Genetic Association Study of the Alpha 7 Nicotinic Receptor (CHRNA7) with the Development of Schizophrenia and Bipolar Disorder in Korean Population

Objective

CHRNA7 has been shown to be a strong candidate gene for schizophrenia and bipolar disorder. It is located on chromosome 15q13-q14, which is one of the replicated linkage spots for schizophrenia and bipolar disorder.

Methods

We conducted an association study to determine whether previous positive association is replicable in the Korean population. We included 254 patients with schizophrenia, 193 patients with bipolar disorder type I, 38 patients with bipolar disorder type II, 64 schizoaffective disorder patients, and 349 controls. All subjects were ethnically Korean. A total of 898 subjects were included, and genotyping was done for three single nucleotide polymorphisms (SNPs) of CHRNA7. These three intronic SNPs were rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G).

Results

There was only one marginally significant association; this association was between rs12916879 and bipolar disorder type I in the male subgroup. In both the allele and genotype distributions, we found a weak signal (Chi-squared=3.57, df=1, p=0.06 for allele, Chi-squared=7.50, df=2, p=0.02 for genotype) only. Unphased haplotype analysis could not provide additional support for this finding. No SNP was associated with schizophrenia or any other affected groups in this Korean sample. The associative finding is marginal and inconclusive.

Conclusion

We could not replicate positive association in other ethnic groups previously studied. This suggests possible heterogeneity in the genes associated with schizophrenia and bipolar disorders. Because of structural complexity of the CHRNA7 gene and the limited statistical power of this study, further genetic studies with more SNPs and larger samples covering various populations, along with more fine molecular exploration of the CHRNA7 gene structure, are required.     

Bipolar disorder and polymorphisms in the dysbindin gene (DTNBP1).

BACKGROUND: Several studies support the dysbindin (dystrobrevin binding protein 1) gene (DTNBP1) as a susceptibility gene for schizophrenia. We previously reported that variation at a specific 3-locus haplotype influences susceptibility to schizophrenia in a large United Kingdom (UK) Caucasian case-control sample. METHODS: Using similar methodology to our schizophrenia study, we have investigated this same 3-locus haplotype in a large, well-characterized bipolar sample (726 Caucasian UK DSM-IV bipolar I patients; 1407 ethnically matched controls). RESULTS: No significant differences were found in the distribution of the 3-locus haplotype in the full sample. Within the subset of bipolar I cases with predominantly psychotic episodes of mood disturbance (n = 133) we found nominally significant support for association at this haploptype (p < .042) and at SNP rs2619538 (p = .003), with a pattern of findings similar to that in our schizophrenia sample. This finding was not significant after correction for multiple testing. CONCLUSIONS: Our data suggest that variation at the polymorphisms examined does not make a major contribution to susceptibility to bipolar disorder in general. They are consistent with the possibility that DTNBP1 influences susceptibility to a subset of bipolar disorder cases with psychosis. However, our subset sample is small and the hypothesis requires testing in independent, adequately powered samples.     

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.     

Influence of TAAR6 polymorphisms on response to aripiprazole

Background

There is some evidence suggesting a role of TAAR6 in schizophrenia. The aim of the present study is to investigate possible influences of a panel of markers in TAAR6 (rs8192625, rs4305745, rs4305746, rs6903874, rs6937506) on clinical outcomes and side effects in a sample of Korean schizophrenic aripiprazole treated patients.

Methods

Efficacy was assessed at baseline and weeks 1, 2, 4, 6, 8 using CGI-S, CGI-I, BPRS and SANS. Side effects were evaluated through SAS, BAS and AIMS. Multivariate analysis of covariance (MANCOVA) was used to test possible influences of single SNPs on clinical and safety scores. Tests for associations using multi-marker haplotypes were performed using the statistics environment “R”.

Results

A significant time per genotype interaction was found between rs4305746 in repeated measures of ANOVA on BPRS scores (F = 2.45, df = 10,365, p = 0.008). In particular G/A and A/A genotype patients were more likely to improve over time as compared to carriers of the G/G genotype. Permutation analysis confirmed a significant effect of rs4305746 on course of BPRS scores over time (p = 0.007). Haplotype analysis did not reveal any significant association with clinical and safety scores at any time.

Conclusion

A possible association could exist between some genotypes in TAAR6 and response to aripiprazole. However, several limitations characterize the present work, such as small sample size, the finding related to a single scale and the possibility of false positive findings, thus further investigation is required.     

RGS4 is not a susceptibility gene for schizophrenia in Japanese: association study in a large case-control population

The regulator of the G-protein signaling 4 (RGS4) has been implicated in the susceptibility to schizophrenia. RGS4 interacts with ErbB3 that acts as receptors for neuregulin 1 and these proteins may play a role in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two meta-analysis studies provided different interpretations for the genetic association between RGS4 and schizophrenia. We attempted to confirm this association in a case-control study of 1918 Japanese patients with schizophrenia and 1909 Japanese control subjects. Four widely studied single nucleotide polymorphisms (SNPs) were genotyped, and none showed association with schizophrenia. SNP 1 (rs10917670), p=0.92; SNP 4 (rs951436), p=0.91; SNP 7 (rs951439), p=0.27; and SNP 18 (rs2661319), p=0.43. A haplotype block constructed by these SNPs spans the 5' flanking region to the 5' mid-region of the RGS4 gene. Previous meta-analysis showed that both two major haplotypes of this block were risk haplotypes. The two common haplotypes were observed in the Japanese population. However, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and SNPs of the RGS4 gene identified thus far are unlikely to contribute to the genetic susceptibility to schizophrenia in the Japanese population.     

Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder

A recent study has suggested that the brain-expressed genes for G72 and D-amino-acid oxidase (DAAO) exert an influence on susceptibility to schizophrenia. Our aim was to replicate this finding in German schizophrenic patients and to assess whether G72 and DAAO might also contribute to the development of bipolar affective disorder. We genotyped seven single-nucleotide polymorphisms (SNPs) in the G72 gene and three in the DAAO gene in 599 patients (299 schizophrenic, 300 bipolar) and 300 controls. At G72, individual SNPs and a four-marker haplotype were associated with schizophrenia. The most significant SNP as well as the haplotype were also associated with bipolar affective disorder (BPAD). DAAO was associated with schizophrenia, but not with BPAD. The association of variation at G72 with schizophrenia as well as BPAD provides molecular support for the hypothesis that these two major psychiatric disorders share some of their etiologic background.     

Is there protective haplotype of dysbindin gene (DTNBP1) 3 polymorphisms for major depressive disorder

Dysbindin gene has been repeatedly associated with psychiatric disorders and schizophrenia in particular. This study aimed to investigate the variants of dysbindin gene in major depressive disorder (MDD). One hundred and eighty eight patients with MDD and 350 controls were investigated for 4 variants within the dysbindin gene (rs3213207 A/G, rs1011313 C/T, rs760761 C/T, and rs2619522 A/C). Haplotype analyses revealed a significant association with MDD (p=0.0007, protective A-C-T-A and A-C-C-C haplotypes), in particular the effect was due to the rs760761 (C/T) and rs2619522 (A/C) haplotype (p=0.000026). These results suggest a protective effect of some dysbindin gene haplotypes on the development of MDD. Coupled with previous findings on schizophrenia, our finding suggests that dysbindin gene variants may have a role in the susceptibility to MDD. Adequately powered further studies in different ethnic groups are warranted.     

FGFR2 is associated with bipolar disorder: A large-scale case–control study of three psychiatric disorders in the Chinese Han population

Objectives. Repetitive linkage analyses have indicated 10q25–q26 as a shared risk region for schizophrenia (SCZ) and bipolar disorder (BPD). A genome-wide association study and follow-up recently identified a significant association between a single nucleotide polymorphism (SNP) of this region (rs17101921) and SCZ. The nearest gene to this SNP is fibroblast growth factor receptor 2 (FGFR2). Methods. We carried out a large scale case–control study to test the association between FGFR2 and three major psychiatric disorders: SCZ, BPD and major depressive disorder (MDD) in the Chinese Han population. Eight tag SNPs were genotyped using Taqman assay in 1139 BPD patients, 1112 SCZ patients, 1119 MDD patients and 1135 shared healthy controls. Results. After correcting the multiple tests by permutation, one SNP (rs11199993), and a haplotype including this SNP, was found to be significantly associated with BPD. Potential population stratification in our samples was analyzed using 70 additional random SNPs dispersed on different chromosomes. No population stratification was detected, so our results could not be affected by this cofounding factor. Limitations of our study include incomplete coverage and insufficient power to detect association for relatively small odds ratio. Conclusions. Association between FGFR2 and BPD is worthy of further confirmation.     

NCAM1 and neurocognition in schizophrenia.

BACKGROUND: Alterations in neurocognition may be fundamental to schizophrenia and may be endophenotypes. Neural cell adhesion molecule 1 (NCAM1, aliases NCAM and CD56) may be a candidate gene for schizophrenia or for neurocognition in schizophrenia as supported by linkage and functional findings. METHODS: Subjects were 641 patients with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) clinical trial. Neurocognition was assessed at study baseline. Nine NCAM1 single nucleotide polymorphisms (SNPs) were blindly genotyped. Analysis of covariance was used to test for single SNP associations and haplotype regression for multilocus associations. RESULTS: As there were suggestions of population stratification, all analyses were conducted stratified by inferred ancestry. In the "Europe only" stratum, there were nominally significant associations with five contiguous SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) with the strongest association at rs1836796 (p = .007). Via permutation testing, the probability of obtaining five consecutive statistically significant SNPs with p-values 相似文献   

Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia

We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.     

Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1?M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.     

Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression.

BACKGROUND: Previous genetic studies investigating a possible involvement of variations at the brain derived neurotrophic factor (BDNF) gene locus in major depressive disorder (MDD), bipolar affective disorder (BPAD), and schizophrenia have provided inconsistent results. METHODS: We performed single-marker and haplotype analyses using three BDNF polymorphisms in 2,376 individuals (465 MDD, 281 BPAD, 533 schizophrenia, and 1,097 control subjects). RESULTS: Single-marker analysis did not provide strong evidence for association. Haplotype analysis of marker combination rs988748-(GT)n-rs6265 produced nominally significant associations for all investigated phenotypes (global p values: MDD p = .00006, BPAD p = .0057, schizophrenia p = .016). Association with MDD was the most robust finding and could be replicated in a second German sample of MDD patients and control subjects (p = .0092, uncorrected). Stratification of our schizophrenia sample according to the presence or absence of a lifetime history of depressive symptoms showed that our finding in schizophrenia might be attributable mainly to the presence of depressive symptoms. CONCLUSIONS: Association studies of genetic variants of the BDNF gene with various psychiatric disorders have been published with reports of associations and nonreplications. Our findings suggest that BDNF may be a susceptibility gene for MDD and schizophrenia-in particular, in a subgroup of patients with schizophrenia with a lifetime history of depressive symptoms.     

ESPECTRA: Searching the Bipolar Spectrum in Eating Disorder patients

Background

Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression.

Methods

We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes.

Results

We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification.

Conclusion

Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.     

The breakpoint cluster region gene on chromosome 22q11 is associated with bipolar disorder.

BACKGROUND: Although the pathogenesis of bipolar disorder remains unclear, heritable factors have been shown to be involved. The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies. The BCR gene encodes a Rho GTPase activating protein, which is known to play important roles in neurite growth and axonal guidance. METHODS: We examined patients with bipolar disorder (n = 171), major depressive disorder (n = 329) and controls (n = 351) in Japanese ethnicity for genetic association using eleven single nucleotide polymorphisms (SNPs), including a missense one (A2387G; N796S), in the genomic region of BCR. RESULTS: Significant allelic associations with bipolar disorder were observed for three SNPs, and associations with bipolar II disorder were observed in ten SNPs including N796S SNP (bipolar disorder, p = .0054; bipolar II disorder p = .0014). There was a significant association with major depression in six SNPs. S796 allele carriers were in excess in bipolar II patients (p = .0046, odds ratio = 3.1, 95% CI 1.53-8.76). Furthermore, we found a stronger evidence for association with bipolar II disorder in a multi-marker haplotype analysis (p = .0002). CONCLUSIONS: Our results suggest that genetic variations in the BCR gene could confer susceptibility to bipolar disorder and major depressive disorder.     

Genetic association study of CSNK1E gene in bipolar disorder and circadian characteristics

Abstract

Background: A circadian rhythm disturbance is one of the essential components of the phenotype of bipolar disorder. It has been reported that casein kinase 1 epsilon (CSNK1E), a member of the clock gene family, is associated with psychiatric phenotypes.

Objectives: We performed a genetic association study to determine the genetic role of CSNK1E in bipolar disorder and circadian rhythm disturbances in the Korean population.

Methods: The present study included 215 patients with bipolar disorder and 773 controls. Circadian characteristics were measured by the Korean version of the Composite Scale of Morningness (CS). Single-nucleotide polymorphisms (SNPs) of CSNK1E, rs1534891 and rs2075984, were genotyped. Chi-square analyses were performed to evaluate associations involving alleles and genotypes. Haplotype analysis was also performed, and the permutation p value was calculated. We also tested further associations involving these SNPs and scores on the CS.

Results: We found a positive association between SNP rs2075984 and bipolar disorder in both the allelic (p?=?.003) and genotypic (p?=?.006) distributions. No allelic or genotypic association between SNP rs1534891 and bipolar disorder was observed. A significant association of haplotype with bipolar disorder was found (p?=?.033). However, no association between the CS and the genotype of either SNP was found in the total sample.

Conclusion: CSNK1E SNP rs2075984 seemed to play a significant role in the development of bipolar disorder in this Korean sample. This association does not seem to relate to the phase preference measured by the CS. Further studies on CSNK1E with larger samples and more SNPs are necessary.     

A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder both have strong inherited components. Recent studies have indicated that schizophrenia and bipolar disorder may share more than half of their genetic determinants. In this study, we performed a meta-analysis (combined analysis) for genome-wide association data of the Affymetrix Genome-Wide Human SNP array 6.0 to detect genetic variants influencing both schizophrenia and bipolar disorder using European-American samples (653 bipolar cases and 1034 controls, 1172 schizophrenia cases and 1379 controls). The best associated SNP rs11789399 was located at 9q33.1 (p=2.38 × 10(-6), 5.74 × 10(-4), and 5.56 × 10(-9), for schizophrenia, bipolar disorder and meta-analysis of schizophrenia and bipolar disorder, respectively), where one flanking gene, ASTN2 (220kb away) has been associated with attention deficit/hyperactivity disorder and schizophrenia. The next best SNP was rs12201676 located at 6q15 (p=2.67 × 10(-4), 2.12 × 10(-5), 3.88 × 10(-8) for schizophrenia, bipolar disorder and meta-analysis, respectively), near two flanking genes, GABRR1 and GABRR2 (15 and 17kb away, respectively). The third interesting SNP rs802568 was at 7q35 within CNTNAP2 (p=8.92 × 10(-4), 1.38 × 10(-5), and 1.62 × 10(-7) for schizophrenia, bipolar disorder and meta-analysis, respectively). Through meta-analysis, we found two additional associated genes NALCN (the top SNP is rs2044117, p=4.57 × 10(-7)) and NAP5 (the top SNP is rs10496702, p=7.15 × 10(-7)). Haplotype analyses of above five loci further supported the associations with schizophrenia and bipolar disorder. These results provide evidence of common genetic variants influencing schizophrenia and bipolar disorder. These findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in schizophrenia and bipolar disorder.     

Association between chromogranin A gene polymorphism and schizophrenia in the Japanese population

It has been reported that expression of the chromogranin A (CHGA) gene is reduced in the prefrontal cortex and cerebrospinal fluid of patients with schizophrenia. Single-marker and haplotype analyses of SNPs within the CHGA gene were performed in 633 subjects with schizophrenia and 589 healthy controls. A significant association with schizophrenia was observed to one SNP marker, rs9658635 (p=0.0269), and with a 2 marker haplotype (p=0.0016). Significant association of rs9658635 was then replicated in a second independent cohort (377 schizophrenia and 338 control samples) (p=0.007). These results suggest that the CHGA gene is associated with the risk of developing schizophrenia in the Japanese population.