The impact of a genome-wide supported psychosis variant in the ZNF804A gene on memory function in schizophrenia
ABSTRACT A recent genome-wide association study showed that a variant (rs1344706) in the ZNF804A gene was associated with schizophrenia and bipolar disorder. Replication studies supported the evidence for association between this variant in the ZNF804A gene and schizophrenia and that this variant is the most likely susceptibility variant. Subsequent functional magnetic resonance imaging studies in healthy subjects demonstrated the association of the high-risk ZNF804A variant with neural activation during a memory task and a theory of mind task. As these cognitive performances are disturbed in patients with schizophrenia, this gene may play a role in cognitive dysfunction in schizophrenia. The aim of the current study was to investigate the potential relationship between this ZNF804A polymorphism and memory function. The effects of the high-risk ZNF804A genotype, diagnosis, and genotype-diagnosis interaction on verbal memory, visual memory (VisM), attention/concentration, and delayed recall (measured by the Wechsler Memory Scale-Revised) were analyzed by two-way analysis of covariance in 113 patients with schizophrenia and 184 healthy subjects. Consistent with previous studies, patients with schizophrenia exhibited poorer performance on all indices as compared to healthy control subjects (P < 0.001). A significant ZNF804A genotype-diagnosis interaction was found for VisM performance (P = 0.0012). Patients with the high-risk T/T genotype scored significantly lower on VisM than G carriers did (P = 0.018). In contrast, there was no genotype effect for any index in the healthy control subjects (P > 0.05). Our data suggest that rs1344706 may be related to memory dysfunction in schizophrenia. © 2010 Wiley-Liss, Inc.
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ABSTRACT: Advances in molecular genetics, fueled by the results of large-scale genome-wide association studies, meta-analyses, and mega-analyses, have provided the means of identifying genetic risk factors for human disease, thereby enriching our understanding of the functionality of the genome in the post-genomic era. In the past half-decade, research on neuropsychiatric disorders has reached an important milestone: the identification of susceptibility genes reliably associated with complex psychiatric disorders at genome-wide levels of significance. This age of discovery provides the groundwork for follow-up studies designed to elucidate the mechanism(s) by which genetic variants confer susceptibility to these disorders. The gene encoding zinc-finger protein 804 A (ZNF804A) is among these candidate genes, recently being found to be strongly associated with schizophrenia and bipolar disorder via one of its non-coding mutations, rs1344706. Neurobiological, molecular, and bioinformatic analyses have improved our understanding of ZNF804A in general and this variant in particular; however, more work is needed to establish the mechanism(s) by which ZNF804A variants impinge on the biological substrates of the two disorders. Here, we review literature recently published on ZNF804A, and analyze critical concepts related to the biology of ZNF804A and the role of rs1344706 in schizophrenia and bipolar disorder. We synthesize the results of new bioinformatic analyses of ZNF804A with key elements of the existing literature and knowledge base. Furthermore, we suggest some potentially fruitful short- and long-term research goals in the assessment of ZNF804A. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2015; 168(1):14-35. DOI:10.1002/ajmg.b.32284 · 3.27 Impact Factor
Schizophrenia Research 12/2014; 160(1-3):228-9. DOI:10.1016/j.schres.2014.10.023 · 4.43 Impact Factor
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ABSTRACT: Psychiatric disorders have a negative impact on society and human lives. Genetic factors are involved in the occurrence and development of psychiatric diseases. ZNF804A has been identified as one of the most compelling risk genes associated with broad phenotypes related to psychosis. We conducted a systematic meta-analysis and reviewed ZNF804A variants in psychosis-related disorders, including schizophrenia, bipolar disorder, and attention-deficit hyperactivity disorder. We also summarized the association between other zinc finger protein genes (ZNFs) and psychiatric diseases. The meta-analysis included a total of six variants of ZNF804A and three variants of other ZNFs (ZDHHC8 and ZKSCAN4), and the effects of ZNF variants on neurocognition and neuroimaging phenotypes were reviewed. The biological functions of these variants are also presented. We verified that ZNF804A was significantly related to psychiatric diseases, and the association between ZNF804A rs1344706 and psychosis (schizophrenia and bipolar disorder) did not vary with disease or ethnicity. The main brain area regulated by ZNF804A rs1344706 was the dorsolateral prefrontal cortex. The effect of ZNF804A variants on cognition did not display consistency with different diseases or methodologies. These findings suggest that ZNF804A might play an important role in common pathogenesis of psychiatric diseases, and its variants are likely involved in regulating the expression of psychosis-related genes, especially the dopamine pathway genes. Further research should focus on the molecular mechanisms by which ZNF804A variants act in psychiatric diseases and related phenotypes. Copyright © 2015 Elsevier B.V. All rights reserved.Schizophrenia Research 02/2015; 162(1-3). DOI:10.1016/j.schres.2015.01.036 · 4.43 Impact Factor