SCN8A as a novel candidate gene associated with bipolar disorder in the Han Chinese population

Background

Bipolar disorder (BPD) is a common, severe and recurrent psychiatric disorder. It has been suggested that BPD patients have a higher risk of suicide than patients with any other psychiatric illnesses. A recent study found that suicide attempt was associated with the SCN8A gene, which has been mapped close to one of the BPD susceptibility loci. Thus, SCN8A is likely to be a candidate gene for BPD.

Methods

In this study, three SNPs (rs1601012, rs303810, rs60637) were analyzed in 506 bipolar patients and 507 controls of Han origin.

Results

We found that two individual SNPs showed statistically significant differences between cases and controls in both allele and genotype distribution, but only rs303810 was still significant in allele distribution (p = 0.0164) after correction. No obvious linkage disequilibrium or haplotypes were observed among these SNPs.

Conclusion

Our results indicate that SCN8A may be a potential susceptibility gene for bipolar disorder in the Han Chinese population.     

Schizencephaly associated with bipolar affective disorder

Schizencephaly is a rare congenital anomaly of the brain, characterized by formation of abnormal unilateral or bilateral clefts in the cerebral hemispheres. It often manifests with partial seizures, mental retardation and hemiparesis. Only two cases of schizencephaly associated with psychosis have been reported in the literature. A patient of schizencephaly, who had bipolar affective disorder is described. It has been compared with the earlier two reported cases of schizencephaly associated with pyschosis.     

Association analysis of genes in serotonin pathway with attention and executive function in patients with bipolar affective disorder

Background

The reason why it is difficult to identify susceptibility genes attributed to bipolar disorder (BPD) is the phenotypic heterogeneity. The use of endophenotypes has been advocated as one possible strategy to discovery cause variants of BPD.

Methods

A total of 164 patients with BPD and 164 matched controls were employed in the present research. Fifty-two single nucleotide polymorphisms (SNPs) within the genes in serotonin pathway were selected for genotyping using the GoldenGate genotyping assay. All participants completed three neurocognitive tests including the tower of Hanoi (TOH), the Wisconsin card sorting test (WCST) and Trail making tests (TMTA and TMTB-M).

Results

Patients with BPD demonstrated a wide range of deficits in mental activities of attention and speed of information processing, and executive function. Significant interactions between rs2760347 in 5HTR2A gene and diagnosis were found for the executive time of TOH, with β = 11.82 and P = 0.002 (adjusted P = 0.03 after Bonferroni correction).

Conclusions

Cognitive impairments existing in BPD may be particularly notable in certain domains of attention and executive function, and 5HTR2A gene may be involved in modulating executive function of BP-I patients.     

Susceptibility of schizophrenia and affective disorder not associated with loci on chromosome 6q in Han Chinese population

Background  

Several linkage studies across multiple population groups provide convergent support for susceptibility loci for schizophrenia – and, more recently, for affective disorder – on chromosome 6q. We explore whether schizophrenia and affective disorder have common susceptibility gene on 6q in Han Chinese population.     

Association analysis of monoamine oxidase A gene and bipolar affective disorder in Han Chinese

Background  

Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in degrading several different biological amines, including serotonin. Although several pieces of evidence suggested that MAOA is important in the etiology of bipolar affective disorder (BPD), associations for markers of the MAOA gene with BPD were not conclusive and the association has not been investigated in Taiwanese population. This study was designed to illustrate the role of MAOA in the etiology of BPD in Han Chinese.     

Analysis of association between common SNPs in ErbB4 and bipolar affective disorder, major depressive disorder and schizophrenia in the Han Chinese population

Neuregulin-1 (NRG1) is associated with schizophrenia. As one of the receptors of NRG1, v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) has also been reported to be associated with schizophrenia. Since there can be shared genetic variants among bipolar affective disorder, major depressive disorder and schizophrenia, we tested the association between ErbB4 and these three major psychiatric disorders in the Han Chinese population. Five single nucleotide polymorphisms (SNPs) were selected based on previous positive reports and linkage disequilibrium information of the HapMap Han Chinese individuals from Beijing (CHB) + individuals from Tokyo, Japan (JPT) population. These SNPs were genotyped in 1140 bipolar affective disorder (BPAD) patients, 1140 schizophrenia (SCZ) patients, 1139 major depressive disorder (MDD) patients and 1140 normal controls. Two SNPs (rs707284 and rs839523) showed nominal significance in the BPAD patients but this was eliminated after permutation. No significant association between ErbB4 and the two other psychiatric disorders was observed, nor did haplotype analysis reveal any positive signal.     

中国汉族人群双相障碍不同疾病状态下的氧化应激损害

目的探索双相障碍患者的氧化应激指标水平,特别是不同的疾病状态是否存在差异。方法纳入53例双相障碍I型患者和59例正常对照组,患者组躁狂发作34例,抑郁发作19例。收集患者临床资料,采用汉密尔顿抑郁量表17项版(HAMD-17)和贝克-拉范森躁狂量表(BRMS)评定症状严重程度。所有受试者抽取清晨空腹外周静脉血,检测生化指标超氧化物歧化酶(Superoxide dismutase,SOD)、谷胱甘肽过氧化物酶(Glutathione peroxidase,GPx)和丙二醛(Malonaldehyde,MDA)水平。结果控制体质指数(BMI)后,1患者组的MDA(F=8.362,P0.01)和GPx(F=4.550,P=0.013)水平均较正常对照组高。2将患者组分为躁狂发作组和抑郁发作组,MDA水平三组间总体差异有统计学意义(F=6.079,P0.01),躁狂发作组和抑郁发作组均较正常对照高(P0.01)。GPx活性三组间总体差异有统计学意义(F=3.355,P=0.022),抑郁发作组比正常对照组高(P=0.012)。3将患者组分为有精神病性症状组和无精神病性症状组,MDA水平三组间总体差异有统计学意义(F=5.646,P=0.001)。有精神病性症状组和无精神病性症状组均比正常对照组高(P0.05或0.01)。GPx活性三组间总体差异有统计学意义(F=4.356,P0.01),有精神病性症状组较正常对照组高(P0.01);4未见发病年龄、住院次数、病程、HAMD和BRMS评分分别与SOD、GPx活性及MDA水平显著相关(P均0.05)。结论双相障碍患者发作期有氧化应激系统失衡,可能和某些临床特征相关。     

Transmission of NOTCH4 and GRIK2 in a population of Han Chinese with schizophrenia and affective disorder*★

BACKGROUND： Increasing evidence suggests overlapped genetic susceptibility across traditional classification systems that divided psychotic disorders into schizophrenia or affective disorder. OBJECTIVE： This study aimed to explore whether schizophrenia and affective disorder share genetic susceptibility in NOTCH4 and GRIK2 loci in a population of Han Chinese. DESIGN： Repetitive measurements. SETTING： The experiment was carried out at Shanghai Mental Health Center and Hongkou Mental Health Center of Shanghai between January 2001 and June 2004. PARTICIPANTS： Sixty-five mixed pedigrees （suffering from various diseases, in combination with schizophrenia and affective disorder）, composed of 45 completed trios and 20 single-parent families, were selected from Shanghai Mental Health Center and Hongkou Mental Health Center of Shanghai between January 2001 and June 2004. Probands received clinical diagnosis according to ICD-10; an independent clinician used identical criteria to review all diagnoses. All subjects were Han Chinese in origin and provided informed consent. There were 65 probands and 110 parents among the subjects. The probands comprised 30 males and 35 females： 33 with schizophrenia, 32 with affective disorder, mean age of （30.9 ± 9.8） years, mean age of onset （24.3 ± 8.8） years, mean duration （6.6 ± 7.0） years, and mean age of parents （58.8 ±10.9） years. METHODS： DNA samples from probands and their biological parents were extracted from peripheral blood according to standard methods. Four polymorphisms, -1725T/G and -25T/C in NOTCH4, rs6922753T/C and rs2227283G/A in GRIK2, were amplified and genotyped with PCR-RFLP techniques. MAIN OUTCOME MEASURES： Association between NOTCH4, GRIK2 polymorphism, and schizophrenia was analyzed by transmission disequilibrium test （TDT）. RESULTS： Sixty-five probands and 110 parents were included in the result analysis, with no dropouts. The results showed that the -25T/C polymorphism of NOTCH4 associated significantly with affecti     

Polymorphisms of Transferrin gene are associated with schizophrenia in Chinese Han population

Several recent studies have provided evidence that abnormalities in oligodendrocyte and myelin function may contribute to the etiopathology of schizophrenia. Transferrin (TF), an iron transport glycoprotein playing an important role in synthesis of myelin and the development of oligodendrocytes, has been identified as down-regulated expression in schizophrenia brain by microarray, quantitative PCR and in situ hybridization method. In order to further assess the role of TF in schizophrenia, we examined seven polymorphisms in TF region using a set sample of Chinese Han subjects consisting of 326 schizophrenia patients and 344 healthy controls. Four single nucleotide polymorphisms (SNPs) namely, rs4481157, rs3811655, rs6762415 and rs1405022 were analyzed in this study. Our results showed that one intronic SNP had strong association with schizophrenia (rs3811655: allele C>G, P=1.34E-6, OR=1.89, 95% CI=1.46-2.46; genotype P=3.72E-6). Two haplotypes A-C and G-G constructed of rs4481157-rs3811655 also revealed significant associations with schizophrenia (global P=0.0001). Our findings support that TF gene may be involved in susceptibility to schizophrenia in the Chinese Han population. However, further studies are needed to confirm these findings in other populations and to identify functional variants in TF that may be implicated in pathogenesis.     

Positive association between the PDLIM5 gene and bipolar disorder in the Chinese Han population

Background

Bipolar disorder is a widespread and severe brain disorder that is strongly affected by genetic factors. The PDZ and LIM domain 5 (PDLIM5) gene encodes a protein as an Enigma homologue LIM domain protein, which has been widely reported as being expressed in various brain regions. The analysis of DNA microarrays in the frontal lobes of patients with bipolar disorder has indicated changes in the expression level of PDLIM5, and subsequent studies have suggested that PDLIM5 might play a role in susceptibility to bipolar disorder. We sought to examine the association between PDLIM5 and bipolar disorder.

Methods

We recruited 502 patients with bipolar disorder and 507 controls from Anhui Province, China. We conducted a case–control study of 4 single-nucleotide polymorphisms (SNPs) of PDLIM5 that have been reported to be significantly associated with bipolar disorder in the Japanese and Chinese population: rs10008257, rs2433320, rs2433322 and rs2438146.

Results

We found that rs2433322 showed significantly different frequencies between patients and controls (p = 0.002). Three of the SNPs, rs10008257, rs2433320 and rs2438146, showed no statistical association with bipolar disorder; however, haplotypes constructed from 3 SNPs, rs2433320, rs2433322 and rs2438146, were significantly associated with bipolar disorder (global p = 0.004 after Bonferroni correction).

Limitations

Our genetic association study only offered evidence for susceptibility of PDLIM5 to bipolar disorder, but the positive SNP rs2433322 could not indicate a direct cause of this complicated brain disorder. In addition, the 4 tagged SNPs that we selected could not cover the whole region of PDLIM5, thus additional reproducible studies of more SNPS in large non-Asian populations are needed.

Conclusion

Our results suggest that PDLIM5 might play a role in susceptibility to bipolar disorder among the Chinese Han population.     

CTLA-4 confers a risk of recurrent schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population

Previous studies have reported that the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, which is related to immunological function such as T-cell regulation, is associated with psychiatric disorders. In this study, we studied the relationship between CTLA-4 and three major psychiatric disorders, schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population. We recruited 1140 schizophrenia patients, 1140 major depressive disorder patients, 1140 bipolar disorder patients, and 1140 normal controls to examine the risk conferred by 6 tag SNPs (rs231777, rs231775, rs231779, rs3087243, rs5742909, rs16840252) in the CTLA-4 gene. We found that rs231779 conferred a risk for schizophrenia (P_allele = 0.0003, P_genotype = 0.0016), major depressive disorder (P_allele = 0.0006, P_genotype = 0.0026) and bipolar disorder (P_allele = 0.0004, P_genotype = 0.0018). In addition, rs231777 and rs16840252 had a significant association with schizophrenia (rs231777: P_allele = 0.0201, rs16840252: P_allele = 0.0081, P_genotype = 0.0117), and rs231777 had significant association with bipolar disorder (rs231777: P_allele = 0.0199). However, after 10,000 permutations, only rs231779 remained significant (schizophrenia: P_allele = 0.0010, P_genotype = 0.0145, major depressive disorder: P_allele = 0.0010, P_genotype = 0.0201, bipolar disorder: P_allele = 0.0008, P_genotype = 0.0125). Our results suggest that shared common risk factors for schizophrenia, major depressive disorder and bipolar disorder exist in the CTLA-4 gene in the Chinese Han population.     

Association of serotonin transporter gene polymorphisms and major depressive disorder in Chinese Han population

BACKGROUND： Serotonin transporter （5-HTT） polymorphisms comprise 5-HTT gene-linked polymorphism region （5-HTTLPR） and variable number of tandem repeats （VNTR）. Studies have revealed an association between 5-HTT polymorphism and major depressive disorder, which suggests that the ＂S＂ allele of 5-HTTLPR and Stin2.9 of 5-HTTVNTR are associated with major depressive disorder. However, there are a number of studies that do not support the 5-HTT polymorphism effect in major depressive disorder. OBJECTIVE： To study the relationship between 5-HTT gene polymorphism and major depressive disorder in Chinese Han population. DESIGN, TIME AND SETTING： Case-controlled study of 5-HTT gene polymorphism. The experiment was performed at the Central Laboratory, Third Affiliated Hospital of Sun Yat-sen University, China from March 2005 to January 2006. PARTICIPANTS： A total of 99 depressive patients of Chinese Han nationality were recruited for this study. All patients met DSM-IV diagnostic criteria for major depressive disorder and had a total score of Hamilton Depression Scale （24 items） ≥21 points. In addition, 101 healthy subjects, matched for age and gender, served as the control group. METHODS： Venous blood was collected from all subjects. 5-HTT genotypes and alleles were determined by polymerase chain reaction. Consistent with the Hardy-Weinberg equilibrium, the association between 5-HTT gene polymorphism and major depressive disorder were analyzed by Chi-square test. MAIN OUTCOME MEASURES： 5-HTTLPR and 5-HTTVNTR genotypes and allele frequencies were measured. RESULTS： No significant differences in 5-HTTLPR genotypes and allele frequencies were determined between patients and controls （P 〉 0.05）. However, significant differences in 5-HTTVNTR genotypes and allele frequencies were detected （P 〈 0.01 ）. The Stin2.10 allele and 10/10 genotype associated with major depressive disorder （OR = 2.61,7.7, P 〈 0.05; analysis of dose-response relationships Х^2 = 12.35, P 〈 0.01）. CONCLUSION： Results from the present study revealed no association between 5-HTTLPR and major depressive disorder. However, a significant association between 5-HTTVNTR and major depressive disorder existed in a population of Chinese Han. The presence of Stin2.10 and 10/10 genotypes increased the risk for major depressive disorder in a dose-dependent manner.     

Mood-related obsessive-compulsive symptoms in a patient with bipolar affective disorder

The authors present a case of coexisting obsessive-compulsive disorder (OCD) and bipolar affective disorder in which the obsessive-compulsive symptoms disappeared during episodes of mania and reappeared during periods of depression. Although patients with coexisting bipolar disorder and OCD are relatively rare, careful study of those patients may increase our understanding of the complex relationship between obsessive-compulsive symptoms and mood. Abnormalities in serotonergic neurotransmission have been postulated in both affective disorders and OCD and may provide important clues to the pathophysiology of OCD.     

Association study of the norepinephrine transporter gene polymorphisms and bipolar disorder in Han Chinese population.

Many studies have indicated that the norepinephrine transporter (NET) may play an important role in the mechanisms underlying affective disorders. Thus, the genes of the NET (SLC6A2) are good candidates for research on bipolar disorder (BPD). This study examined whether the NET gene is a susceptibility factor for the BPD in Han Chinese. A promoter -182 T/C polymorphism (rs 2242446) and the exonic polymorphism 1287 G/A (rs 5569) of the NET gene were analysed using a polymerase chain reaction (PCR)-based method in 261 BPD patients and 245 unrelated, age- and gender-matched controls. Furthermore, to reduce the clinical heterogeneity, we also carried out analysis in clinical subgroups of bipolar patients defined according to type I and type II BPD, presence or absence of family history of major affective disorders and the age at onset of BPD. No significant difference was found between either bipolar patients or its more homogeneous subgroups and healthy controls in the genotype and allele frequencies for the investigated NET polymorphisms. Our results suggest that the investigated polymorphisms of NET are not major risk factors responsible for predisposition to BPD or its clinical subtypes in Han Chinese. However, replication studies with larger different ethnic samples are needed.     

Hashimoto's encephalopathy presenting with bipolar affective disorder

OBJECTIVE: We report on a rare case of Hashimoto's encephalopathy associated with a bipolar affective disorder. CASE REPORT: A 32-year-old woman presented with a bipolar affective disorder and Hashimoto's thyroiditis. Neurological investigations (magnetic resonance imaging of the brain and cerebrospinal fluid) did not reveal any pathological findings except for a pathological electroencephalogram (EEG). Despite consequent antidepressant treatment, the patient remitted only in conjunction with normalization of the EEG after short-term treatment with high doses of prednisolone. CONCLUSION: In treatment resistant courses of disorders, the thorough clinical and laboratory investigation of our patient revealed a very efficient treatment strategy. Cases of Hashimoto's encephalopathy associated with the occurrence of a manic episode and hence with bipolar disorder are rare; this is the first reported case. However, clinicians should be alert to this possibility.     

Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene

The authors report on a family with dominantly inherited progressive external ophthalmoplegia and a diagnostic and statistical manual (fourth revised edition) diagnosis of bipolar psychiatric disorder in several members. Skeletal muscle biopsy from the proposita showed decreased cytochrome c oxidase staining, several ragged-red fibers, and multiple mtDNA deletions. The authors identified a missense mutation (leucine 98-->proline) in the adenine nucleotide translocator 1 gene. The presence of bipolar affective disorder expands the phenotype of adenine nucleotide translocator 1 allelic variants.     

The role of the arginine-nitric oxide pathway in the pathogenesis of bipolar affective disorder

Abstract. There is a reciprocal regulation of arginase and nitric oxide synthase (NOS) in L-arginine-metabolizing pathways. Nitric oxide (NO) may be involved in some psychiatric disorders like schizophrenia, depression and bipolar affective disorder (BPAD). To our knowledge, there is no study in the literature in which the role of arginase, an important part of the arginine regulatory system affecting NOS activity, was investigated in BPAD. This study aims to investigate arginase, manganese (Mn) and total nitrite levels (a metabolite of NO) and their relationship to the arginine-NO pathway in patients with BPAD. Arginase activities, Mn and total nitrite levels were measured in plasma from forty-three patients with BPAD (Type one) and thirty-one healthy control subjects. Plasma arginase activities and Mn were found to be significantly lower and total nitrite level higher in patients with BPAD compared with controls. Our results suggest that the arginine-NO pathway is involved in the pathogenesis of BPAD.     

The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder

OBJECTIVE: Efforts to identify genetic loci for bipolar disorder (BPD) have thus far proved elusive. The identification of processes mediating between genotype and phenotype (endophenotypes) may help resolve the carrier status of family members in genetic studies of polygenetic disorders with imperfect penetrance, such as BPD. We reviewed the literature to determine if neuropsychological measures could be used as effective endophenotypes to aid molecular genetic studies searching for genes predisposing to BPD. METHODS: Four prerequisites for endophenotypic markers are described, and a critical review of relevant literature was undertaken to determine if neurocognitive measures satisfy these four requirements in BPD. RESULTS: We found evidence that executive functions and declarative memory may be candidate neurocognitive endophenotypes for BPD. However, we cannot exclude other areas of cognition as being affected by BPD susceptibility genes, given the limits of the current knowledge of the neuropsychology of BPD. In particular, the paucity of studies measuring cognition in healthy relatives of BPD patient limits conclusion regarding familial aggregation of particular neurocognitive deficits (i.e. attention). Furthermore, the effects of clinical state and/or medication usage on cognitive functioning in BPD probands should be further explored. CONCLUSIONS: Molecular genetic studies of BPD may benefit from the application of select neuropsychological measures as endophenotypic markers. The use of these markers, once defined, may improve power for detecting genes predisposing to BPD and may help to better define diagnostic criteria.     

Branched-chain amino acids are associated with metabolic parameters in bipolar disorder

Abstract

Objectives: An important aspect of bipolar disorder (BD) research is the identification of biomarkers pertaining to the somatic health state. The branched-chain essential amino acids (BCAAs), viz valine, leucine and isoleucine, have been proposed as biomarkers of an individual’s health state, given their influence on protein synthesis and gluconeogenesis inhibition.

Methods: BCAA levels of 141 euthymic/subsyndromal individuals with BD and 141 matched healthy controls (HC) were analysed by high-pressure lipid chromatography and correlated with clinical psychiatric, anthropometric and metabolic parameters.

Results: BD and HC did not differ in valine and isoleucine, whereas leucine was significantly lower in BD. Furthermore, correlations were found between BCAAs and anthropometric and glucose metabolism data. All BCAAs correlated with lipid metabolism parameters in females. There were no associations between BCAAs and long-term clinical parameters of BD. A negative correlation was found between valine and Hamilton Depression-Scale, and Beck Depression Inventory II, in male individuals

Conclusions: Our results indicate the utility of BCAAs as biomarkers for the current state of health, also in BD. As BD individuals have a high risk for overweight/obesity, in association with comorbid medical conditions (e.g. cardiovascular diseases or insulin resistance), health state markers are urgently required. However, no illness-specific associations were found in this euthymic/subsyndromal BD group.