Genetic Association of the PERIOD3 (Per3) Clock Gene with Bipolar Disorder.

OBJECTIVE: Circadian rhythms have been linked to psychiatric disorders such as Depression and Bipolar Disorder (BD). Given previous evidences of sleep/circadian disturbances as well as the genetic susceptibility for BD, we decided to investigate the possible link between the PERIOD3 (Per3) circadian gene and BD. METHODS: This is a genetic association case (BD) vs. control study of the Per3 gene. We further subdivided our BD sample into "good sleepers" (PSQI ≤5) and "poor sleepers" (PSQI>5) according to the Pittsburgh Sleep Quality Index (PSQI) global score, and then we assessed genetic association of the Per3 gene with sleep quality in the BD group. RESULTS: There were 209 cases and 213 controls in our sample. The GT genotype of the SNP rs707467 significantly associated with BD (χ2=8.80; p-value=0.01; adjusted residual=±2.6). We also found significant association of the SNP rs10462020 allele T with BD (χ2=5.81; p-value=0.01) as well as the genotype TT (χ2= 6.01; p-value=0.04; adjusted residual=±2.4). CONCLUSION: In this study we demonstrated evidences of genetic association between the Per3 gene and BD. The results of association between the Per3 gene and BD in our sample may bring additional evidence to the former findings of association between the Per3 gene and BD.

Association between the Catechol O-methyltransferase (COMT) Val158met polymorphism and different dimensions of impulsivity.

BACKGROUND: Impulsivity is a multidimensional construct which has been associated with dopaminergic neurotransmission. Nonetheless, until this moment, few studies addressed the relationship between different types of impulsivity and the single nucleotide polymorphism caused by a substitution of valine (val) with methionine (met) in the 158 codon of the Catechol-o-Methyltransferase gene (COMT-val158met). The present study aimed to investigate the association between val158met COMT polymorphism and impulsive behavior measured by two neuropsychological tests. METHODOLOGY/PRINCIPAL FINDINGS: We administered two neuropsychological tests, a Continuous Performance Task and the Iowa Gambling Task were applied to 195 healthy participants to characterize their levels of motor, attentional and non-planning impulsivity. Then, subjects were grouped by genotype, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional and motor impulsivity. Those participants who were homozygous for the met allele performed worse in the Iowa Gambling Task than val/val and val/met subjects. CONCLUSIONS/SIGNIFICANCE: Our results suggest that met allele of val158met COMT polymorphism is associated with poor performance in decision-making/cognitive impulsivity task. The results reinforce the hypothesis that val and met alleles of the val158met polymorphism show functional dissociation and are related to different prefrontal processes.

Association between tryptophan hydroxylase-2 gene and late-onset depression.

OBJECTIVE: The aim of this study was to examine the association between polymorphisms (SNP) in the tryptophan hydroxylase-2 (TPH2) gene and late-onset depression (LOD) in the Brazilian population. METHODS: We genotyped 8 tag SNPs in the TPH2 gene in 84 outpatients with LOD and 79 individuals belonging to the comparison group to investigate an association between the TPH2 gene and LOD. RESULTS: Our findings suggested an association between tag SNP rs4565946 heterozygous C/T (p = 0.034; χ2 = 6.7; df = 2) and decreased risk of LOD. The tag SNP rs11179000 ancestral homozygous A/A (p = 0.025; χ2 = 7.3; df = 2) and increase risk of LOD and allelic association of ancestral allele A and increase risk of LOD was demonstrated (p = 0.005; χ2 = 7.8; df = 1). CONCLUSION: We found the statistically significant association between two tag SNPs and LOD. Our results support the hypothesis that the TPH2 gene is associated with LOD.

The role of BDNF genetic polymorphisms in bipolar disorder with psychiatric comorbidities.

BACKGROUND: Bipolar disorder (BD) is a complex disorder where genetic factors play a major role in its etiology. Probably, no other axis I diagnosis has a co-morbidity prevalence as high as BD. Since BDNF is involved in different ways in various psychiatric disorders we hypothesized that its genetic polymorphisms could be associated with the co-morbidity phenomenon in BD. METHODS: We studied 320 subjects (160 BD patients and 160 healthy controls). Genotyping was performed using made-to-order TaqMan genotyping assays (rs4923463, rs6265, rs2049045, and rs7103411). Statistical analyses were performed using UNPHASED version 3.0.12 and Haploview 4.1. RESULTS: No genotypic, allelic or haplotype differences were found between bipolar patients and healthy controls. Concerning exclusively the rs4923463 (G/G) there was a significant association with alcoholism (p=0.009), smoking (p=0.006) and violent suicide attempt (p=0.03). We further found that the G-G haplotype (rs4923463-rs2049045) (adjusted p=0.029) and the G-T haplotype (rs4923463-rs7103411) (adjusted p=0.029) were significantly more frequent in the group with alcoholism co-morbidity when compared with the group without this co-morbidity. LIMITATIONS: Sample size and retrospective assessment of suicide behavior and psychiatric comorbidities. CONCLUSIONS: The results obtained in our study indicate that BDNF variants may confer susceptibility to additional psychiatric diagnosis in BD.

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.

Association of polymorphisms of the tryptophan hydroxylase 2 gene with risk for bipolar disorder or suicidal behavior.

Bipolar disorder (BD) is a severe psychiatric illness characterized by the occurrence of elevated mood alternating with depressive episodes, having a estimated lifetime prevalence of 0.4-1.6% using DSM-IV criteria. Disturbances of the central serotonergic system has been associated with the pathophysiology of affective disorders and suicidal behavior. Tryptophan hydroxylase 2 (TPH2) which is a rate limiting enzyme in the serotonin synthesis is considered an important candidate gene associated with psychiatric disorders. Our sample consisted of 527 subjects (303 diagnosed with bipolar disorder and 224 healthy controls) which were genotyped for eight tagSNPs (rs4448731, rs4565946, rs11179000, rs7955501, rs10506645, rs4760820, rs1487275 and rs10879357) covering the whole gene of the human TPH2. Statistical analyses were performed using UNPHASED version 3.0.12 and Haploview((R)). Single markers, genotype and haplotype association analysis did not show significant genetic association with bipolar disorder or suicidal behavior. Our findings do not support the association between diagnosis of BD or suicidal behavior and TPH2 polymorphisms.