结果在第7外显子周围未发现其它的单核苷酸多态性。单相抑郁患者和健康对照者TPH2 rs7305115基因型和等位基因频率无统计学意义的差别(P>0.05),但患者组内有自杀行为的个体携带基因型AA的频率及等位基因A的频率均较低,两组比较差异有统计学意义(P<0.05)。结论TPH2基因rs7305115单核苷酸多态性与单相抑郁无明显关联,与自杀行为有关联。其可能与抑郁症自杀行为易感性相关。     

Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder

Genetic factors may be associated with disease subtype as well as susceptibility. We have therefore typed polymorphisms at the serotonin transporter, dopamine receptor, tryptophan hydroxylase, tyrosine hydoxylase, and monoamine oxidase A (MAOA) loci in 139 unipolar and 131 bipolar patients and investigated associations with gender, number of episodes, age of onset, history of psychotic symptoms, history of suicidal behavior, and history of substance abuse. In bipolar subjects, the promoter variable number tandem repeat (VNTR) allele 132 of MAOA was associated with history of suicide attempts, P = 0.029, particularly in females, P = 0.006. The Fnu4HI allele 1 of MAOA was also associated with history of suicide attempts in females, P = 0.0162. The serotonin transporter promoter allele 2 was associated with increasing number of manic episodes, P = 0.02, and history of psychotic symptoms, P = 0.0243. One significant association was found in the unipolar group: dopamine D2 receptor promoter allele 2 with history of psychotic symptoms, P = 0. 0165. We have tested multiple loci for a variety of different clinical variables and performed 228 tests of significance in total. It is possible that these preliminary findings are type 1 errors, because one would expect 11 of the 228 tests to reach a nominal significance level of P < 0.05 by chance alone if all the tests were independent. The associations with the MAOA and serotonin transporter loci are consistent with previous data suggesting associations with susceptibility to bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:36-42, 2000 Copyright 2000 Wiley-Liss, Inc.     

A Tryptophan Hydroxylase 2 Gene Polymorphism is Associated with Panic Disorder

Panic disorder (PD) is a complex and heterogeneous psychiatric condition. Dysfunction within the serotonergic system has been hypothesized to play an important role in PD. The novel brain-specific serotonin synthesizing enzyme, tryptophan hydroxylase 2 (TPH2), which represents the rate-limiting enzyme of serotonin production in the brain, may therefore be of particular importance in PD. We investigated the TPH2 703G/T SNP for association with PD. Patients with PD (n = 108), and control subjects (n = 247), were genotyped for rs4570625 (TPH2 703G/T). Male and female subjects were analyzed separately. The severity of their symptoms was measured using the Spielberger state-trait anxiety inventory (STAI), panic disorder severity scale (PDSS), anxiety sensitivity index (ASI), acute panic inventory (API), and Hamilton’s rating scale for depression (HAMD). The genotype and allele frequencies of the PD patients and controls were analyzed using χ ² statistics. There was a significant difference in the allele frequency in rs4570625 between the PD patients and normal controls. The T allele was significantly less frequent in the PD patients. We also found a significant association with rs4570625 in the female subgroup. There was no difference in symptom severity among the genotypes of this polymorphism. This result suggests that rs4570625 polymorphism may play a significant role in the pathogenesis of PD. Moreover, rs4570625 may have a gender-dependent effect on susceptibility to PD. Further studies are needed to replicate the association that we observed. Edited by Tatiana Foroud.     

Family‐based association study of 5‐HTTLPR,TPH, MAO‐A,and DRD4 polymorphisms in mood disorders

Variants of the functional polymorphism in the serotonin transporter (upstream regulatory region: 5‐HTTLPR), the tryptophan hydroxylase (TPH), the monoamine oxidase A (MAO‐A), and the dopamine receptor D4 (DRD4) genes have all been associated with mood disorders. The aim of this study was to test those hypotheses by using a family‐based association approach. Both diagnoses and psychopathology were used for phenotype definitions. A total of 134 nuclear families with mood disorders, with probands affected by bipolar (n = 103) or major depressive (n = 58) disorders, were included in the study. All subjects were typed for the above‐mentioned gene variants using polymerase chain reaction (PCR) technique. No significant transmission disequilibrium was found in the overall sample for any polymorphism. A separate analysis of bipolar subjects only, or the use of continuous psychopathologic traits as affectation status did not influence the observed results. Our study did not support the involvement of 5‐HTTLPR, TPH, MAO‐A, or DRD4 polymorphisms in mood disorders. © 2002 Wiley‐Liss, Inc.     

Monoamines: biochemical markers of suicide?

The purpose of this article is to give the clinician not proficient in biochemistry an understanding of the biochemical research data on neurotransmitters and suicide. This literature review reports the current findings on serotonin (5-HT), dopamine (DA), and norepinephrine (NE) as possible biochemical markers of depression and suicide. In conjunction with known environmental and behavioral indicators of suicide, neurotransmitter balance could be a factor in determining the severity of depression and the possible suicidal ideation in patients. Numerous studies have been performed on the monoamines: Serotonin, Dopamine and Norepinephrine, neurotransmitters that innervate parts of the spinal cord and all areas of the brain. Studies appear to suggest a relationship among monoamine levels, depression, and suicide. Significantly low levels of serotonin and the neurotransmitter metabolite (5-HIAA) may be correlated with suicidal behavior.     

Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder

The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] controls a broad range of biological functions that are disturbed in affective disorder. In the brain, 5-HT production is controlled by tryptophan hydroxylase 2 (TPH2). In order to assess the possible contribution of TPH2 genetic variability to the aetiology of bipolar affective disorder (BPAD), we systematically investigated common and rare genetic variation in the TPH2 gene through a sequential sequencing and SNP-based genotyping approach. Our study sample comprised two cohorts of BPAD from Germany and Russia, totalling 883 patients and 1300 controls. SNPs located in a haplotype block covering the 5' region of the gene as well as a rare, non-synonymous SNP, resulting in a Pro206Ser substitution, showed significant association with bipolar disorder. The odds ratio for the minor allele in the pooled sample was 1.5 (95% CI 1.2-1.9) for rs11178997 (in the 5'-associated haplotype block) and 4.8 (95% CI 1.6-14.8) for rs17110563 encoding the Pro206Ser substitution. Examination of the functional effects of TPH2 Pro206Ser provided evidence for a reduced thermal stability and solubility of the mutated enzyme, suggesting reduced 5-HT production in the brain as a pathophysiological mechanism in BPAD.     

Monoamine oxidase a gene is associated with borderline personality disorder

OBJECTIVE: Monoamine oxidase A is a mitochondrial enzyme involved in the degradation of certain neurotransmitter amines: serotonin and norepinephrine. As for its role in aggression, impulsivity, suicide and mood liability, monoamine oxidase A can be considered a functional candidate in borderline personality disorder. METHODS: To test for this hypothesis we genotyped two polymorphic markers in monoamine oxidase A gene, a promoter VNTR and an rs6323 (T941G) in exon 8, in 111 Caucasian borderline personality disorder patients and 289 Caucasian healthy controls. Association analyses using individual marker and haplotype data were performed by a program of COCAPHASE in UNPHASED (MRC Human Genome Mapping Project Resource Centre, Cambridge, UK). RESULTS: We found that the borderline personality disorder patients had a high frequency of the high activity VNTR alleles (chi=4.696, P=0.03) and a low frequency of the low activity haplotype (chi=5.089, P=0.02). CONCLUSION: These results show that the monoamine oxidase A gene may play an important role in the etiological development of the borderline personality disorder.     

Bipolar pharmacotherapy and suicidal behavior. Part I: Lithium, divalproex and carbamazepine

INTRODUCTION: The anti-suicidal benefit of lithium on suicidal behavior in bipolar disorder is well-established. Data are mixed on the effects of divalproex and carbamazepine. METHODS: Retrospective chart review study of 405 veterans with bipolar disorder followed for a mean of 3 years, with month by month review of clinical progress notes, and systematic assessment of current pharmacotherapy and suicide completion, attempt or hospitalization for suicidality. Comparison of suicide event rates (events/100 patient years) between mood stabilizers and during-vs-after discontinuation of mood stabilizers, with linear regression analysis for influence of potential confounding variables, and robust bootstrap confirmation analysis. RESULTS: No completed suicides occurred during or after discontinuation of monotherapy. Rates of non-lethal suicidal behavior were similar during lithium (2.49), divalproex (4.67) and carbamazepine (3.80) monotherapies. There was a sixteen fold greater, highly statistically significant non-lethal suicidal event rate after discontinuation compared with during mood stabilizer monotherapy (55.89 vs. 3.48 events/100 patient years; Chi2=13.95; df=1; p<0.0002). On compared with off treatment differences were similar for the three different agents. LIMITATIONS: Treatments were uncontrolled in this naturalistic setting, and data were analyzed retrospectively. CONCLUSIONS: Lithium and the anticonvulsants may show similar benefits in protecting bipolar patients from non-lethal suicidal behavior when careful analysis of clinical data is done to confirm medication adherence/non-adherence. Findings in this study were similar to those of a previous study that applied the same methodology in a private practice setting.     

Does first episode polarity predict risk for suicide attempt in bipolar disorder?

BACKGROUND: Defining bipolar disorder (BD) subtypes with increased risk of suicidal behavior may help clinical management. We tested the hypothesis that the polarity of a patient's first mood episode would be a marker for BD subtypes with differential risk for suicidality. METHODS: One hundred thirteen subjects with DSM-IV defined BD were classified based on whether their first reported episode was manic/hypomanic (FM) or depressed (FD). They were compared on demographic and clinical variables. Logistic regression adjusting for potential confounds tested the association between first episode polarity and history of suicide attempt. RESULTS: Multiple logistic regression analysis showed that FD group membership was associated with eightfold odds of a past suicide attempt, adjusting for years ill and total number of lifetime major depressive episodes. LIMITATIONS: Sample size, retrospective design, recall bias, assessment during a mood episode, and imprecise recall of hypomania. CONCLUSIONS: Polarity of patients' first reported mood episode suggested a depression-prone subtype with a greater probability of past suicide attempt. The FM group had more alcoholism and psychosis, but less likelihood of past suicide attempt. Validation of these putative subtypes requires prospective study.     

Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene (TPH A779C), but not with polymorphisms in five other serotonergic genes

BACKGROUND: There is a heritable component to suicidal behaviour, encouraging the search for the associated risk alleles. Given the putative role of the 5-HT (5-hydroxytryptamine; serotonin) system in suicidal behaviour, serotonergic genes are leading candidates. In particular, several studies have reported an association with variants in the tryptophan hydroxylase (TPH) gene. METHOD: We studied six serotonergic gene polymorphisms in a well-characterized sample of 129 deliberate self-harm subjects and 329 comparison subjects. The polymorphisms were TPH (A779C), 5-HT transporter (5-HTT, LPR S/L), monoamine oxidase A (MAOA G941T), 5-HT1B receptor (HTR1B G861C), 5-HT2A receptor (HTR2A T102C), and 5-HT2C receptor (HTR2C Cys23Ser). Genotyping was done using polymerase chain reaction (PCR)-based assays. The primary analyses compared allele and genotype frequencies between cases and controls. There were a limited number of planned secondary analyses within the deliberate self-harm group. RESULTS: The TPH A779 allele was more common in deliberate self-harm subjects than in controls (OR 1.38, 95% CI 1.02-1.88; P = 0.03). None of the other polymorphisms was associated with deliberate self-harm. Within the deliberate self-harm group there were no associations with impulsivity, suicide risk, lifetime history of depression, or family history of deliberate self-harm. CONCLUSIONS: Our data extend the evidence that allelic variation in the TPH gene is a risk factor for deliberate self-harm. No evidence was found to implicate the other polymorphisms.     

Lithium,anticonvulsants and suicidal behavior in bipolar disorder

BACKGROUND: Lithium has been found to be effective in reducing suicide rates during long term treatment of patients with bipolar disorders. Data on the efficacy of anticonvulsant mood stabilizers in reducing suicide risk are sparse. METHOD: Charts of 140 bipolar patients treated continuously for a minimum of 6 months during a 23-year period of private practice by the senior author were extracted from nearly 4000 patient records. Data extracted from the charts were incidence of completed suicide, number of suicide attempts, and number of hospitalizations for suicidal ideation or behavior per 100 patient-years of either 'on' or 'off' lithium or anticonvulsant mood stabilizer monotherapy. RESULTS: Only one completed suicide (during a period off of lithium) occurred in the patients studied. Incidence of non-lethal suicidal behavior was not different during treatment with lithium, compared with anticonvulsants. Being on a mood stabilizer significantly protected against suicidal behavior. The relative protective effect was more modest than in reports from other treatment settings. LIMITATIONS: This was a retrospective chart review study of naturalistically treated patients. CONCLUSIONS: Treatment of patients with bipolar disorder with either lithium or anticonvulsant mood stabilizers was associated with reduced risk of suicidal behavior. This study did not find evidence for a difference in the protective effect of the two types of mood stabilizing medications against non-lethal suicidal behavior in the naturalistic setting of private practice.     

Suicidal behavior in bipolar mood disorder: clinical characteristics of attempters and nonattempters

OBJECTIVE: Bipolar Disorder is associated with a higher frequency of attempted suicide than most other psychiatric disorders. The reasons are unknown. This study compared bipolar subjects with a history of a suicide attempt to those without such a history, assessing suicidal behavior qualitatively and quantitatively, and examining possible demographic, psychopathologic and familial risk factors. METHODS: Patients (ages 18 to 75) with a DSM III-R Bipolar Disorder (n = 44) diagnosis determined by a structured interview for Axis I disorders were enrolled. Acute psychopathology, hopelessness, protective factors, and traits of aggression and impulsivity were measured. The number, method and degree of medical damage was assessed for suicide attempts, life-time. RESULTS: Bipolar suicide attempters had more life-time episodes of major depression, and twice as many were in a current depressive or mixed episode, compared to bipolar nonattempters. Attempters reported more suicidal ideation immediately prior to admission, and fewer reasons for living even when the most recent suicide attempt preceded the index hospitalization by more than six months. Attempters had more lifetime aggression and were more likely to be male. However, attempters did not differ from nonattempters on lifetime impulsivity. LIMITATIONS: The generalizability of the results is limited because this is a study of inpatients with a history of suicide attempts. Patients with Bipolar I and NOS Disorders were pooled and a larger sample is needed to look at differences. We could not assess psychopathology immediately prior to the suicide attempt because, only half of the suicide attempters had made attempts in the six months prior to admission. Patients with current comorbid substance abuse were excluded. No suicide completers were studied. CONCLUSIONS: Bipolar subjects with a history of suicide attempt experience more episodes of depression, and react to them by having severe suicidal ideation. Their diathesis for acting on feelings of anger or suicidal ideation is suggested by a higher level of lifetime aggression and a pattern of repeated suicide attempts.     

Association study of tryptophan hydroxylase 2 gene polymorphisms in bipolar disorder patients with panic disorder comorbidity

Frequent comorbidity between panic disorder (PD) and mood disorders has been widely reported in clinical and epidemiological studies and, recently, an increasing attention has been paid to the cooccurrence of PD and bipolar disorder (BD). Several studies have shown that an imbalance of serotonin activity could be related to panic symptoms. Tryptophan hydroxylase 2 (TPH2) are plausible candidates for the association with PD. The aim of this study is to investigate a possible association between TPH2 gene polymorphisms and the PD comorbidity susceptibility.Our sample consisted of 515 patients; 274 patients with BD (subtypes I and II), including 45 patients with lifetime panic disorder comorbidity and 241 controls. These patients were genotyped for eight tagging single nucleotide polymorphisms of the gene of human TPH2. We found significant differences between patients with BD, with panic disorder comorbidity, and controls in the allelic analysis (rs4448731, P=0.0069; rs4565946, P=0.0359; rs4760820, P=0.0079; rs1487275, P=0.0439) and genotypic analysis (rs4448731, P=0.011; rs4760820, P=0.0259). We also identified significant differences between patients with BD, with and without panic disorder comorbidity in the allelic analysis (rs4448731, P=0.004; rs4565946, P=0.011; rs11179000, P=0.031; rs4760820, P=0.018; rs1487275, P=0.038; rs10879357, P=0.023) and genotypic analysis (rs4448731, P=0.004; rs4565946, P=0.010; rs4760820, P=0.023; rs10879357, P=0.052). The haplotype analysis in the group of patients with BD, with and without panic disorder comorbidity, was also significant (rs4448731-rs4565946, P=0.0190; rs4448731-rs4565946, P=0.0220; rs10506645-rs4760820, P=0.0360). Further studies are needed to replicate the positive association that we observed.