C825T polymorphism in the G protein beta3-subunit gene is associated with seasonal affective disorder.

BACKGROUND: Heterotrimeric G proteins play a pivotal role in the intracellular transduction of many transmitter-receptor interactions. Alterations in signal transduction and in G protein concentrations have been reported in seasonal and nonseasonal affective disorder. A single-nucleotide polymorphism (C825T) in the G protein beta3-subunit gene has been shown to influence intracellular response to G protein-coupled stimuli, and the T-allele of this polymorphism has been associated with hypertension and major depression. METHODS: We genotyped deoxyribonucleic acid from peripheral mononuclear cells of 172 patients with seasonal affective disorder, winter type (SAD), and 143 healthy control subjects. RESULTS: Patients with SAD were significantly more likely to be either homo- or heterozygous for the G(beta)3 T-allele when compared with healthy control subjects (p =.001), and they displayed a higher frequency of the G(beta)3 C825T T-allele (p =.021). The polymorphism was not associated with seasonality, which is the tendency to experience variations in mood and behavior with changing of the seasons. CONCLUSIONS: The G(beta)3 C825T polymorphism was associated with SAD in our study sample. This finding strengthens the evidence for the involvement of G protein-coupled signal transduction in the pathogenesis of affective disorder.     

A single nucleotide polymorphism in SLC1A1 gene is associated with age of onset of obsessive-compulsive disorder

Different genetic polymorphisms in the SLC1A1 have been shown to be associated with obsessive-compulsive disorder. Rs301430 is a T/C functional polymorphism affecting the gene expression and extrasynaptic glutamate concentration.We observed that Rs301430 influence age at onset in obsessive-compulsive disorder.     

A single nucleotide polymorphism of dopamine transporter gene is associated with Parkinson's disease

We identified two polymorphisms out of all coding regions of the dopamine transporter gene. One existed in exon 9 (1215A/G) and another in exon 15 (1898T/C). The 1215G was significantly less frequent among patients with Parkinson's disease than the controls. Although the polymorphism caused no amino acid substitution, we concluded that it was associated with decreasing the susceptibility to Parkinson's disease through mechanisms other than the protein function of dopamine transporter.     

A major single nucleotide polymorphism of the PDLIM5 gene associated with recurrent major depressive disorder

OBJECTIVE: The PDLIM5 gene is known to interact specifically with the N-type calcium channel alpha-1B subunit and protein kinase C epsilon and is critical for rapid, efficient potentiation of the calcium channel activation by protein kinase C in neurons. Increasing amounts of data suggested that PDLIM5 might be involved in the pathophysiology of major depressive disorder (MDD). The aim of this study was to examine whether genetic variations in the human PDLIM5 gene might contribute to the liability to develop MDD. METHOD: We undertook a gene-based association analysis of single nucleotide polymorphisms (SNPs). Three SNPs (rs10008257, rs2433320 and rs2452600) were identified in the PDLIM5 gene and genotyped in patients diagnosed with recurrent MDD and in matched control subjects. RESULTS: We observed significant allele (p = 0.007) and genotype (p = 0.007) association with rs2433320, and the G allele of rs2433320 was significantly overrepresented in control subjects in comparison with MDD patients. CONCLUSION: These results support the hypothesis of a protective effect for the G allele of rs2433320 in the PDLIM5 gene in recurrent MDD.     

Nogo CAA 3'UTR Insertion polymorphism is not associated with Schizophrenia nor with bipolar disorder

The Nogo gene maps to 2p14-p13, a region consistently associated with schizophrenia and bipolar disorder. The association of a polymorphism in Nogo was previously investigated by two groups, with divergent results. In this report, using an alternative approach, we evaluated this same polymorphism in 725 individuals, including patients with schizophrenia, bipolar disorder, normal controls and non-human primate samples. Our results indicate that the polymorphism is not associated with any of these diseases, but has a remarkably biased distribution in ethnic groups. Genotyping of primate samples, suggest that this polymorphism is a recent event in human speciation.     

Dopamine receptor D1 gene -48A/G polymorphism is associated with bipolar illness but not with schizophrenia in a Polish population

Dysregulation of dopaminergic neurotransmission has been implicated in the etiology of major psychoses. The dopamine D(1) receptor (DRD1) plays a role in some brain functions and mechanisms of psychotropic drugs. Therefore, the DRD1 gene makes a good candidate gene for molecular genetic studies in schizophrenia and bipolar affective disorder. In the present study, the -48A/G polymorphism of the DRD1 gene was estimated in patients with schizophrenia (n=407) or bipolar affective disorder (n=380), and in healthy controls (n=399). No association was found between the polymorphism studied and schizophrenia, either in the whole group of patients or in subgroups divided by gender, age at onset or predominance of positive or negative symptoms. A statistical trend was obtained for an association between this polymorphism and bipolar affective disorder (p=0.059 for genotypes, p=0.073 for alleles). The G/G genotype and G allele were significantly more frequent in patients with bipolar disorder, type II (p=0.016 for genotypes, p=0.008 for alleles), especially in the women subgroup (p=0.054 for genotypes, p=0.024 for alleles). An association between the G/G genotype and bipolar affective disorder with disease onset after 18 years of age was also found (p=0.022). These data suggest that the -48A/G polymorphism of the DRD1 gene may be involved in the etiology of bipolar disorder in a Polish population.     

Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene

The G1246A polymorphism in the gene of the hypocretin receptor 2 (HCRTR2) has been linked to the risk for cluster headache (CH). The authors examined this association in a large sample of 226 patients with CH and 266 controls from Germany. The genotype and allele distribution varied significantly between patients and controls. Homozygous carriers of the G-allele had a twofold increase in risk for CH (OR 1.97; 95% CI 1.32 to 2.92; p = 0.0007).     

Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder

Objectives:  In affective disorders, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is a frequently observed phenomenon. Subtle changes in glucocorticoid receptor (GR) functioning caused by polymorphisms of the GR gene ( NR3C1 ) may be at the base of the altered reaction of the HPA axis to stress and subsequently related to the development and course of affective disorders. The aim of our study is to evaluate associations between GR gene polymorphisms and bipolar disorder (BD).
Methods:  In this study, 245 patients with BD were interviewed to confirm diagnosis and BD subtype. Data on medication use and sociodemographic details were also collected. The control group consisted of 532 healthy blood donors, from which data on sex and age were collected. To perform genotyping, blood was collected from all patients and healthy controls.
Results:  A trend was found for a protective effect of the exon 9β polymorphism (p = 0.14) and the TthIII I polymorphism (p < 0.05) on the manifestation of the disease. These effects were significantly influenced by male gender for both polymorphisms. Patients with BD and the A/G variant in exon 9β had significantly fewer manic and hypomanic episodes than noncarriers (p < 0.05). No further associations were found with the other investigated GR gene polymorphisms and BD. These findings were not corrected for multiple comparisons.
Conclusions:  We conclude that the exon 9β polymorphism and the TthIII I polymorphism of the GR gene may be associated with a protective effect on the clinical manifestation and course in patients with BD. Furthermore, no associations were found between the other studied GR gene polymorphisms and this disease.     

双相情感障碍与DRD3、DRD2和COMT基因多态性的关联分析

目的　探索多巴胺D3受体 (DRD3)、多巴胺D2受体 (DRD2 )和儿茶酚氧位甲基转移酶 (COMT)基因多态性与双相情感障碍的关系。方法　使用病例 对照的关联分析方法 ,对 10 5名双相情感障碍患者和 12 8名对照者之DRD3、DRD2和COMT的多态性进行检测 ,并进行关联分析。结果　DRD3等位基因在两组间的分布有显著性差异 (χ2 =5 77,P =0 0 2 ) ,Logistic多元回归分析发现基因型 1/ 1和 2 / 2在两组间分布的有显著性差异 (P =0 0 36 ,OR=5 72 7) ,等位基因分析也有显著性差异 (P =0 0 2 2 ,OR =6 786 ) ;DRD2和COMT基因型和等位基因的分布在两组间无显著性差异 (χ2 =1 983,P =0 37/ χ2 =1 6 7,P =0 4 1;χ2 =0 2 16 ,P >0 0 5 / χ2 =0 14 3,P >0 0 5 ) ;将DRD3和DRD2共同分析时发现OR值升高 (OR =6 6 97)。结论　DRD3基因多态性与双相情感障碍有关联 ,且与DRD2有协同作用。     

Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder

There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.     

Response to lithium augmentation in depression is associated with the glycogen synthase kinase 3-beta -50T/C single nucleotide polymorphism.

BACKGROUND: Glycogen synthase kinase 3-beta (GSK3B) is a serine/threonine kinase which is directly inhibited by lithium. A -50T/C single nucleotide polymorphism (SNP) localized within the promoter region of the GSK3B gene has previously been shown to be associated with response to lithium prophylaxis in bipolar disorder. This study investigates the association of the GSK3B -50T/C SNP and response to lithium augmentation in acutely depressed antidepressant nonresponders. METHODS: Eighty-one patients who had not responded to at least one adequate trial of antidepressant monotherapy underwent a standardized trial of lithium augmentation for up to 8 weeks. We genotyped for the GSK3B -50T/C SNP using polymerase chain reaction and restriction fragment length polymorphism methods and investigated the association with remission. RESULTS: The allele frequencies in our sample were CC 14.8%, CT 48.2% and TT 37% (no deviation from the Hardy-Weinberg equilibrium). Carriers of the C-allele of the -50T/C SNP showed a significantly better response to lithium augmentation (hazard ratio: 2.70, p = .007), with a mean remission rate of 56.25% after 4 weeks compared to 31% in patients with the TT-genotype (chi(2) = 4.1; p = .04). CONCLUSIONS: Our results support the finding of recent studies demonstrating a superior response of C-allele carriers with bipolar disorder to lithium prophylaxis.     

Association of a new polymorphism in ALOX12 gene with bipolar disorder

Bipolar disorder (BPD) is characterised by episodes of excitement interspersed with periods of depression. The role of genetic factors in BPD is indicated by studies in monozygotic twins showing 40-70 % of concordance. Studies using genetic markers showed linkage of genes for affective disorders in different chromosome regions, emphasising the polygenic and multifactorial traits. The main goal of our research is to search non-synonymous SNPs (those that result in modifications in protein sequence) in genes that can be associated with psychiatric diseases as suggested by genomic mapping and/or by physiological function of the protein. Using DNA sequencing we could confirm a new non-synonymous SNP in the conservative domain of the ALOX12 gene (17p13.1), suggested by EST alignment. This SNP is an alteration from G to A that leads to a change of an arginine (A) to a glutamine in one of the most important domains of the protein. This SNP was evaluated by DNA sequencing in 182 patients with BPD and 160 control individuals. An increased presence of allele A among patients (60 % in controls and 73.1 % in cases; chi(2) = 6.581, P = 0.010; OR = 1.8095, 95 % CI = 1.1477-2.853) was found, suggesting an association of this polymorphism with the BPD in this Brazilian sample.     

Anxiety is associated with impulsivity in bipolar disorder

Impulsivity and anxiety, common features of bipolar disorder (BD), are each associated with a number of negative outcomes in BD. The relationship between anxiety and impulsivity, however, has not been a focus of study in BD. In this paper, we present data regarding the association between anxiety and impulsivity as measured by the Barratt impulsiveness scale (BIS-11) in 114 outpatients with BD. Results revealed that patients with a comorbid anxiety disorder displayed significantly higher levels of impulsivity relative to patients without an anxiety disorder. Moreover, a broad range of anxiety-related symptom domains was associated with greater impulsivity. Exploratory analyses also revealed that baseline anxiety symptoms were associated with elevated impulsivity at 9-month follow-up, although these relationships were less robust after covariate adjustment. These data demonstrate that anxiety is positively associated with impulsivity in patients with BD. Further studies are needed to elucidate the implications of and reasons for this association.     

Interleukin-10 gene promoter polymorphism is not associated with schizophrenia in the Korean population

The present study was aimed at examining the interleukin (IL)-10 gene promoter region polymorphic variants in patients with schizophrenia in the Korean population. Two hundred and thirty-three Korean patients diagnosed to have schizophrenia on the basis of Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) and 181 normal healthy controls participated in the present study. The DNA was extracted from whole blood using proteinase K and the IL-10 gene promoter region was amplified by polymerase chain reaction. Gene typing was performed by restriction fragment length polymorphism and single-strand conformation polymorphism. Distribution of the alleles and haplotypes in patients with schizophrenia was not significantly different from those of controls. The present study suggests that IL-10 gene promoter polymorphism is not associated with the development of schizophrenia in the Korean population.     

A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits.

BACKGROUND: Suicidal behavior is often correlated with other-directed aggression, which is partially mediated by catecholaminergic neurotransmission. Catechol-O-methyltransferase (COMT) is an enzyme involved in catecholamine inactivation. In this study, we examined the influence of a functional COMT (V158M) polymorphism on suicidal behavior and anger-related traits. METHODS: This polymorphism was examined in 149 German suicide attempters and 328 German control subjects. Both groups were administered self-report questionnaires for anger-related traits. RESULTS: There was no overall difference in allele/genotype frequency between patients and control subjects; however, the low-activity L-allele and genotype frequencies were higher among violent suicide attempters. For anger-related traits, a multivariate effect of the COMT genotype was observed after controlling for age and educational level. LL-carriers expressed their anger more outwardly, whereas HH-carriers expressed it more inwardly and reported more state anger, as assessed by the self-report questionnaire. CONCLUSIONS: These findings support the hypothesis that the functional polymorphism in the COMT gene may modify the phenotype of suicide attempts and anger-related traits. This, however, being a novel finding, should warrant further investigation.     

Serotonin transporter promoter polymorphism is associated with executive function impairments in patients with obsessive compulsive disorder

Objective: In the present study, we investigate the association between the 5-HTTLPR polymorphism and executive functions in a sample of patients with obsessive compulsive disorder (OCD). Method: A total of 98 unmedicated patients diagnosed with OCD according to DSM-IV criteria and 80 healthy controls were included in this study. The genotype frequencies of 5-HTTLPR polymorphism were compared in OCD and healthy control groups. The four subgroups of OCD and healthy control participants, determined according to having LaLa genotype (high expressing) or S- and/or Lg alleles (low expressing), were also compared using neuropsychological tests of executive functions. Results: The frequency of SLa genotype of 5-HTTLPR polymorphism was found to be higher in patients with OCD compared with healthy controls. The mean scores of conceptual level responses of the Wisconsin Card Sorting Test (WCST) were significantly lower in the OCD-high-expressing subgroup compared with the low-expressing control group. The mean scores of the number of moves of the Tower of London were found to be significantly higher in the OCD-high-expressing subgroup, compared with the high-expressing subgroup of healthy controls. Conclusion: Our findings suggest that the high-expressing variant may be associated with lower performance on some abstraction and planning measures in OCD patients.