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A sex-related genetic difference in bipolar disorder: tryptophan hydroxylase 1 gene 218 A>C polymorphism/Ikiuclu bozuklukta cinsiyetler arasi genetik bir farklilik: triptofan hidroksilaz gen polimorfizmi.


Bipolar disorder (BD) is a chronic condition with onset in the late adolescence and early adulthood, with relapsing symptoms afterwards, and in which genetic predisposition is thought to be the principal etiological factor. BD is seen equally among males and females, and its incidence varies between 0.5 and 1.5% in the general population (1).

Genetic predisposition is accepted to be the basis of the disease, although infectious agents, labour trauma and environmental factors are also suggested in the etiology of the disorder (2).

Studies on families, twins and adopted children have suggested significantly increased risk of the disease in biological relatives of the patients. However, the type of genetic linkage is yet to be identified. Genetic predisposition was related with the effects of more than one susceptibility gene (2,3). Various chromosomal disorders, gene locus and abnormalities associated with BD were identified; however, all of the studies are controversial (2,4).

Tryptophan hydroxylase 1 (TPH1) is the enzyme that catalyzes the initial step in the biosynthesis of serotonin (5-hydroxytryptamine, 5-HT). Pharmacologically, 5-HT is the most active indoleamine. However, it rapidly loses its biological activity when bounded to platelets or tissue cells. Availability of tryptophan hydroxylase is the rate-limiting step of serotonin synthesis. The enzyme TPH1 is encoded by gene localized to 11p15.3-p14. Polymorphism of this gene area causes regional increase in tryptophan density and decrease in serotonin density. TPH1 gene, which has a length of 29 kilobase (kb), involves 11 exons of a single promotor and a single transcriptional initiation sequence (5). In the studies on TPH gene, 12 polymorphisms have been identified (6).

Neurobiological and genetic studies in patients with BD suggest that this disease has a genetic basis. Catechol-O-methyl transferase (COMT), 5-hydroxytryptamine transporter (5HTT) and finally TPH1 genes were studied for this purpose. Serretti et al., in a review of 169 patients with BD (103 type I, 66 type II) who have suffered from a previous severe mania or hypomania episode at least once, demonstrated that patients and controls were comparable in respect to serotonin transporter (SERT), TPH1, COMT and 5HT2A gene polymorphisms (7). Besides, depressive patients cycling to mania/hypomania were shown not to be different regarding the same gene polymorphisms. In their study on SERT gene polymorphism in BD, Barlas et al. (8) did not report a difference between patients and controls.

Serotonin level and activity in brain and cerebrospinal fluid (CSF) are directly affected by the polymorphisms of TPH1 gene (9,10). The influence of TPH1 gene polymorphisms on psychiatric diseases has also been studied. Among studies investigating the association of TPH1 gene polymorphism with BD (5,11,12), impulsive-aggressive behaviors (13), activity alterations by antidepressant treatment (14), suicidal behavior (15-17), schizophrenia (18), nicotine addiction and smoking behavior (19) and migraine (20,21), those on BD and TPH1 gene gave contradictory results. Bellivier et al. made a comparison between 152 BD patients and 94 healthy controls regarding TPH1 gene alleles and despite the predisposition of TPH1 gene to BD, they concluded that such kind of predisposition was not present in case of suicidality (11). Rietschel et al. reported that 218 A>C polymorphism was not associated with this disease in their 95 patients with BD (12). Serretti et al. compared 1424 patients with major psychoses, defined according to DSM IV diagnostic criteria, with 380 healthy controls and investigated TPH 1 gene 218 A>C gene variants (5). While TPH 1 gene variants were not found to be associated with major psychoses, it was observed that patients with BD had a high predisposition to TPH1 gene A/A genotype. According to symptomatology, male patients with TPH1 gene A allele were found to have lower depressive symptoms compared to patients with TPH1 C allele, although TPH1 gene 218 A>C variants did not exhibit a significant difference. They suggested that TPH1 gene 218 A>C variants were not the basic sensitivity factors for psychoses at least in their sample, however, they determined that for male patients TPH1 gene A allele containing variants might be a protective factor for depressive symptoms or might be a subtype of mood disorder associated with manic symptoms of this genotype. Possible factors, such as current age and disease onset, age were not found to be affecting the observed results. In summary, BD exhibits a genetic inheritance pattern involving more than one gene (polymorphic-polygenic) and multiple factors (multifactorial) (22,23).

Considering the studies concerning serotonin's effect on TPH1 gene, brain and the neurotransmitter monoamines in addition to the studies concerning the serotonin levels of CSF in bipolar patients (BD), we aimed with the present study to investigate the frequencies and distribution of A/A, A/C and C/C genotypes for the TPH1 gene 218 A>C (rs1800532) polymorphism among patients with BD and healthy controls for the first time in Turkish population.


a) Selection of Patient and Control Groups

One hundred and sixteen patients, diagnosed with BD, according to DSM-IV diagnostic criteria, in the Mood Disorders Unit, Psychiatry Department, Gaziantep University Medical School, and 150 healthy subjects, a hospital staff at Gaziantep University Medical School, were included as patient and control groups, respectively. Informed written consents were obtained from the patients and their relatives. Diagnosis was established by at least two specialists. Venous blood samples (5 ml) were drawn into ethylenediaminetetra acedic acid (EDTA) tubes from all patients and control subjects, and kept under -20[degrees]C until DNA isolation. The patients, who were followed on treatment for BD, and with recent onset of the disease, were included in the study. Patients with mental retardation and chronic physical disability were excluded from the study.

b) Molecular Genetic Analysis DNA Extraction and Analysis

With written informed consent, a blood sample was drawn from each individual. Venous blood samples were collected in EDTA-containing tubes. DNA was extracted from whole blood by salting-out procedure (24).

Genotypic Analysis of the TPH1 Gene 218 A>C (rs1800532) Polymorphism

Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays were used to determine TPH1 gene 218 A>C (rs1800532) polymorphism.

The oligonucleotide primers used to determine the TPH1 gene 218 A>C (rs1800532) polymorphism within the TPH1 gene have been previously described (25). The primers, forward 5'-TTCCATCCGTCCTGTGGCTGGTTA-3'; reverse 5'-TTTGAACAGCCTCCTCTGAAGCGC-3', were used to amplify the TPH1 gene. PCR was performed in a 25 [micro]l volume with 50 ng DNA, 100 [micro]m dNTPs, 20 pmol of each primer, 1.5 mM Mg[Cl.sub.2], 1x PCR buffer with (N[H.sub.4])S[O.sub.4] (Fermentas, Vilnius, Lithuania,) and 1U Taq DNA polymerase (Fermentas, Vilnius, Lithuania). Amplification was performed on an automated Thermal Cycler (Techne Flexigene, Cambridge, UK). PCR conditions were 3 min for initial denaturation at 95[degrees]C; 35 cycles at 95[degrees]C for 45 s for denaturation, 45 s at 68[degrees]C for annealing and 1 min at 72[degrees]C for extension, followed by 7 min at 72[degrees]C for final extension. After amplification, PCR products were digested by restriction endonuclease 10 U Nhel (Fermentas, Vilnius, Lithuania) for 14 h at 37[degrees]C; the genotyping of the TPH1 gene was determined by fragment separation at 120 V for 40-50 min on a 2.5% Agarose gel containing 0.5 [micro]g/ml ethidium bromide. A 100 bp marker (100 bp DNA Ladder, Fermentas) was used as a size standard for each gel lane. The gel was visualized under UV light using visualization system for gel electrophoresis (Vilber Lourmat). The NheI restricted products of TPH1 gene 218 A>C; A/A, A/C and C/C genotypes had band sizes of 1024bp, 1024bp/660bp/364bp and 660bp/364bp, respectively. Genotyping was based upon independent scoring of the results obtained by two reviewers, who were unaware of case/control status.

c) Statistical Analysis

Distribution differences of TPH1 genotypes and alleles between patients and controls were determined using chi-square test and Fischer's exact test. In calculation of average of quantitative variables such as age distribution and education time in subgroups of patients, student-t test was used in their paired groups comparisons and ANOVA analysis was used in the multigroup comparisons. Genotype distribution was compared using Hardy-Weinberg equilibrium. P 0.05 was considered as statistically significant.


Patient group consisted of 116 subjects (52 females, 64 males) and control group consisted of 150 subjects (62 females, 88 males). The mean age of the patient group was 36.62 [+ or -] 12.98 with age range of 20-73 years. The mean age of the control group was 34.65 [+ or -] 11.24 years. Age and gender distributions were not significantly different between patients and the control group (p>0.05).

The distribution of TPH1 genotypes in patients with BD was as follows: A/A: 18 (15.5%), A/C: 49 (42.2%), C/C: 49 (42.2%). The distribution in the control group was: A/A: 20 (13.3%), A/C: 69 (46.0%), C/C: 61 (40.6%) (Table 1). The distribution of A/A, A/C and C/C genotypes in patient and control groups was comparable (15.5%, 13.3%; 42.2%, 42.2%; 46%, 40%) ([chi square]=0.46, df=2, p>0.05). Genotype distribution among the groups was in Hardy-Weinberg equilibration.

Among patients with BD, A allele was found in 85 (36.6%) and C allele in 147 (63.3%) patients, whereas in the control group, A allele was found in 109 (36.3%) and C allele in 191 (63.6%) subjects ([chi square]=0.00, df=1, p>0.05).

When both groups were divided into two new groups according to the presence and absence of C allele (C/C and A/C genotype versus A/A genotype), 58 patients (90.6%) and 72 control subjects (82.7%) had C allele, whereas 6 patients (9.3%) and 15 control subjects (17.2%) did not have C allele ([chi square]=9.37, df=8, p>0.05).

When the subjects in both groups were divided into two groups according to the presence and absence of A allele (A/A and A/C genotype versus C/C genotype), 35 patients (54.6%) and 51 control subjects (58.6%) had A allele, whereas 29 patients (45.3%) and 36 control subjects (41.3%) did not have A allele ([chi square]=0.23 df=1, p>0.05).

The distribution of genotypes in male patients and male controls were as follows: A/A (6: 9.3%; 16: 18.1%), A/C (29: 45.3%; 36: 40.9%) and C/C (29: 45.3%; 36: 40.9%) (p>0.05). The distribution of genotypes in female patients and female controls were as: A/A (23.0%; 6.4%), A/C (38.4%; 53.2%) and C/C (38.4%; 40.3%) (p>0.05). A/A genotype had the lowest frequency in patient and control groups. The frequency of A/A genotype was the lowest among female controls (Table 2). The frequency of A/A genotype in female patients was significantly higher compared to female controls ([chi square]=6.92, df=2, p<0.05).


The influence of TPH gene polymorphisms on psychiatric diseases has been studied. Zill et al. suggested an association between TPH2 gene variants and major depression (26). Eley et al. studied gene-environment interactions, 5HTT, 5HTR2A, 5HTR2C, monoamine oxidase subtype A (MAOA) and TPH1 genes in depressions during adolescence (27). They suggested that among depressive patients, particularly females, environmental risks together with SERT gene are important. HTR2A and TPH1 genes were important predictors independent of the effects and interactions of environmental risk and gender factor. Rotondo et al. reported that the distribution of TPH1 polymorphism was different in bipolar patients with panic disorder compared to bipolar patients without panic disorder (28). They also supported the hypothesis, which suggests that patients with accompanying panic disorder would be a separate subtype of BD.

Cusin et al. reported that there is no difference in the frequency of TPH1 gene among patients with unipolar depressions, BD and rapid-cycling BD (29). Serretti et al. reported less depressive symptoms in male patients with TPH1 A allele compared to patients with TPH1 gene C allele, although TPH1 gene 218 A>C gene variant was not different between groups (5). They suggested that variants containing TPH1 gene A allele might be a protective factor for depressive symptoms in male patients or this genotype might be related to a subtype of mood disorders characterized by manic symptoms.

Furlong et al. could not find a significant difference between patients with affective disorder with or without suicide attempts in respect to TPH1 gene polymorphism (30). Sourey et al. reported no difference in TPH1 218 A>C polymorphism in patients with unipolar or bipolar mood disorder, however, the frequency of C/C genotype was higher among patients with unipolar mood disorder having history of suicide attempt compared to the controls (31).

Serretti et al. reported that bipolar and depressive patients having TPH1 A/A genotype had poor response to lithium therapy (32).

Serretti et al. reported poor response to therapy with serotonin reuptake inhibitors in depressive and bipolar depressive patients having TPH1 A/A genotype (24).

Mizuno et al. demonstrated a lack of relationship between smoking and TPH1 218 A>C gene polymorphism in Japanese population, but confirmed the early onset of smoking in patients with A/A genotype (33). Sekizawa et al. suggested a two-fold increased risk of early onset schizophrenia in children with TPH1 A/A genotype compared to the other genotypes (34).

The major evidence in our study is the observation of A/A genotype at higher frequency in female patients than female controls. Neither genotype nor allele distribution differences were present between patient and control groups with regard to the other variables. Also according to gender, no difference was established regarding genotype and allele distributions among patients.

Yildiz et al. reported a gender-specific relationship between rapid cycling and use of antidepressants, prior to the first episode of mania/hypomania in patients with BD (35). They suggested that the use of antidepressants would be associated with an increased risk of rapid cycling in female patients compared to males. This suggests that gender factor and serotonergic system should be considered in the context of BD.

We herein report different distribution of TPH1 gene 218 A>C gene polymorphism between patients and healthy controls which could be explained by different clinical presentation and course in male and female patients with BD. Furthermore, this gene polymorphism would be a contributing factor in female patients for the development of the disease. This is the first study demonstrating the female gender-related difference in TPH1 gene polymorphism among patients with BD.

In conclusion, the relation between BD and TPH1 gene 218 A>C polymorphism demands further investigations. Studies are required containing independent samples with higher number of patients. Focusing on the phenotypic subtypes of the disease would enable us to conduct studies on a relatively homogenous population and would give us the opportunity to identify the genes influencing a complex disease. Possible important subtypes of TPH gene polymorphism are: BD with or without suicidal behavior, early or late onset, rapid cycling, responsiveness/irresponsiveness to lithium therapy. Future studies on the association of genes with the clinical signs and symptoms, and the course of the disease (number and type of attacks, etc) would open up new horizons.

DOI: 10.4274/npa.5326


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Murat Eren OZEN, Mehmet YUMRU *, M. Emin ERDAL **, Hasan HERKEN ***, Haluk A. SAVAS ****

Nobel Tip Merkezi, Psikiyatri Bolumu, Adana, Turkiye

* Dunya Tip Merkezi, Psikiyatri Bolumu, Antalya, Turkiye

** Mersin Universitesi Tip Fakultesi, Genetik Anabilim Dali, Mersin, Turkiye

*** Pamukkale Universitesi Tip Fakultesi, Psikiyatri Anabilim Dali, Denizli, Turkiye

**** Gaziantep Universitesi Tip Fakultesi, Psikiyatri Anabilim Dali, Gaziantep, Turkiye

Address for Correspondence/Yazisma Adresi: Dr. Murat Eren Ozen, Nobel Tip Merkezi, Psikiyatri Bolumu, Adana, Turkiye

E-posta: Received/Gelis tarihi: 12.06.2009 Accepted/Kabul tarihi: 20.04.2010
Table 1. Genotype distribution in BD and control samples

          A/A (%)     A/C (%)      C/C (%)      Total (%)

BD        18 (15.5)   49 (42.2)    49 (42.2)    116 (100.0)
Control   20 (13.3)   69 (46.0)    61 (40.6)    150 (100.0)
Total     38 (14.2)   118 (44.3)   110 (41.3)   266 (100.0)

([chi square]=0.46, df=2, p>0.05)

Table 2. Genotype distribution in female
patients and female controls

           A/A (%)     A/C (%)     C/C (%)     Total (%)

Patient   12 (23.0)   20 (38.4)   20 (38.4)   52 (100.0)
Control    4 (6.4)    33 (53.2)   25 (40.3)   62 (100.0)
Total     16 (14.0)   53 (46.4)   45 (39.4)   114 (100.0)

([chi square] = 6.92 df = 2 p=.031)
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Title Annotation:Research Article/Arastirma Makalesi
Author:Ozen, Murat Eren; Yumru, Mehmet; Erdal, M. Emin; Herken, Hasan; Savas, Haluk A.
Publication:Archives of Neuropsychiatry
Article Type:Clinical report
Geographic Code:7TURK
Date:Jun 1, 2010
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