No Evidence of an Association between A218C Polymorphism of the Tryptophan Hydroxylase 1 Gene and Aggression in Schizophrenia in a Korean Population

Purpose

We investigated the association between the tryptohan hydroxylase 1 (TPH1) gene and aggression in schizophrenia in a Korean population.

Materials and Methods

The sample included 61 aggressive patients as well as 104 non-aggressive patients from psychiatric hospitals and 335 healthy volunteers in Korea. Blood samples were collected from all participants for TPH1 A218C genotyping. The patients were administered standard psychiatric interviews as well as a self-report questionnaire for anger-related traits.

Results

In the case-control phenotypic comparisons, there was no significant association between the aggressive patients and the TPH1 A218C polymorphism. There was no significant effect of the TPH1 genotype on the anger-related traits, or no significant interaction between the genotype and group (aggressive and non-aggressive patients).

Conclusion

These findings suggest that TPH1 does not play a major role in aggressive behavior via anger in schizophrenic patients.     

Population-specific functional variant of the TPH2 gene 2755C>A polymorphism contributes risk association to major depression and anxiety in Chinese peripartum women

The rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase 2 (TPH2), is one of the most promising candidate genes for psychiatric disorders. Although evidence strongly suggests that the TPH2 is significant in the etiology of major depression and anxiety disorder, whether it also contributes to the etiology of peripartum major depression and anxiety disorder, a specific subtype influenced considerably by other environmental factors like hormones, is unclear. This study investigated the role of TPH2 in the etiology of peripartum major depression and anxiety disorder in a Han Chinese population in Taiwan. Six single nucleotide polymorphisms were selected from previously profiled genetic information of TPH2 in Han Chinese. A cohort of postpartum Chinese women that included 117 patients with major depression, anxiety disorder, or both and 83 healthy controls were genotyped with selected TPH2 markers. The TPH2 2755A allele was found only in women with peripartum major depression and anxiety disorder (p = 0.043) and exhibited a dominant gene action (p = 0.038) with an estimated disease risk of 1.73. Although the sample size is small, results from this study suggest that the TPH2 C2755A polymorphism may represent a population-specific risk factor for peripartum major depression and anxiety disorder, perhaps by interacting with hormones.     

Resting state functional connectivity of five neural networks in bipolar disorder and schizophrenia

Background

Bipolar disorder (BPD) and schizophrenia (SCZ) share clinical characteristics and genetic contributions. Functional dysconnectivity across various brain networks has been reported to contribute to the pathophysiology of both SCZ and BPD. However, research examining resting-state neural network dysfunction across multiple networks to understand the relationship between these two disorders is lacking.

Methods

We conducted a resting-state functional connectivity fMRI study of 35 BPD and 25 SCZ patients, and 33 controls. Using previously defined regions-of-interest, we computed the mean connectivity within and between five neural networks: default mode (DM), fronto-parietal (FP), cingulo-opercular (CO), cerebellar (CER), and salience (SAL). Repeated measures ANOVAs were used to compare groups, adjusting false discovery rate to control for multiple comparisons. The relationship of connectivity with the SANS/SAPS, vocabulary and matrix reasoning was investigated using hierarchical linear regression analyses.

Results

Decreased within-network connectivity was only found for the CO network in BPD. Across groups, connectivity was decreased between CO-CER (p<0.001), to a larger degree in SCZ than in BPD. In SCZ, there was also decreased connectivity in CO-SAL, FP-CO, and FP-CER, while BPD showed decreased CER-SAL connectivity. Disorganization symptoms were predicted by connectivity between CO-CER and CER-SAL.

Discussion

Our findings indicate dysfunction in the connections between networks involved in cognitive and emotional processing in the pathophysiology of BPD and SCZ. Both similarities and differences in connectivity were observed across disorders. Further studies are required to investigate relationships of neural networks to more diverse clinical and cognitive domains underlying psychiatric disorders.     

The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression

Background  

The COMT gene is located on chromosome 22q11, a region strongly implicated in the aetiology of several psychiatric disorders, in particular schizophrenia. Previous research has suggested that activity and expression of COMT is altered in schizophrenia, and is mediated by one or more polymorphisms within the gene, including the functional Val¹⁵⁸Met polymorphism.     

Tryptophan hydroxylase 1 gene (TPH1) moderates the influence of social support on depressive symptoms in adults

BACKGROUND: Tryptophan hydroxylases (TPHs) are involved in the biosynthesis of serotonin and are therefore candidate genes for psychiatric disorders, including depression. We examined whether the common 218 A > C and 779 A > C polymorphisms in the tryptophan hydroxylase 1 gene (TPH1) moderated the association between perceived social support and sub-clinical depressive symptoms in adults. METHODS: The subjects were a randomly selected subsample (n=341) of individuals participating in the Cardiovascular Risk in Young Finns study, who had data on social support on one assessment time and depressive symptoms on two assessment times. Social support was assessed on the Perceived Social Support Scale Revised (PSSS-R) and depressive symptoms on a modified version of the Beck's Depression Inventory (BDI). RESULTS: We found that low social support predicted depressive symptoms more strongly in individuals carrying A alleles of the TPH1 than in others. The interaction effect was observed in a cross-sectional analysis and when predicting depressive symptoms over a four-year period. LIMITATIONS: We did not have data on TPH2, which has recently been identified as the primary TPH isomorphism affecting serotonin synthesis in the brain. CONCLUSIONS: TPH1 gene may be involved in the development of depressive symptoms by moderating the impact of depressogenic social influences.     

Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms

Background

Major depressive disorder (MDD) and bipolar disorder (BPD) have significant genetic predisposition. The P2RX7 gene (coding for P2X7 purinergic receptor) has been suggested as a susceptibility gene for both MDD and BPD. In the current study the genetic effects of rs2230912 (Gln460Arg) and rs1653625 (located in the 3′ untranslated region of the P2RX7 gene) were explored in mood disorders.

Methods

Genotype frequencies were established in 315 patients (195 with MDD and 120 with BPD diagnosis) and in 373 controls. Depression severity was assessed by the clinician-rated Montgomery–Åsberg Depression Rating Scale (MADRS) and by the self-report Hospital Anxiety and Depression Scale (HADS).

Results

In the case-control analysis we did not find any significant differences between genotype frequencies of either BPD or MDD cases and controls. However, BPD patients carrying at least one rs2230912 G-allele scored higher on both MADRS and HADS-depression scale (nominal p-value was 0.028 and 0.003, respectively). The rs1653625 AA genotype was also associated with higher depression scores in the BPD group (nominal p-value of MADRS: 0.019, HADS-depression: 0.017). After correction for multiple testing, the association between rs2230912 and HADS-depression score remained significant in the BPD group (p<0.006); this genetic effect explained 9% of the variance (partial η²=0.09). In the MDD group we did not find any significant genetic effect.

Limitations

The relatively small number of BPD patients warrants for a replication study.

Conclusions

Our genetic association study supports the association between P2RX7 gene and severity of depressive symptoms in BPD patients.     

Comparison of early maladaptive schemas between borderline personality disorder and chronic depression

Borderline personality disorder (BPD) and chronic depression (CD) are common and challenging mental disorders. Maladaptive cognitive schemas have been proposed to increase vulnerability to both disorders. In order to elucidate the role of maladaptive cognitive schemas in BPD and CD, this study compared psychiatric outpatients with BPD (N = 30) and CD (N = 30) in terms of early maladaptive schemas (EMSs). The groups were compared using the Young Schema Questionnaire short form‐extended (YSQ‐S2‐extended) and the 15D health status questionnaire. BPD patients showed higher endorsement on the majority of EMSs, poorer social functioning, and greater concurrent distress than CD patients. However, after controlling for concurrent effects of psychological distress, the groups did not differ in 14 out of the 18 EMSs. These findings point to significant similarities in maladaptive beliefs between the 2 disorders and do not support broad, specific patterns of EMSs associated with either disorder. The results highlight the need for further study of the role of maladaptive schemas in the development and treatment of chronic mental disorders.     

Variation in tryptophan hydroxylase-2 gene is not associated to male completed suicide in Estonian population

Dysfunction of the central serotonergic system has been related to a spectrum of psychiatric disorders, including suicidal behavior. Tryptophan hydroxylase isoform 2 (TPH2) is the rate-limiting enzyme in the biosynthetic pathway of serotonin, being expressed in serotonergic neurons of raphe nuclei. We investigated genetic variation in TPH2 gene in two samples of male subjects: 288 suicide completers and 327 volunteers, in order to reveal any associations between 14 single nucleotide polymorphisms and completed suicide. No associations were revealed neither on allelic nor haplotype level. Our finding does not support the hypothesis of TPH2 being a susceptibility factor for completed suicide in males of Estonian origin.     

Evaluation of <Emphasis Type="Italic">SLC11A1</Emphasis>as an inflammatory bowel disease candidate gene

Background  

Significant evidence suggests that a promoter polymorphism withinthe gene SLC11A1 is involved in susceptibility to both autoimmune and infectious disorders. The aim of this study was to evaluate whether SLC11A1 has a role in the susceptibility to inflammatory bowel disease (IBD) by characterizing a promoter polymorphism within the gene and two short tandem repeat (STR) markers in genetic proximity to SLC11A1.     

Modeling complex genetic and environmental influences on comorbid bipolar disorder with tobacco use disorder

Background  

Comorbidity of psychiatric and substance use disorders represents a significant complication in the clinical course of both disorders. Bipolar Disorder (BD) is a psychiatric disorder characterized by severe mood swings, ranging from mania to depression, and up to a 70% rate of comorbid Tobacco Use Disorder (TUD). We found epidemiological evidence consistent with a common underlying etiology for BD and TUD, as well as evidence of both genetic and environmental influences on BD and TUD. Therefore, we hypothesized a common underlying genetic etiology, interacting with nicotine exposure, influencing susceptibility to both BD and TUD.     

The impact of the Catechol-O-methyltransferase Val158Met polymorphism on survival in the general population – the HUNT study

Background  

The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met which has been related to common diseases like cancer, psychiatric illness and myocardial infarction. Whether the Val158Met polymorphism is associated with survival has not been evaluated in the general population. The aim of this prospective study was to evaluate the impact of codon 158 COMT gene polymorphism on survival in a population-based cohort.     

A common TPH2 haplotype regulates the neural processing of a cognitive control demand

The monoamine neurotransmitter, serotonin, critically regulates the function of the cerebral cortex and is involved in psychiatric disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin with the neuron-specific TPH2 isoform present exclusively in the brain and encoded by the TPH2 gene on chromosome 12q21. The haplotype structure of TPH2 was defined for 16 single-nucleotide polymorphisms (SNPs) in a healthy subject population and a haplotype block analysis confirmed the presence of a six SNP haplotype in a yin configuration that has previously been associated with risk for suicidality, depression, and anxiety disorders. Functional magnetic resonance imaging (fMRI) was used to assess the influence of TPH2 variation on brain function related to cognitive control using the Multi-Source Interference Task (MSIT). The MSIT-related blood oxygen level-dependent (BOLD) response was increased with increasing copies of the TPH2 yin haplotype for the dorsal anterior cingulate cortex (dACC), right inferior frontal cortex (IFC), and anterior striatum. A functional connectivity analysis further revealed that increasing numbers of the TPH2 yin haplotype was associated with diminished functional coupling between the dACC and the right IFC, precentral gyrus, parietal cortex and dlPFC. A moderation analysis indicated that the relationship between neural processing networks and cognitive control was significantly modulated by allelic variation for the TPH2 yin haplotype. These findings suggest that the association of risk for psychiatric disorders with a common TPH2 yin haplotype is related to the inefficient functional engagement of cortical areas involved in cognitive control and alterations in the mode of functional connectivity of dACC pathways. ? 2012 Wiley Periodicals, 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.     

Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes

Background

The TPH2 gene encodes the enzyme responsible for serotonin (5-HT) synthesis in the Central Nervous System (CNS). Stereotypic and repetitive behaviors are influenced by 5-HT, and initial studies report an association of TPH2 alleles with childhood-onset obsessive-compulsive disorder (OCD) and with autism. GLO1 encodes glyoxalase I, the enzyme which detoxifies α-oxoaldehydes such as methylglyoxal in all living cells. The A111E GLO1 protein variant, encoded by SNP C419A, was identifed in autopsied autistic brains and proposed to act as an autism susceptibility factor. Hyperserotoninemia, macrocephaly, and peptiduria represent some of the best-characterized endophenotypes in autism research.

Methods

Family-based and case-control association studies were performed on clinical samples drawn from 312 simplex and 29 multiplex families including 371 non-syndromic autistic patients and 156 unaffected siblings, as well as on 171 controls. TPH2 SNPs rs4570625 and rs4565946 were genotyped using the TaqMan assay; GLO1 SNP C419A was genotyped by PCR and allele-specific restriction digest. Family-based association analyses were performed by TDT and FBAT, case-control by χ², endophenotypic analyses for 5-HT blood levels, cranial circumference and urinary peptide excretion rates by ANOVA and FBAT.

Results

TPH2 alleles and haplotypes are not significantly associated in our sample with autism (rs4570625: TDT P = 0.27, and FBAT P = 0.35; rs4565946: TDT P = 0.45, and FBAT P = 0.55; haplotype P = 0.84), with any endophenotype, or with the presence/absence of prominent repetitive and stereotyped behaviors (motor stereotypies: P = 0.81 and 0.84, verbal stereotypies: P = 0.38 and 0.73 for rs4570625 and rs4565946, respectively). Also GLO1 alleles display no association with autism (191 patients vs 171 controls, P = 0.36; TDT P = 0.79, and FBAT P = 0.37), but unaffected siblings seemingly carry a protective gene variant marked by the A419 allele (TDT P < 0.05; patients vs unaffected siblings TDT and FBAT P < 0.00001).

Conclusion

TPH2 gene variants are unlikely to contribute to autism or to the presence/absence of prominent repetitive behaviors in our sample, although an influence on the intensity of these behaviors in autism cannot be excluded. GLO1 gene variants do not confer autism vulnerability in this sample, but allele A419 apparently carries a protective effect, spurring interest into functional correlates of the C419A SNP.     

Predominant expression of tryptophan hydroxylase 1 mRNA in the pituitary: A postmortem study in human brain

Although the predominant role of tryptophan hydroxylase 2 (TPH2) in the CNS and its influence on the vulnerability to psychiatric disorders have clearly been demonstrated in several studies, the role of TPH1 on neuronal mechanisms, respectively on behavioral traits is still poorly understood. In a previous study of tryptophan hydroxylase 1 (TPH1) and TPH2 mRNA expression in different human brain regions we observed significantly higher TPH1 than TPH2 mRNA concentrations in the pituitary (unpublished observations). Considering the importance of the pituitary in the functional circuits between brain and body, we investigated the TPH1 and TPH2 mRNA expression in more detail, using human postmortem samples of the posterior and anterior pituitary compared to cortex, hippocampus and raphe nuclei. Specimens were available from different psychiatric patients (drug abusers, n=12; suicide victims, n=11; schizophrenics, n=9) and controls (n=15). Additionally we performed immunohistochemical analysis applying monospecific antibodies for both TPH isoforms to verify that the mRNA is of cellular and not just vascular or other origin. Highest TPH2 mRNA levels were observed in the raphe nuclei in patients and controls. By contrast, in the anterior and posterior pituitary TPH1 was found to be the predominantly expressed isoform in all subgroups. TPH1 and TPH2 mRNA expression in the further brain regions was only marginal and nearly identical except in the hypothalamus where higher TPH1 than TPH2 mRNA levels could be measured. Interindividual differences between the subgroups were not detectable. The results of the present study extended our previous findings by the additional immunohistochemical determination of the neuronal TPH1 and TPH2 protein expression in the anterior pituitary and provide evidence against a strictly separated duality of the serotonergic system. It seems that TPH1 might also have an impact on neuronal mechanisms via hypothalamic–pituitary–adrenal axis regulation by its predominant localization in the pituitary. These observations may open up new research strategies not only for several psychiatric disorders, but also for the relationship between psychiatric and somatic diseases.     

Psychometric properties of the Spanish version of the involvement evaluation questionnaire in caregivers of patients with borderline personality disorders

The involvement evaluation questionnaire (IEQ) was created to evaluate the caregiver's experience of burden and the consequences of providing care to people with psychotic disorders. To date, the IEQ has not been validated with caregivers of people diagnosed with borderline personality disorder (BPD). The main objective of the study was to confirm the psychometric properties and factorial structure of the Spanish version of the IEQ in 151 caregivers of people with BPD, with an average age of 54.52 (SD = 9.91). Two models were tested by means of confirmatory factor analysis, following the original factor structure. The Models 1 and 2 displayed adequate fit, with comparative fit index and Tucker‐Lewis index > 0.90 and root‐mean‐square root of approximation < 0.08; however, Model 2 was more parsimonious. The Cronbach's alphas are adequate, ranging from 0.70 to 0.85. The consequences of providing care to people with BPD had a low or moderate association with the Level of Expressed Emotion scores. IEQ scores of caregivers of people diagnosed with BPD with psychiatric comorbidity did not differ from those of caregivers of people diagnosed with BPD without psychiatric comorbidity. The IEQ has adequate psychometric properties and can be utilized to assess burden in caregivers of people with BPD.     

Promoter polymorphism -119C/G in MYG1 (C12orf10) gene is related to vitiligo susceptibility and Arg4Gln affects mitochondrial entrance of Myg1

Background

The gene encoding carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (NOS1AP) is located on chromosome 1q23.3, a candidate region for schizophrenia, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Previous genetic and functional studies explored the role of NOS1AP in these psychiatric conditions, but only a limited number explored the sequence variability of NOS1AP.

Methods

We analyzed the coding sequence of NOS1AP in a large population (n = 280), including patients with schizophrenia (n = 72), ASD (n = 81) or OCD (n = 34), and in healthy volunteers controlled for the absence of personal or familial history of psychiatric disorders (n = 93).

Results

Two non-synonymous variations, V37I and D423N were identified in two families, one with two siblings with OCD and the other with two brothers with ASD. These rare variations apparently segregate with the presence of psychiatric conditions.

Conclusions

Coding variations of NOS1AP are relatively rare in patients and controls. Nevertheless, we report the first non-synonymous variations within the human NOS1AP gene that warrant further genetic and functional investigations to ascertain their roles in the susceptibility to psychiatric disorders.     

Recurrent suicide attempts in patients with depressive and anxiety disorders: The role of borderline personality traits

Background

The presence of a comorbid borderline personality disorder (BPD) may be associated with an increase of suicidal behaviors in patients with depressive and anxiety disorders. The aim of this study is to examine the role of borderline personality traits on recurrent suicide attempts.

Methods

The Netherlands Study on Depression and Anxiety included 1838 respondents with lifetime depressive and/or anxiety disorders, of whom 309 reported at least one previous suicide attempt. A univariable negative binomial regression analysis was performed to examine the association between comorbid borderline personality traits and suicide attempts. Univariable and multivariable negative binomial regression analyses were performed to identify risk factors for the number of recurrent suicide attempts in four clusters (type and severity of axis-I disorders, BPD traits, determinants of suicide attempts and socio-demographics).

Results

In the total sample the suicide attempt rate ratio increased with 33% for every unit increase in BPD traits. A lifetime diagnosis of dysthymia and comorbid BPD traits, especially the symptoms anger and fights, were independently and significantly associated with recurrent suicide attempts in the final model (n=309).

Limitations

The screening of personality disorders was added to the NESDA assessments at the 4-year follow-up for the first time. Therefore we were not able to examine the influence of comorbid BPD traits on suicide attempts over time.

Conclusions

Persons with a lifetime diagnosis of dysthymia combined with borderline personality traits especially difficulties in coping with anger seemed to be at high risk for recurrent suicide attempts. For clinical practice, it is recommended to screen for comorbid borderline personality traits and to strengthen the patient's coping skills with regard to anger.     

Treatment course and its predictors in patients with somatoform disorders: A routine outcome monitoring study in secondary psychiatric care

Aim

Somatoform disorders are common and often chronic. It would be helpful to distinguish those patients who are likely to have a positive treatment course from those who are likely to follow a negative course. Such studies of different somatoform disorders are scarce, especially in secondary psychiatric care. This study examined the 6‐month treatment course of psychological, physical symptoms, and functioning, and its predictors in a naturalistic sample of secondary psychiatric care outpatients with somatoform disorders.

Method

The present study used routine outcome monitoring data of patients with somatoform disorders regarding their 6‐month treatment course of psychological and physical symptoms as well as functioning. The following patient groups were included: total group of somatoform disorders (N = 435), and undifferentiated somatoform disorder (N = 242), pain disorder (N = 102), body dysmorphic disorder (N = 51), and hypochondriasis (N = 40). Measures were Mini‐International Neuropsychiatric Interview plus, Brief Symptom Inventory, Montgomery–?sberg Depression Rating Scale, Brief Anxiety Scale, Short Form Health Survey 36, and Physical Symptom Checklist (PSC).

Results

The study population generally showed high co‐morbidity, especially with anxiety and mood disorders. The PSC total score, body dysmorphic disorder, and hypochondriasis were significant predictors for the treatment course of symptoms (Brief Symptom Inventory), whereas the PSC total score was the only significant predictor for the course of functioning (Short Form Health Survey 36).

Conclusion

Secondary psychiatric care outpatients with somatoform disorders showed high co‐morbidity with anxiety and mood disorders, and an unfavourable 6‐month course of both symptoms and functioning. Clinical implications are discussed, such as additional treatment of co‐morbidity in somatoform disorders.