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.
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- "Overall, our results contribute, from a biological approach, to the understanding of the genetic mechanisms involved in SSD and BPD and also of the relationship between genetic variability and the clinical heterogeneity of these disorders. Then, our findings suggest the role of Neuritin 1 gene as a mixed susceptibility/modifier gene (Fanous and Kendler 2008), which increases the susceptibility to these disorders and modifies certain presentations. However, new studies should be developed to further acknowledge the involvement of NRN1 and its interaction with other genes in the aetiology of mental disorders. "
ABSTRACT: Objectives Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results The frequency of the haplotype C-C (rs645649–rs582262) was significantly increased in patients compared to controls (P = 0.0043), while the haplotype T-C-C-T-C-A (rs3763180–rs10484320–rs4960155–rs9379002–rs9405890–rs1475157) was more frequent in controls (P = 3.1 × 10−5). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P = 0.005). Conclusions Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF.
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- "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). "
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.
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- "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 "
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.
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