Association study of MAO‐A,COMT, 5‐HT2A,DRD2, and DRD4 polymorphisms with illness time course in mood disorders

The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO‐A), catechol‐O‐methyltransferase (COMT), serotonin receptor 2A (5‐HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR‐based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO‐A, COMT, 5‐HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders. © 2002 Wiley‐Liss, Inc.     

Serotonin‐2C and serotonin‐1A receptor genes are not associated with psychotic symptomatology of mood disorders

The serotonergic system is involved in both pathophysiology and treatment of mood disorders. In the present study we investigated the possible influence of the polymorphisms of the serotonin‐1A and 2C receptor genes on the symptomatology of mood disorders. Eighty‐four inpatients affected by mood disorders (72 bipolar and 12 major depressive disorder) were assessed by the Operational Criteria Checklist for Psychotic Illness to score their lifetime psychotic symptomatology. The subjects were also typed for 5HT1A and 5HT2C variants using polymerase chain reaction techniques. No association was found between 5HT2C and psychopathology as defined by the four symptomatologic factors used as phenotype definition (mania, depression, delusion, and disorganization) even when bipolar subjects were analyzed separately. Only one subject with the 5HT1A variant was observed. Genetic variation at the 5HT1A and 5HT2C receptor genes does not, therefore, play a major role in the pathogenesis of mood disorders symptomatology. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:161–166, 2000. © 2000 Wiley‐Liss, Inc.     

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.     

Cognitive effects of genetic variation in monoamine neurotransmitter systems: A population‐based study of COMT,MAOA, and 5HTTLPR

Individual differences in cognitive function are highly heritable and most likely driven by multiple genes of small effect. Well‐characterized common functional polymorphisms in the genes MAOA, COMT, and 5HTTLPR each have predictable effects on the availability of the monoamine neurotransmitters dopamine, noradrenaline, and serotonin. We hypothesized that 5HTTLPR genotype would show little association with prefrontal cognitive performance, but that COMT and MAOA would have interacting effects on cognition through their shared influence on prefrontal catecholamine availability. We assessed the individual and epistatic effects of functional polymorphisms in COMT, MAOA, and 5HTTLPR on children's prefrontal cognitive function in nearly 6,000 children from the population‐based Avon Longitudinal Study of Parents and Children (ALSPAC). Neither MAOA nor 5HTTLPR polymorphisms showed significant effects on cognitive function. In boys but not girls, there was a modest but statistically significant interaction between MAOA and COMT genotypes such that increased prefrontal catecholamine availability was associated with better working memory. These results suggest that assessment of multiple genes within functionally related systems may improve our understanding of the genetic basis of cognition. © 2010 Wiley‐Liss, Inc.     

Pharmacogenetics of lithium prophylaxis in mood disorders: Analysis of COMT,MAO‐A,and Gβ3 variants

We studied the possible association between the prophylactic efficacy of lithium in mood disorders and the following gene variants: catechol‐O‐methyltransferase (COMT) G158A, monoamine oxydase A (MAO‐A) 30‐bp repeat, G‐protein β 3‐subunit (Gβ3) C825T. A total of 201 subjects affected by bipolar (n = 160) and major depressive (n = 41) disorder were followed prospectively for an average of 59.8 months and were typed for their gene variants using PCR techniques. COMT, MAO‐A, and Gβ3 variants were not associated with lithium outcome, even when possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment, and previous episodes were included in the model. The pathways influenced by those variants are not therefore involved with long‐term lithium outcome in our sample. © 2002 Wiley‐Liss, Inc.     

No interaction between serotonin transporter gene and dopamine receptor D4 gene in symptomatology of major psychoses

Previously, we reported an association of the dopamine receptor D4 (DRD4) gene with delusional symptomatology of major psychoses. However, DRD4 variants accounted for only 2% of the phenotypic variance, indicating that contributions from other genes were probable. The serotonin transporter gene is a primary candidate in major psychoses, and a functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has recently been reported to be associated with a number of psychopathological conditions. In the present study we investigated the original cohort of subjects to evaluate the 5-HTTLPR possible influence on the psychopathology of major psychoses in interaction with DRD4. Four hundred and sixty-one inpatients affected by major psychoses were assessed by the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and were also typed for the 5-HTTLPR and DRD4 variants using polymerase chain reaction techniques. Mania, depression, delusion, and disorganization were the four symptomatologic factors used as phenotype definition. 5-HTTLPR variants did not significantly influence the previously reported association of DRD4 with delusional symptoms. No interaction was observed on the other symptom factors. The serotonin transporter gene does not, therefore, interact with DRD4 in determining the symptomatology of major psychoses. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:481–485, 1999. © 1999 Wiley-Liss, Inc.     

No association between 5HT‐2A and bipolar disorder irrespective of genomic imprinting

Recent evidence that 5HT‐2A may be subjected to genomic imprinting prompted us to examine a collection of Irish family trios (an affected individual and both parents) for evidence of an association between 5HT‐2A and bipolar disorder. Family trios offer an advantage over case control studies in regard to genomic imprinting since with family trios it is possible to trace the path of alleles from the parents to the offspring. Using haplotype‐based haplotype relative risk (HHRR) and transmission/disequilibrium (TDT) analyses, no evidence was found for an association of 5HT‐2A with bipolar affective disorder under the assumption of no imprinting and of imprinting. © 2001 Wiley‐Liss, Inc.     

Family‐based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking

A recent study showed an association between the dopamine D2 receptor gene (DRD2) and smoking. The purpose of this study was to determine if the familial transmission of smoking is linked to variation at the DRD2 locus in a genetically informative sample. Subjects were identified in alcohol treatment centers and their relatives were recruited for study. All subjects were interviewed to assess alcohol dependence, smoking habits, and psychiatric disorders. Two polymorphisms within the DRD2 gene were analyzed, including the TaqIA polymorphism. The sample consisted of 138 nuclear families with at least one offspring with habitual smoking, and analysis was by the transmission disequilibrium test (TDT), which avoids problems due to population stratification. There was no significant difference in the frequency between DRD2 alleles transmitted and not transmitted to habitual smokers. There also was no evidence for unequal transmission of DRD2 alleles for the phenotypes “ever smoker” or comorbid alcohol dependence and habitual smoking. This study does not support linkage of the DRD2 with smoking. Am. J. Med. Genet. 90:299–302, 2000. © 2000 Wiley‐Liss, Inc.     

Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders

The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.     

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.     

Alterations in the steroid biosynthetic pathways in the human prefrontal cortex in mood disorders: A post‐mortem study

Altered levels of steroids have been reported in the brain, cerebral spinal fluid and plasma of patients with mood disorders. Neuroimaging studies have reported both functional and structural alterations in mood disorders, for instance in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). In order to determine whether the endogenous production of steroids is altered in the ACC and DLPFC of patients with major depressive disorder (MDD) or bipolar disorder (BPD), quantitative real‐time PCR was performed to detect mRNA expression level of key enzymes in the steroid biosynthetic pathways. In MDD, a significant decrease in mRNA level of cytochrome P450 17A1 (CYP17A1, synthesizing C19 ketosteroids) in the ACC and a significant increase in mRNA levels of hydroxysteroid sulfotransferase 2A1 [SULT2A1, catalyzing the sulfate conjugation of dehydroepiandrosterone (DHEA)] were observed in the DLPFC, suggesting alterations in DHEA and its sulfate metabolite DHEAS levels. Decreased intensity and distribution of CYP17A1 immunohistochemical staining was found in the ACC of MDD patients. Interestingly, there was a significant positive correlation between the mRNA levels of CYP17A1 and tyrosine‐related kinase B (TrkB) full length isoform. In a unique post‐mortem human brain slice culture paradigm, BDNF mRNA expression was found to be significantly increased following incubation with DHEA. Together, these data indicate a close relationship between DHEA and BDNF‐TrkB pathways in depression. Furthermore, in the DLPFC, higher mRNA levels of 11β‐hydroxysteroid dehydrogenase‐1 (HSD11B1, reducing cortisone to the active hormone cortisol) and steroidogenic acute regulatory protein (STAR, facilitating the shuttle of cholesterol through the intermembrane space) were found in the MDD patients and BPD patients, respectively. In conclusion, this study suggests the presence of a disturbance in the endogenous synthesis of DHEA and DHEAS in mood disorders, which has a close relationship with BDNF‐TrkB signaling.     

Testing the diathesis‐stress model: 5‐HTTLPR,childhood emotional maltreatment,and vulnerability to social anxiety disorder

Regarding the development of social anxiety disorder (SAD), a diathesis‐stress paradigm including biological vulnerabilities and environmental stressors can be assumed. However, studies dealing with the etiology of SAD did not integrate both aspects so far. We examined a particular diathesis‐stress model for SAD in which we included a functional polymorphism of the serotonin transporter (5‐HTTLPR) as a genetic vulnerability factor and childhood emotional maltreatment (CEM) as an environmental stressor. Current analyses were based on individuals who participated in the Study of Health in Pomerania. Psychiatric disorders were assessed with diagnostic interviews according to DSM‐IV criteria. The triallelic genotype of 5‐HTTLPR was determined. Statistical analyses were performed in 78 individuals with SAD and 1,035 without an axis I disorder. Logistic regression analysis revealed that the experience of CEM (odds ratio [OR] 4.56; 95% confidence interval [CI] 2.65–7.84), the l/l genotype of 5‐HTTLPR (OR 2.13; 95% CI 1.31–3.48), female gender (OR 3.03; 95% CI 1.80–5.08) and younger age (OR 1.04; 95% CI 1.02–1.06) increased the odds for SAD. The data suggest that CEM, the l/l genotype of 5‐HTTLPR, female gender and younger age are risk factors for SAD. This is in favor of the tested diathesis‐stress model. © 2013 Wiley Periodicals, Inc.     

Association Analysis of TPH2, 5-HT2A,and 5-HT6 With Executive Function in a Young Chinese Han Population

Abstract: The 5-hydroxytryptamine (5-HT) system is widely distributed in the central nervous system. A growing body of evidence has suggested that the neurotransmitter system is implicated in the functions of the prefrontal cortex. So far, several studies have revealed that some functional genetic variants in TPH2, 5-HT2A, and 5-HT6 genes are possibly related to executive function. To investigate the potential influences of TPH2, 5-HT2A, and 5-HT6 on the components of executive function, the authors performed a population-based study with standard cognitive paradigms in a young Chinese Han group. The results indicated that ?703 G/T polymorphism of TPH2 was associated with the performance of response inhibition (p = .002) and the T allele carriers (TT and GT) had fewer errors than the noncarriers (GG) did in the response inhibition test. Furthermore, there were no significant associations of the T102C in 5-HT2A and T267C in 5-HT6 with the components of executive function after correcting for multiple tests (p > .05). The present study suggests that TPH2 contributes distinctively to the inhibition domain of executive function, whereas 5-HT2A and 5-HT6 show no striking effects on executive function in the Chinese Han population.     

A dimensional impulsive‐aggressive phenotype is associated with the A218C polymorphism of the tryptophan hydroxylase gene: A pilot study in well‐characterized impulsive inpatients

Tryptophan hydroxylase (TPH) is the rate‐limiting enzyme in the biosynthesis of serotonin, and association and linkage studies of its variants in suicidal and impulsive‐aggressive behavior have brought conflicting results. This pilot study was designed to investigate whether TPH A218C genotypes could be associated with impulsive behavioral tendencies (IBTs) in consecutively admitted nonpsychotic nonorganic inpatients. Patients (20 females and 34 males; age, 38.8 ± 11.8) did not differ from healthy nonimpulsive controls (16 females and 11 males; age, 35.2 ± 10.2) regarding TPH genotypes, but in the patients, the number of IBT was related to the presence of the 218C allele. It was concluded that impulsive‐aggressive behavior may be associated with the TPH genotype in well‐characterized impulsive patients and that the present results stress the importance of considering impulsiveness‐aggressiveness in studies investigating the relationship between suicidal behavior and TPH genotypes. © 2002 Wiley‐Liss, Inc.