Association Between Neurotensin Receptor 1 (NTR1) Gene Polymorphisms and Schizophrenia in a Han Chinese Population

Neurotensin (NT) is a multifunctional gut hormone, neurotransmitter, and neuromodulator that triggers many physiological responses by binding to the high-affinity neurotensin receptor 1 (NTR1). Previous studies have implicated the roles of NT and NTR1 in the etiology or expression of schizophrenia. This case–control study examined the associations between schizophrenia and three NTR1 gene polymorphisms (rs6090453C/G, rs6011914C/G, and rs2427422A/G) previously linked to working memory performance in a Han Chinese population. These three polymorphisms were genotyped in 390 schizophrenic patients and 565 healthy subjects. Compared with those of the controls, the frequencies for C allele in the rs6090453C/G polymorphism were higher in the schizophrenic patients (p?=?0.049) and their female subgroup (p?=?0.014). The frequencies for the rs6090453C/rs6011914G/rs2427422G (CGG) haplotype were also higher in the patients (p?=?0.016) and their female subgroup (p?=?0.005). Moreover, in the female subgroup, the frequencies for the rs6090453G/rs6011914C/rs2427422G (GCG) haplotype were higher in the controls (p?=?0.028). Our results suggest that the C allele (CC or CG genotype) in the rs6090453C/G polymorphism and the CGG haplotype may enhance schizophrenia susceptibility in the Han Chinese population, while the GCG haplotype may be a protective factor, particularly in females.     

No Association Between Polymorphisms of Neuronal Oxide Synthase 1 Gene (NOS1) and Schizophrenia in a Japanese Population

The neuronal nitric oxide synthase gene (NOS1) is located on 12q24, in a susceptibility region for schizophrenia, and produces nitric oxide (NO) in the brain. NO plays a role in neurotransmitter release and is the second messenger of the N-methyl-d-aspartate (NMDA) receptor. Furthermore, it is connected to the dopaminergic and serotonergic neural transmission systems. Therefore, abnormalities in the NO pathway are thought to be involved in the pathophysiology of schizophrenia. Several genetic studies showed an association of NOS1 with schizophrenia. However, results of replication studies have been inconsistent. Therefore, we conducted a replication study of NOS1 with schizophrenia in a Japanese sample. We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs2682826, and rs6490121) in NOS1 that were positively associated with schizophrenia in previous studies. Two SNPs showed an association with Japanese schizophrenic patients (542 cases and 519 controls, rs3782219: P allele = 0.0291 and rs3782206: P allele = 0.0124, P genotype = 0.0490), and almost these significances remained with an increased sample size (1154 cases and 1260 controls, rs3782219: P allele = 0.0197 and rs3782206: P allele = 0.0480). However, these associations also might have resulted from type I error on account of multiple testing (rs3782219: P allele = 0.133 and rs3782206: P allele = 0.168). In conclusion, we could not replicate the association between seven SNPs in NOS1 and schizophrenia found in several earlier studies, using larger Japanese schizophrenia and control samples.     

Association Between NOS1 Gene Polymorphisms and Schizophrenia in Asian and Caucasian Populations: A Meta-Analysis

Schizophrenia is a complex psychiatric disorder characterized by memory impairments with delusions and hallucinations. Several investigations have focused on determining the association between NOS1 (nitric oxide synthase-1) polymorphisms and risk of schizophrenia (SZ). However, the association of rs2682826, rs3782206, rs499776, rs3782219, rs41279104, rs3782221, rs1879417, rs4767540, rs561712, and rs6490121 polymorphisms with schizophrenia remains inconclusive. We performed a systematic meta-analysis for each polymorphism to determine its association with SZ by calculating their pooled odds ratio and 95% confidence intervals. The heterogeneity between studies was evaluated using Cochran’s Q test to adopt random effects or fixed effects model. Based on our analysis, the rs3782206 polymorphism showed a strongest association with schizophrenia in allelic OR 1.15 (95% CI [1.05–1.25]), homozygote OR 1.35 (95% CI [1.09–1.66]), dominant OR 1.16 (95% CI [1.04–1.29]), and recessive OR 1.29 (95% CI [1.05–1.58]) models in Asian population. Similarly, in Caucasian population, the rs499776 polymorphism attributes risk association in homozygote OR 0.70 (95% CI [0.50–0.98]), dominant OR 3.57 (95% CI [2.34–5.27]), and recessive models OR 0.68 (95% CI [0.50–0.93]) with schizophrenia. Further, the sensitivity analysis was carried out based on leave-one-out method to confirm the reliability of the analysis. Overall, our meta-analysis demonstrates the significance of NOS1 genetic variants that are functionally associated with cognitive and neuropsychiatric symptoms of schizophrenia.     

Association Between a Casein Kinase 1 Epsilon Gene Polymorphism and Schizophrenia in a Chinese Han Population

The casein kinase 1 (Csnk1) family of serine/threonine kinases regulates dopamine receptor (DR) signaling by phosphorylating the 32-kDa dopamine- and cAMP-regulated phosphoprotein DARPP-32, leading to inhibition of protein phosphatase 1 and a shift in the phosphorylation state of many downstream proteins. By modulating DR-activated phosphorylation cascades, Csnk1 plays a central role in neuropsychiatric disorders and modulates the stimulant response to amphetamine. No published study, however, has established a correlation between Csnk1 gene polymorphisms and schizophrenia. We genotyped the rs135745C/G polymorphism of the Csnk1ε gene in 384 schizophrenic patients and 502 healthy controls drawn from the Chinese Han population. There were significantly higher CG and CC genotype frequencies in schizophrenic patients compared to control subjects (CG, p?=?0.0086, odds ratio (OR)?=?1.477, 95% confidence interval (CI), 1.103-1.978; CC, p?=?0.0431, OR?=?2.571; 95% CI, 0.998-6.624). The C allele frequency was also higher in the schizophrenics (p?=?0.0022; OR?=?1.474; 95% CI, 1.149-1.891). In the dominant model, subjects with genotypes CC or CG were at greater risk for schizophrenia (p?=?0.0032; OR?=?1.532; 95% CI, 1.153-2.037), suggesting that a genetic variant in the Csnk1ε gene significantly enhances the probability of schizophrenia in the Chinese Han population.     

Association Between the G1001C Polymorphism in the GRIN1 Gene Promoter and Schizophrenia in the Iranian Population

Schizophrenia is a complex genetic disorder to which genetic variation in the glutamatergic signaling pathways is believed to play a substantial role in the etiology of the disease. Association studies have implicated the N-methyl-d-aspartate receptor subunit gene, GRIN1, as a candidate gene for schizophrenia. In this report, we used a case control study to establish the possible association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia in an Iranian cohort of 200 unrelated patients and 200 controls. The allelic and genotypic frequencies of the polymorphism were determined using polymerase chain reaction restriction fragment length polymorphism. Data analysis using logistic regression and the Mantel–Haenszel chi-square test revealed a strong association between the G1001C polymorphism and schizophrenia (CG genotype: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.34–3.48, P = 0.001 and CC genotype: OR = 29.10, 95% CI 3.40–565.78, P < 0.001). Furthermore, the C allele is significantly associated with an increasing risk of schizophrenia. An erratum to this article can be found at     

Association Study between Norepinephrine Transporter Gene Polymorphism and Schizophrenia in a Korean Population

Objective

We aimed to investigate possible associations between three norepinephrine transporter gene (SLC6A2) single nucleotide polymorphisms (T182C, A3081T, and G1287A) and schizophrenia. Also, we investigated the relationships of those polymorphisms with clinical severity and characteristics of schizophrenia.

Methods

Participants were 220 schizophrenia patients in the acute phase and 167 healthy controls. The genotype, allele frequency, and haplotype of each group were analyzed for T182C, A3081T, and G1287A polymorphisms. Of the 220 schizophrenia patients, 163 patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Korean version of the Calgary depression scale for schizophrenia (K-CDSS) at baseline.

Results

We found no significant differences between the schizophrenia patient group and the control group in genotype distribution or allele frequency of the three tested polymorphisms. Likewise, we could not find any significant differences in genotype or allele frequency by analyzing according to gender. In the haplotype study, no significant association emerged between specific haplotype combinations and schizophrenia. We also found no association between clinical scales (PANSS and K-CDSS) and the studied polymorphisms.

Conclusion

Our results suggest that the investigated polymorphisms of the NET gene are not associated with susceptibility to schizophrenia or its clinical features in a Korean population. However, this study remains significant because it is the first haplotype study to investigate associations between NET gene (SLC6A2) single nucleotide polymorphisms and schizophrenia in a Korean population. Future research with a larger sample size and more genetic markers is needed to replicate our results.     

载脂蛋白E基因多态性与颈动脉粥样硬化的相关性研究

目的:研究载脂蛋白E(ApoE)基因多态性与颈动脉粥样硬化的相关性。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术,对25例B超检测颈动脉内中膜厚度(IMT)增厚患者(增厚组)和25例同期健康体检者(对照组)的ApoE基因多态性进行分析。结果:IMT增厚组ε3等位基因频率较对照组降低(P<0.05),ε4等位基因频率较对照组升高(P<0.01)。IMT增厚组的ε3/ε4基因型频率显著要高于对照组。对以上两组再按ApoE基因型分别分为3组:ApoE2(ε2/2 ε2/3),ApoE3(ε3/3)和ApoE4(ε3/4 ε4/4)。结果显示颈动脉IMT在不同基因型间差异显著,ApoE4组显著增加,颈动脉多发斑块率在此组也显著增加。结论:ApoE基因多态性与颈动脉粥样硬化形成有相关性,ε4基因是颈动脉粥样硬化形成的危险因子。     

The Association Between Childhood Trauma and Memory Functioning in Schizophrenia

Objective: Both neurocognitive impairments and a history of childhood abuse are highly prevalent in patients with schizophrenia. Childhood trauma has been associated with memory impairment as well as hippocampal volume reduction in adult survivors. The aim of the following study was to examine the contribution of childhood adversity to verbal memory functioning in people with schizophrenia. Methods: Eighty-five outpatients with a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnosis of chronic schizophrenia were separated into 2 groups on the basis of self-reports of childhood trauma. Performance on measures of episodic narrative memory, list learning, and working memory was then compared using multivariate analysis of covariance. Results: Thirty-eight (45%) participants reported moderate to severe levels of childhood adversity, while 47 (55%) reported no or low levels of childhood adversity. After controlling for premorbid IQ and current depressive symptoms, the childhood trauma group had significantly poorer working memory and episodic narrative memory. However, list learning was similar between groups. Conclusion: Childhood trauma is an important variable that can contribute to specific ongoing memory impairments in schizophrenia.     

Association Between Learning Capabilities and Practice-Related Activation Changes in Schizophrenia

The present functional magnetic resonance imaging study investigated the neural correlates of practice-associated activation changes in patients with schizophrenia and their association with symptom severity. A group of patients (n = 24) were divided into more successful and less successful learners and were asked to perform a verbal overlearning task in the scanner. We found that both patient groups profited from practice, showing significant decreases in mean response times as well as significant learning-related decreases in cerebral activation. Direct comparison between groups yielded a relative hyperactivation in the group of the less successful learners at the beginning of practice, which showed a reduction with increasing practice. This was reflected by relatively stronger signal decreases in a predominantly fronto-parieto-cerebellar network. In the group of less successful learners, there was a negative correlation between general symptom scores and learning-related signal decreases in a task-relevant network involving cerebellar, inferior and middle frontal (BA 45/47, 46), superior parietal (BA 31), and superior temporal (BA 39) regions. Present data indicate that hyperactivity under high task demands might serve to identify those patients with less potential to profit from practice. However, at least in the context of moderate– to low–working memory demands, this activation abnormality seems to constitute a state rather than a trait characteristic, which patients manage to reduce by successful short-term learning. The findings also suggest that successful learners can better compensate potentially interfering effects exerted by disorder-related psychopathology.     

2个精神分裂症多发家系GRM3基因多态性位点的连锁研究

目的 探讨代谢型谷氨酸受体3亚型(GRM3)基因与精神分裂症的连锁关系.方法 收集到2个精神分裂症多发家系共54个个体,其中9个受累个体,选取GRM3基因附近3对微卫星标记引物(D7S644、D7S2555、D7S2481),采用两点和多点非参数连锁(NPL)分析对这2个家系进行遗传学分析.结果 D7S644两点NPL值为0.953(P=0.095),多点NPL值为1.672(P=0.046),达到验证性连锁的阈值.D7S2555两点和多点NPL值分别为0.079(P=0.331)和0.234(P=0.286),D7S2481两点和多点NPL值分别为0.438(P=0.225)和0.629(P=0.159).结论 GRM3基因位点可能与精神分裂症存在相关.     

Global Association Between Cortical Thinning and White Matter Integrity Reduction in Schizophrenia

Previous neuroimaging studies have revealed that both gray matter (GM) and white matter (WM) are altered in several morphological aspects in schizophrenia patients. Although several studies reported associations between GM and WM alterations in restricted regions, the existence of a global association between GM and WM pathologies is unknown. Considering the wide distribution of GM morphological changes and the profound genetic background of WM abnormalities, it would be natural to postulate a global association between pathologies of GM and WM in schizophrenia. In this investigation, we studied 35 schizophrenia patients and 35 healthy control subjects using T1-weighted magnetic resonance imaging and diffusion tensor imaging (DTI) and investigated the association between GM thickness and WM fractional anisotropy (FA) as a proxy of pathology in each tissue. To investigate cortical thickness, surface-based analysis was used. The mean cortical thickness for the whole brain was computed for each hemisphere, and group comparisons were performed. For DTI data, mean FA for the whole brain was calculated, and group comparisons were performed. Subsequently, the correlation between mean cortical thickness and mean FA was investigated. Results showed that the mean cortical thickness was significantly thinner, and the mean FA was significantly lower in schizophrenia patients. Only in the patient group the mean cortical thickness and mean FA showed significant positive correlations in both hemispheres. This correlation remained significant even after controlling for demographic and clinical variables. Thus, our results indicate that the GM and WM pathologies of schizophrenia are intertwined at the global level.Key words: schizophrenia, white matter integrity, diffusion tensor imaging, cortical thickness, surface-based approach     

Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees

OBJECTIVE The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). METHOD The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs. RESULTS No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10-17, explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families. CONCLUSIONS Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.     

No Association between PAWR Gene Polymorphisms and Tardive Dyskinesia in Schizophrenia Patients

Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with the prolonged use of antipsychotic drugs. Since prostate apoptosis response 4 (Par-4) is a key ligand of the dopamine D2 receptor, the Par-4 gene (PAWR) is a good candidate gene to study in the context of TD susceptibility. We examined the association between PAWR gene polymorphisms and TD. Three single nucleotide polymorphisms of PAWR were selected for the analysis: rs7979987, rs4842318, and rs17005769. Two hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). Genotype/allele-wise and haplotype-wise analyses were performed. There were no significant differences in genotype and allele frequencies between the two groups. Haplotype analysis also did not reveal a difference between the two groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that PAWR gene variants do not significantly contribute to an increased risk of TD.