Association of the ZNF804A gene polymorphism rs1344706 with white matter density changes in Chinese schizophrenia

Background

ZNF804A gene polymorphism rs1344706, the first genetic risk variant to achieve genome wide significance for schizophrenia, has been linked to neural functional connectivity. Dysconnectivity of WM may be the primary pathological mechanism of schizophrenia. Association of this variant with regional WM density has not been investigated in schizophrenic patients.

Methods

69 healthy controls and 80 patients with schizophrenia underwent genotyping of rs1344706 SNPs, and were examined for WM density (T1-weighted MRI). The association of rs1344706 with WM changes in schizophrenia patients and healthy controls was analyzed using a full-factorial 2 × 2 analysis of variance.

Results

1. There was an interaction on WM density in the left prefrontal lobe between the rs1344706 genotype and schizophrenic diagnosis, where the risk T allele carriers presented higher WM density in the schizophrenia patients and lower WM density in healthy controls in comparison with the non-risk allele carriers.2. The risk allele was associated with an increased WM density of the bilateral hippocampus in both the patients and the healthy group.

Limitation

The influence of antipsychotics to the white matter in schizophrenic patients was not fully eliminated.

Conclusions

The ZNF804A variant may confer risk for schizophrenia by exerting its effects on the WM in the left prefrontal lobe together with other risk factors for schizophrenia.     

Association analysis of ZNF804A (zinc finger protein 804A) rs1344706 with therapeutic response to atypical antipsychotics in first-episode Chinese patients with schizophrenia

`The single-nucleotide polymorphism rs1344706 located in the ZNF804A zinc finger protein 804A gene is a well-established genome-wide significant variant for schizophrenia. The aim of this study was to investigate the potential association between this ZNF804A polymorphism and treatment response to atypical antipsychotic. Seventy-one first-episode inpatients with schizophrenia receiving olanzapine, aripiprazole, or quetiapine monotherapy were enrolled. Symptom response to treatment was assessed using the Positive and Negative Syndrome Scale (PANSS) on admission and reassessed after 4 weeks of treatment. Single-nucleotide polymorphism rs1344706 was genotyped by direct sequencing. There was substantial difference in treatment response among patients with 3 different genotypes regarding total PANSS score and positive subscore (for total PANSS score, F = 4.608, df = 2, P = .013; for positive subscore, F = 4.183, df = 2, P = .019). Compared with G homozygotes, T carriers showed significantly less improvement in total PANSS score as well as positive subscore (for total PANSS score, F = 8.724, df = 1, P = .004; for positive subscore, F = 9.392, df = 1, P = .005). Our results suggest that ZNF80A rs1344706 polymorphism may play a role in treatment response to atypical antipsychotic, although replication is required to confirm this finding.     

Spontaneous Regional Brain Activity in Healthy Individuals is Nonlinearly Modulated by the Interaction of ZNF804A rs1344706 and COMT rs4680 Polymorphisms

ZNF804A rs1344706 has been identified as one of the risk genes for schizophrenia.However,the neural mechanisms underlying this association are unknown.Given that ZNF804A upregulates the expression of COMT,we hypothesized that ZNF804 A may influence brain activity by interacting with COMT.Here,we genotyped ZNF804A rs1344706 and COMT rs4680 in 218 healthy Chinese participants.Amplitudes of low-frequency fluctuations(ALFFs)were applied to analyze the main and interaction effects of ZNF804A rs1344706 and COMT rs4680.The ALFFs of the bilateral dorsolateral prefrontal cortex showed a significant ZNF804A rs1344706 x COMT rs4680 interaction,manifesting as a U-shaped modulation,presumably by dopamine signaling.Significant main effects were also found.These findings suggest that ZNF804A affects the resting-state functional activation by interacting with COMT,and may improve our understanding of the neurobiological effects of ZNF804A and its association with schizophrenia.     

Evidence of IQ-modulated association between ZNF804A gene polymorphism and cognitive function in schizophrenia patients

ZNF804A gene polymorphism rs1344706 has been suggested as the most compelling case of a candidate gene for schizophrenia by a genome-wide association study and several replication studies. The current study of 570 schizophrenia patients and 448 controls again found significantly different genotype frequencies of rs1344706 between patients and controls. More important, we found that this association was modulated by IQ, with a stronger association among individuals with relatively high IQ, which replicated results of Walters et al, 2010. We further examined whether this IQ-modulated association also existed between the SNP and the intermediate phenotypes (working memory and executive functions) of schizophrenia. Data were available from an N-back task (366 patients and 414 controls) and the attention network task (361 patients and 416 controls). We found that the SNP and IQ had significant interaction effects on the intermediate phenotypes for patients, but not for controls. The disease risk allele was associated with poorer cognitive function in patients with high IQ, but better cognitive function in patients with low IQ. Together, these results indicated that IQ may modulate the role of rs1344706 in the etiology of both schizophrenia and its cognitive impairments, and pointed to the necessity of considering general cognitive function as indexed by IQ in the future studies of genetic bases of schizophrenia.     

Further evidence for genetic association of CACNA1C and schizophrenia: New risk loci in a Han Chinese population and a meta-analysis

CACNA1C (12p13.3) has been implicated as a susceptibility gene for schizophrenia by several replicated genome wide association studies. While these results have been consistent among studies in European populations, the findings in East Asian populations have varied. To test whether CACNA1C is a risk gene for schizophrenia, we conducted a case–control study in 5897 schizophrenic patients and 6323 healthy control subjects selected from Han Chinese population. Our study replicated the positive associations of rs1006737 (P = 0.0108, OR = 1.16, 95% CI: 1.03–1.29) and rs1024582 (P = 0.0062, OR = 1.18, 95% CI: 1.05–1.33), and identified a novel risk locus, rs2007044 (P = 0.0053, OR = 1.08, 95% CI: 1.02–1.14). A meta-analysis of rs1006737 combining our study and previous studies was conducted in a total of 8222 schizophrenia cases and 24,661 healthy controls. In the meta-analysis, the association between rs1006737 and schizophrenia remained significant (OR = 1.14, 95% CI: 1.07–1.22, P = 0.0001). Stratified analysis showed no heterogeneity between East Asian and European ancestries (χ²[1] = 0.07, P = 0.795), and the difference in pooled ORs between ancestries was not significant (Z = 0.25, P = 0.801). Our results provide further support for associations of rs1006737 and rs1024582 with schizophrenia, identify a new risk locus rs2007044 in a Han Chinese population, and further establish CACNA1C as an important susceptibility gene for the disease across world populations.     

Further evidence of VRK2 rs2312147 associated with schizophrenia

Objectives: Previous genome-wide association studies (GWAS) have reported that rs2312147 near the VRK2 gene was significantly associated with schizophrenia in populations of European descent, but negative results have also been observed.

Methods: To perform a systematic meta-analysis, we collected statistical data of rs2312147 from both GWAS and individual replication samples in European and Asian populations, which finally included up to 30,867 schizophrenia patients and 59,863 healthy controls.

Results: The VRK2 rs2312147 was genome-wide significantly associated with schizophrenia in combined populations (P?=?1.31?×?10^?15, odds ratio, OR?=?1.10) as well as in Europeans only (P?=?2.35?×?10^?12, OR =1.09). In Asian samples, the SNP did not reach genome-wide level of statistical significance (P?=?1.23?×?10?^??⁵, OR =1.19), which is likely due to the limited power of small sample size in this population (2,974 cases and 4,786 controls). However, the effect size of rs2312147 did not alter significantly between populations, and is also in agreement with the observed effect sizes of other genetic risk loci in large scale studies.

Conclusions: Our data provides further evidence for the genetic contributions of VRK2 rs2312147 to schizophrenia susceptibility especially in Europeans, while further replication analyses in Asian populations are still needed, and future studies, e.g., the underlying molecular mechanisms of genetic risk, are necessary.     

The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms

Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive symptoms (7.35 ± 0.46) compared to patients with a protective allele (9.41 ± 0.71, P = 0.022). This provides further evidence that ZNF804A is of functional relevance to schizophrenia and indicates that ZNF804A may be a novel target for pharmacological interventions.     

Lack of association of NALCN genetic variants with schizophrenia

NALCN (sodium leak channel, non-selective) is located on chromosome 13q (suggested linkage region for schizophrenia). We analyzed 21 polymorphisms in 464 schizophrenia subjects, 220 controls subjects and 119 small nuclear families. We observed nominal association with rs9518320 and rs9518331, suggesting that NALCN is not related to schizophrenia risk.     

Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families.

BACKGROUND: Involvement of AKT signaling pathways in schizophrenia has been recently suggested, on the basis of several lines of evidence. In addition to impairment of protein-levels and phosphorylation levels in the pathway, association of DNA sequence variants in the AKT1 gene with schizophrenia has been detected in a family sample. METHODS: We investigated the reported association of DNA sequence variants in the AKT1 gene in a sample of 79 sib-pair families with schizophrenia using the five single nucleotide polymorphisms (SNPs) of the original study and two additional SNPs in the neighborhood of the SNP for which association had been reported. RESULTS: We obtained statistical significance for single markers (p = .002) and multilocus haplotypes (p = .0013) located in the same region as has been reported in the previous study. CONCLUSIONS: The replication of association of variants in the AKT1 gene in a family sample with similar ethnical background as in the original study adds further evidence for involvement of AKT1 in development of schizophrenic disorders.     

Associations between the schizophrenia susceptibility gene ZNF804A and clinical outcomes in psychosis

We sought to test the hypothesis that the rs1344706 A allele will be associated with worse clinical outcome in first-episode psychosis. A data linkage was set up between a large systematic study of first-episode psychosis and an electronic health-record case register at the South London and Maudsley NHS Foundation Trust—a large provider of secondary mental-health care. A sample of 291 patients, who presented with a first psychotic episode (ICD10 diagnoses F20–29 or F30–33) and in whom the rs1344706 genotype had been assayed, were followed to examine the duration of mental-health in-patient care during the 2 years following first service contact, as a primary outcome. Secondary outcome measures were whether or not an in-patient episode occurred and the number of in-patient episodes during this period. A strong association was found between the number of rs1344706 A alleles and the cumulative duration of mental-health in-patient stay over the 2 years since initial presentation. In the 84.2% who experienced an in-patient episode during this period, the mean duration of admission was an additional 38 days for each A allele increment. Therefore, in addition to its potential role as a risk factor for psychosis, the ZNF804A rs1344706 A allele is associated with worse clinical outcome.     

Further evidence for a male-selective genetic association of synapse-associated protein 97 (SAP97) gene with schizophrenia

Background  

The synapse-associated protein 97 gene (SAP97) encodes a regulatory scaffold protein for the localization of L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) type glutamate receptors. We have recently demonstrated nominally significant associations between SAP97 gene and schizophrenia among Japanese males. The present study aimed to replicate these findings using an independent and larger sample.