Genetics of clinical features and subtypes of schizophrenia: A review of the recent literature
Washington VA Medical Center, 50 Irving Street NW, Washington, DC 20422, USA. Current Psychiatry Reports
(Impact Factor: 3.24).
05/2008; 10(2):164-70. DOI: 10.1007/s11920-008-0028-z
Since its earliest descriptions, schizophrenia has been thought to be clinically heterogeneous. Symptomatic features and subtypes tend to aggregate in families, suggesting that genetic factors contribute to individual differences in illness presentation. Over the past 5 years, evidence from genetic linkage and association studies has mounted to suggest that some susceptibility genes are etiologic factors for more or less specific illness subtypes. Furthermore, modifier genes may affect clinical features dimensionally only after a given patient is already affected with the illness. In this paper, we review recent findings supporting the existence of such "modifier" genes. To date, DTNBP1 has provided the greatest evidence of illness modification, as associations with negative and cognitive symptoms and worse outcome have been published in independent samples. Future directions include using whole-genome association studies to search for genetic modifiers of schizophrenia.
- "Developmental or synaptic alternations have been documented in SCZ, and especially the impaired adult neurogenesis has been implicated in SCZ (Kempermann et al., 2008; Balu and Coyle, 2011; Ming and Song, 2011). DTNBP1 (dystrobrevin-binding protein 1), which encodes dysbindin-1, is a leading susceptibility gene of SCZ (Straub et al., 2002; Fanous and Kendler, 2008). The sandy (sdy) mutant, which carries a spontaneously occurring large deletion in the Dtnbp1 gene on the DBA/2J inbred strain (Li et al., 2003), is an appropriate mouse model of SCZ (Feng et al., 2008; Hattori et al., 2008; Takao et al., 2008; Bhardwaj et al., 2009). "
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ABSTRACT: Schizophrenia (SCZ) is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 (dystrobrevin-binding protein 1) gene encodes dysbindin-1 and is a leading susceptibility gene of SCZ. We previously reported that the dysbindin-1C isoform regulates the survival of the hilar glutamatergic mossy cells in the dentate gyrus, which controls the adult hippocampal neurogenesis. However, the underlying mechanism of hilar mossy cell loss in the dysbindin-1-deficient sandy (sdy) mice (a mouse model of SCZ) is unknown. In this study, we did not observe the apoptotic signals in the hilar mossy cells of the sdy mice by using the TUNEL assay and immunostaining of cleaved caspase-3 or necdin, a dysbindin-1- and p53-interacting protein required for neuronal survival. However, we found that the steady-state level of LC3-II, a marker of autophagosomes, was decreased in the hippocampal formation in the mice lacking dysbindin-1C. Furthermore, we observed a significant reduction of the cytosolic LC3-II puncta in the mossy cells of sdy mice. In addition, overexpression of dysbindin-1C, but not 1A, in cultured cells increased LC3-II level and the LC3 puncta in the transfected cells. These results suggest that dysbindin-1C deficiency causes impaired autophagy, which is likely implicated in the pathogenesis of SCZ.
Copyright © 2014 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.
Journal of Genetics and Genomics 01/2015; 42(1):1-8. DOI:10.1016/j.jgg.2014.12.001 · 3.59 Impact Factor
Available from: Jia Cheng
- "SCZ is a complex mixed disorder with two major subtypes, paranoid and undifferentiated SCZ. The classic features of paranoid SCZ are delusions or auditory hallucinations, and the undifferentiated SCZ shows significant changes in personal behavior and mixed clinical syndrome [Fanous and Kendler, 2008]. Since ideal endophenotypes are stable over time, and are associated with the clinical psychotic features [Hall et al., 2006], epigenetic marks "
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ABSTRACT: Schizophrenia (SCZ) is a complex mental disorder contributed by both genetic and epigenetic factors. Long noncoding RNAs (lncRNAs) was recently found playing an important regulatory role in mental disorders. However, little was known about the DNA methylation of lncRNAs, although numerous SCZ studies have been performed on genetic polymorphisms or epigenetic marks in protein coding genes. We presented a comprehensive genome wide DNA methylation study of both protein coding genes and lncRNAs in female patients with paranoid and undifferentiated SCZ. Using the methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), 8,163 and 764 peaks were identified in paranoid and undifferentiated SCZ, respectively (p < 1×10-5). Gene ontology analysis showed that the hypermethylated regions were enriched in the genes related to neuron system and brain for both paranoid and undifferentiated SCZ (p < 0.05). Among these peaks, 121 peaks were located in gene promoter regions that might affect gene expression and influence the SCZ related pathways. Interestingly, DNA methylation of 136 and 23 known lncRNAs in Refseq database were identified in paranoid and undifferentiated SCZ, respectively. In addition, ∼20% of intergenic peaks annotated based on Refseq genes were overlapped with lncRNAs in UCSC and gencode databases. In order to show the results well for most biological researchers, we created an online database to display and visualize the information of DNA methyation peaks in both types of SCZ (http://www.bioinfo.org/scz/scz.htm). Our results showed that the aberrant DNA methylation of lncRNAs might be another important epigenetic factor for SCZ.
Copyright © 2014. Published by Elsevier Masson SAS.
European Journal of Medical Genetics 12/2014; 58(2). DOI:10.1016/j.ejmg.2014.12.001 · 1.47 Impact Factor
Available from: Danjie Jiang
- "Paranoid and undifferentiated SCZ are two most common subtypes of SCZ according to DSM-IV criteria (American Psychiatric Association, 2000). The clinic symptoms of paranoid and undifferentiated SCZ include delusions, hallucinations, extremely disorganized behavior and negative symptoms (Fanous and Kendler, 2008). SCZ is a complex mental disorder. "
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ABSTRACT: The current study was the first one to reveal the contribution of DRD3 methylation to the risk of different SCZ subtypes. This study was involved with a total of 30 paranoid (15 males and 15 females) and 29 undifferentiated (15 males and 14 females) SCZ patients and 26 age- and gender-matched controls. Our results showed a significant association of CpG2 with SCZ. A breakdown analysis by gender showed that CpG2 and CpG3 methylation were significantly higher in male patients than male controls, and that CpG5 methylation was significantly higher in female patients than female controls. A further breakdown analysis by both gender and SCZ subtype showed that CpG2 and CpG3 methylation were significantly higher in male paranoid SCZ and male undifferentiated SCZ than male controls. In contrast, CpG2 and CpG3 methylation were significantly lower in female undifferentiated SCZ than female controls. Additionally, CpG5 methylation was significantly higher in female paranoid SCZ than female controls. In conclusion, our findings supported that DRD3 gene body hypermethylation was significantly associated with the risk of SCZ. Future study is needed to clarify the mechanisms by which DRD3 gene body hypermethylation contributes to the risk of SCZ.
Psychiatry Research 08/2014; 220(3). DOI:10.1016/j.psychres.2014.08.032 · 2.47 Impact Factor
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