Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study.

The available data from preclinical and pharmacological studies on the role of the serotonin transporter (5-HTT) support the hypothesis that a dysfunction in brain serotonergic system activity contributes to the vulnerability to affective disorders (AD). 5-HTT is the major site of serotonin reuptake into the presynaptic neuron, and it has been shown that the polymorphic repeat polymorphism in the 5-HTT promotor region (5-HTTLPR) may affect gene-transcription activity. 5-HTT maps to chromosome 17 at position 17q11.17-q12, and the 5-HTTLPR polymorphisms have been extensively investigated in AD with conflicting results. The present study tested the genetic contribution of the 5-HTTLPR polymorphism in a large European multicenter case-control sample, including 539 unipolar (UPAD), 572 bipolar patients (BPAD), and 821 controls (C). Our European collaboration has led to efforts to optimize a methodology that attenuates some of the major limitations of the case-control association approach. No association was found with primary psychiatric diagnosis (UPAD and BPAD) and with phenotypic traits (family history of AD, suicidal attempt, and presence of psychotic features). Our negative findings are not attributable to the lack of statistical power, and may contribute to clarify the role of 5-HTTLPR polymorphism in AD.

Genetic association between the phospholipase A2 gene and unipolar affective disorder: a multicentre case-control study.

The co-segregation in one pedigree of bipolar affective disorder with Darier's disease whose gene is on chromosome 12q23-q24.1, and findings from linkage and association studies with the neighbouring gene of phospholipase A2 (PLA2) indicate that PLA2 may be considered as a candidate gene for affective disorders. All relevant genetic association studies, however, were conducted on bipolar patients. In the present study, the possible association between the PLA2 gene and unipolar affective disorder was examined on 321 unipolar patients and 604 controls (all personally interviewed), recruited from six countries (Belgium, Bulgaria, Croatia, Germany, Greece, and Italy) participating in the European Collaborative Project on Affective Disorders. After controlling for population group and gender, one of the eight alleles of the investigated marker (allele 7) was found to be more frequent among unipolar patients with more than three major depressive episodes than among controls (P<0.01); genotypic association was also observed, under the dominant model of genetic transmission (P<0.02). In addition, presence of allele 7 was correlated with a higher frequency of depressive episodes (P<0.02). These findings suggest that structural variations at the PLA2 gene or the chromosomal region around it may confer susceptibility for unipolar affective disorder.

Lack of association between the 5HT2A receptor polymorphism (T102C) and unipolar affective disorder in a multicentric European study.

We report here a case-control association study with T102C polymorphism in the serotonin 2A receptor gene (HTR2A) in patients affected by unipolar affective disorder (UPAD) and in controls. A total of 284 subjects were genotyped (142 UPAD and 142 controls). All subjects were interviewed using standard diagnostic interviews and matched. A homogenous population of unipolar patients with suicidal attempt was identified. Conditional logistic regression was applied. No association of the HTR2A polymorphism was found in the overall sample of 142 UPAD-control pairs regarding allele and genotype frequencies (P=0.36 and P=0.52 respectively) and homo-heterozygote distributions (P=0.91). This study confirms, in a multicentric European sample, the earlier observations that the T102C HTR2A polymorphism is not associated with UPAD. Nevertheless, a type 2 statistical error cannot be excluded. Therefore, to exclude the implication of HTR2A in UPAD, this result must be replicated in larger samples and in other populations using the transmission disequilibrium test and different polymorphisms around HTR2A.

Gene-environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms.

Genetic and environmental factors, as well as their interactions, are likely to be involved in psychiatric disorders. Considerable progress has been made in association and linkage studies with various candidate genes, at times with conflicting or ambiguous results. An environmental factor that has persistently shown associations with several psychiatric and neurological disorders is the season of birth. If it is the interaction of a specific gene allele with a specific season of birth that constitutes an increased (or decreased) risk for a disorder, then the individuals with this disorder are likely to have a season of birth variation in this gene allele. We investigated the variations in TPH, 5-HTTLPR and DRD4 gene polymorphisms according to seasonality of birth in 954 patients with unipolar affective disorder, bipolar affective disorder, and schizophrenia, respectively, and in 395 controls. We first analyzed season of birth variations in the gene alleles with one cycle or two cycles per year, and then compared specified birth seasons with each other. We found season of birth variations in these gene alleles that were different for different psychiatric disorders. Significant differences between cases and controls could be obtained when restricting the analysis within certain birth seasons but not within others. Our results thus suggest an interaction between the seasons of birth and the expression of the candidate genes, and that season of birth is a confounding variable when investigating the role of the candidate genes in susceptibility to psychiatric disorders.

Dopamine receptor D2 and D3 gene variants are not associated with the antidepressant effect of total sleep deprivation in bipolar depression.

Total sleep deprivation (TSD) is an effective treatment for mood disorders that is thought to act through an enhancement in several neurotransmitter pathways including dopaminergic transmission. Genetic factors are likely to play a major role in determining individual differences in TSD response. The aim of this study is to investigate the influence of dopamine receptor D3 (DRD3) and dopamine receptor D2 (DRD2) variants on TSD antidepressant efficacy in bipolar disorder. One hundred twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were treated with TSD and were genotyped for DRD3 first exon Gly/Ser variants and DRD2 codon 311 Ser/Cys variants using polymerase chain reaction techniques. DRD3 and DRD2 variants were not associated with TSD outcome. Consideration of possible stratification effects such as gender, age at onset and duration of illness did not reveal any association either. The tested gene variants are not a main factor influencing TSD outcome in bipolar disorder.

Multicentre Italian family-based association study on tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders.

OBJECTIVE: The aim of the present study was to investigate tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 genes in mood disorders using a family-based association approach. METHODS: The sample included 134 nuclear mood disorder families, with subjects affected by bipolar disorder (n=103) or major depressive disorder (n=58). All subjects were genotyped using polymerase chain reaction techniques. RESULTS: No significant transmission disequilibrium was found in the overall sample for any polymorphism. Analysis considering bipolar subjects only, or psychopathology traits as affection status did not influence the observed results. CONCLUSIONS: The study could not support the involvement of tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders.

SSRIs antidepressant activity is influenced by G beta 3 variants.

The aim of the present study was to test a possible effect of the G-protein beta3-subunit (Gbeta3) C825T gene variant on the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) in a sample of major and bipolar depressives, with or without psychotic features. Four hundred and ninety inpatients were treated with fluvoxamine 300 mg/day (n=362) or paroxetine 40 mg/day (n=128) and either placebo or pindolol in a double-blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. Gbeta3 allelic variants were determined in each subject using a PCR-based technique. Subjects with Gbeta3 T/T variants showed better response to treatment (P=0.009) and this effect was independent from analyzed demographic and clinical variables. These results confirm preliminary reports and shed further light on the genetics of the response to antidepressant treatments.

Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity.

The aim of the present study was to test a possible effect of the monoamine oxidase A (MAOA) and serotonin receptor 2A (5-HT-2A) gene variants on the antidepressant activity of fluvoxamine and paroxetine in a sample of major (n = 248) and bipolar (n = 195) depressives, with or without psychotic features. A total of 443 in-patients were treated with 300 mg fluvoxamine (n = 307) or 20-40 mg paroxetine (n = 136) for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD). Allele variants were determined in each subject using a PCR-based technique. We observed a marginal association between 5-HT-2A variants and antidepressant response while MAOA genotypes were not associated. Possible stratification factors, such as sex, diagnosis, presence of psychotic features, HAMD scores at baseline, pindolol augmentation and SSRIs plasma levels did not significantly influence the observed results. The investigated MAOA and 5-HT-2A gene variants, therefore, do not seem to play a major role in SSRI antidepressant activity.

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.

Pharmacogenetics of lithium prophylaxis in mood disorders: analysis of COMT, MAO-A, and Gbeta3 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 beta 3-subunit (Gbeta3) 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 Gbeta3 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.

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.

Pharmacogenetics in affective disorders.

Pharmacogenetics will be of substantial help in the field of affective disorders pharmacotherapy. The possible definition of a genetic liability profile for drug side-effects and efficacy will be of great help in treatments that need weeks to months to be effective. During the last few years, a number of groups have reported possible liability genes. The efficacy and time of onset of selective serotonin reuptake inhibitors have been associated with a polymorphism in the promoter region of the transporter (SERTPR) in many independent studies, while variants at the tryptophan hydroxylase gene, 5-HT2a receptor and G-protein beta3 have been associated with them in pilot studies. Lithium long-term prophylactic efficacy has been associated with SERTPR, TPH and inositol polyphosphate 1-phosphatase variants, though in unreplicated samples. A number of further candidate genes were not associated with these treatments. In conclusion, both acute and long-term treatments appear to be, at least to some extent, under genetic influence and preliminary data have identified possible liability genes.

Dopamine receptor D3 gene and response to lithium prophylaxis in mood disorders.

Lithium has established itself as an effective prophylactic agent in mood disorders, but not all patients respond to lithium therapy. It is probable that genetic factors play a substantial role in determining the differences in response to lithium. The aim of this study was to investigate the association between the dopamine receptor D3 (DRD3) gene and prophylactic efficacy of lithium in mood disorders. Fifty-five subjects affected by bipolar (n=43) and major depressive (n=12) disorder were followed prospectively for an average of 49 months and were also typed for their DRD3 variant, using polymerase chain reaction techniques. DRD3 variants were not associated with lithium outcome. Consideration of possible stratification effects, such as gender, polarity, family history, age at onset or duration of lithium treatment, also did not reveal any associations. DRD3 variants are not, therefore, a major factor influencing the prophylactic efficacy of lithium in mood disorders.