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A brain-wide association study of DISC1 genetic variants reveals a relationship with the structure and functional connectivity of the precuneus in schizophrenia  [PDF]
Xiaohong Gong,Wenlian Lu,Keith M. Kendrick,Weidan Pu,Chu Wang,Li Jin,Guangmin Lu,Zhening Liu,Haihong Liu,Jianfeng Feng
Quantitative Biology , 2014, DOI: 10.1002/hbm.22560
Abstract: The Disrupted in Schizophrenia Gene 1 (DISC1) plays a role in both neural signalling and development and is associated with schizophrenia, although its links to altered brain structure and function in this disorder are not fully established. Here we have used structural and functional MRI to investigate links with six DISC1 single nucleotide polymorphisms (SNPs). We employed a brain-wide association analysis (BWAS) together with a Jacknife internal validation approach in 46 schizophrenia patients and 24 matched healthy control subjects. Results from structural MRI showed significant associations between all six DISC1 variants and gray matter volume in the precuneus, post-central gyrus and middle cingulate gyrus. Associations with specific SNPs were found for rs2738880 in the left precuneus and right post-central gyrus, and rs1535530 in the right precuneus and middle cingulate gyrus. Using regions showing structural associations as seeds a resting-state functional connectivity analysis revealed significant associations between all 6 SNPS and connectivity between the right precuneus and inferior frontal gyrus. The connection between the right precuneus and inferior frontal gyrus was also specifically associated with rs821617. Importantly schizophrenia patients showed positive correlations between the six DISC-1 SNPs associated gray matter volume in the left precuneus and right post-central gyrus and negative symptom severity. No correlations with illness duration were found. Our results provide the first evidence suggesting a key role for structural and functional connectivity associations between DISC1 polymorphisms and the precuneus in schizophrenia.
DISC1 and Striatal Volume: A Potential Risk Phenotype For mental Illness  [PDF]
M. Mallar Chakravarty,Daniel Felsky,Jason P. Lerch,Benoit H. Mulsant,James L. Kennedy,Aristotle N. Voineskos
Frontiers in Psychiatry , 2012, DOI: 10.3389/fpsyt.2012.00057
Abstract: Disrupted-in-schizophrenia 1 was originally discovered in a large Scottish family with abnormally high rates of severe mental illness, including schizophrenia, bipolar disorder, and depression. An accumulating body of evidence from genetic, postmortem, and animal data supports a role for DISC1 in different forms of mental illness. DISC1 may play an important role in determining structure and function of several brain regions. One brain region of particular importance for several mental disorders is the striatum, and DISC1 mutant mice have demonstrated an increase in dopamine (D2) receptors in this structure. However, association between DISC1 functional polymorphisms and striatal structure have not been examined in humans. We, therefore hypothesized that there would be a relationship between human striatal volume and DISC1 genotype, specifically in the Leu607Phe (rs6675281) and Ser704Cys (rs821618) single nucleotide polymorphisms. We tested our hypothesis by automatically identifying the striatum in 54 healthy volunteers recruited for this study. We also performed an exploratory analysis of cortical thickness, cortical surface area, and structure volume. Our results demonstrate that Phe allele carriers have larger striatal volume bilaterally (left striatum: p = 0.017; right striatum: p = 0.016). From the exploratory analyses we found that the Phe carriers also had larger left hemisphere volumes (p = 0.0074) and right occipital lobe surface area (p = 0.014) compared to LeuLeu homozygotes. However, these exploratory findings do not survive a conservative correction for multiple comparisons. Our findings demonstrate that a functional DISC1 variant influences striatal volumes. Taken together with animal data that this gene influences D2 receptor levels in striatum, a key risk pathway for mental illnesses such as schizophrenia and bipolar disorder may be conferred via DISC1’s effects on the striatum.
DISC1 (Disrupted-in-Schizophrenia-1) Regulates Differentiation of Oligodendrocytes  [PDF]
Tsuyoshi Hattori, Shoko Shimizu, Yoshihisa Koyama, Hisayo Emoto, Yuji Matsumoto, Natsuko Kumamoto, Kohei Yamada, Hironori Takamura, Shinsuke Matsuzaki, Taiichi Katayama, Masaya Tohyama, Akira Ito
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088506
Abstract: Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes.
Replication of the Association of a MET Variant with Autism in a Chinese Han Population  [PDF]
Xue Zhou, Yang Xu, Jia Wang, Hongbo Zhou, Xian Liu, Qasim Ayub, Xuelai Wang, Chris Tyler-Smith, Lijie Wu, Yali Xue
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027428
Abstract: Background Autism is a common, severe and highly heritable neurodevelopmental disorder in children, affecting up to 100 children per 10,000. The MET gene has been regarded as a promising candidate gene for this disorder because it is located within a replicated linkage interval, is involved in pathways affecting the development of the cerebral cortex and cerebellum in ways relevant to autism patients, and has shown significant association signals in previous studies. Principal Findings Here, we present new ASD patient and control samples from Heilongjiang, China and use them in a case-control and family-based replication study of two MET variants. One SNP, rs38845, was successfully replicated in a case-control association study, but failed to replicate in a family-based study, possibly due to small sample size. The other SNP, rs1858830, failed to replicate in both case-control and family-based studies. Conclusions This is the first attempt to replicate associations in Chinese autism samples, and our result provides evidence that MET variants may be relevant to autism susceptibility in the Chinese Han population.
DISC1 Pathway in Brain Development: Exploring Therapeutic Targets for Major Psychiatric Disorders  [PDF]
Atsushi Kamiya,Thomas W. Sedlak,Mikhail V. Pletnikov
Frontiers in Psychiatry , 2012, DOI: 10.3389/fpsyt.2012.00025
Abstract: Genetic risk factors for major psychiatric disorders play key roles in neurodevelopment. Thus, exploring the molecular pathways of risk genes is important not only for understanding the molecular mechanisms underlying brain development, but also to decipher how genetic disturbances affect brain maturation and functioning relevant to major mental illnesses. During the last decade, there has been significant progress in determining the mechanisms whereby risk genes impact brain development. Nonetheless, given that the majority of psychiatric disorders have etiological complexities encompassing multiple risk genes and environmental factors, the biological mechanisms of these diseases remain poorly understood. How can we move forward to our research for discovery of the biological markers and novel therapeutic targets for major mental disorders? Here we review recent progress in the neurobiology of disrupted in schizophrenia 1 (DISC1), a major risk gene for major mental disorders, with a particular focus on its roles in cerebral cortex development. Convergent findings implicate DISC1 as part of a large, multi-step pathway implicated in various cellular processes and signal transduction. We discuss links between the DISC1 pathway and environmental factors, such as immune/inflammatory responses, which may suggest novel therapeutic targets. Existing treatments for major mental disorders are hampered by a limited number of pharmacological targets. Consequently, elucidation of the DISC1 pathway, and its association with neuropsychiatric disorders, may offer hope for novel treatment interventions.
Association study of SHANK3 gene polymorphisms with autism in Chinese Han population
Jian Qin, Meixiang Jia, Lifang Wang, Tianlan Lu, Yan Ruan, Jing Liu, Yanqing Guo, Jishui Zhang, Xiaoling Yang, Weihua Yue, Dai Zhang
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-61
Abstract: We performed an association study between SHANK3 gene polymorphisms and autism in Chinese Han population. We analyzed the association between five single nucleotide polymorphisms (SNPs) of the SHANK3 gene and autism in 305 Chinese Han trios, using the family based association test (FBAT). Linkage disequilibrium (LD) analysis showed the presence of LD between pairwise markers across the locus. We also performed mutation screening for the rare de novo mutations reported previously.No significant evidence between any SNPs of SHANK3 and autism was observed. We did not detect any mutations described previously in our cohort.We suggest that SHANK3 might not represent a major susceptibility gene for autism in Chinese Han population.Autism is a pervasive developmental disorder mainly characterized by limited or absent verbal communication, lacking of reciprocal social interaction or responsiveness and restricted, stereotypical, and ritualized patterns of interests and behavior. Autism together with childhood disintegrative disorder, pervasive not otherwise specified (PDD-NOS, or atypical autism) and Asperger syndrome share the similar characteristics and are all included as autism spectrum disorder (ASD), also known as pervasive developmental disorder (PDD). Family and twin studies have conclusively described autism as a highly heritable neuropsychiatry disorder with heritability estimates of over 90% and the environmental factors contributing no more than 10% [1-3]. Nevertheless, autism is etiologically heterogeneous.Shank3 (SH3 and multiple ankyrin repeat domains 3; also termed ProSAP2, proline-rich synapse-associated protein 2) is a master synaptic scaffolding protein[4,5]. In rats and human beings, Shank3 is expressed preferentially in cerebral cortex and cerebellum[6,7]. With its multiple protein interaction domains, this molecule directly or indirectly connects with neurotransmitter receptors and cytoskeleton proteins[8,9]. It also participates in the formation, matur
The Evidence for Association of ATP2B2 Polymorphisms with Autism in Chinese Han Population  [PDF]
Wen Yang, Jing Liu, Fanfan Zheng, Meixiang Jia, Linnan Zhao, Tianlan Lu, Yanyan Ruan, Jishui Zhang, Weihua Yue, Dai Zhang, Lifang Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061021
Abstract: Background Autism is a neurodevelopmental disorder with a high estimated heritability. ATP2B2, located on human chromosome 3p25.3, encodes the plasma membrane calcium-transporting ATPase 2 which extrudes Ca2+ from cytosol into extracellular space. Recent studies reported association between ATP2B2 and autism in samples from Autism Genetic Resource Exchange (AGRE) and Italy. In this study, we investigated whether ATP2B2 polymorphisms were associated with autism in Chinese Han population. Methods We performed a family based association study between five SNPs (rs35678 in exon, rs241509, rs3774180, rs3774179, and rs2278556 in introns) in ATP2B2 and autism in 427 autism trios of Han Chinese descent. All SNPs were genotyped using the Sequenom genotyping platform. The family-based association test (FBAT) program was used to perform association test for SNPs and haplotype analyses. Results This study demonstrated a preferential transmission of T allele of rs3774179 to affected offsprings under an additive model (T>C, Z = 2.482, p = 0.013). While C allele of rs3774179 showed an undertransmission from parents to affected children under an additive and a dominant model, respectively (Z = ?2.482, p = 0.013; Z = ?2.591, p = 0.0096). Haplotype analyses revealed that three haplotypes were significantly associated with autism. The haplotype C-C (rs3774180–rs3774179) showed a significant undertransmission from parents to affected offsprings both in specific and global haplotype FBAT (Z = ?2.037, p = 0.042; Global p = 0.03). As for the haplotype constructed by rs3774179 and rs2278556, C-A might be a protective haplotype (Z = ?2.206, p = 0.027; Global p = 0.04), while T-A demonstrated an excess transmission from parents to affected offsprings (Z = 2.143, p = 0.032). These results were still significant after using the permutation method to obtain empirical p values. Conclusions Our research suggested that ATP2B2 might play a role in the etiology of autism in Chinese Han population.
Expression of DISC1-Interactome Members Correlates with Cognitive Phenotypes Related to Schizophrenia  [PDF]
Antonio Rampino, Rosie May Walker, Helen Scott Torrance, Susan Maguire Anderson, Leonardo Fazio, Annabella Di Giorgio, Paolo Taurisano, Barbara Gelao, Raffaella Romano, Rita Masellis, Gianluca Ursini, Grazia Caforio, Giuseppe Blasi, J. Kirsty Millar, David John Porteous, Pippa Ann Thomson, Alessandro Bertolino, Kathryn Louise Evans
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099892
Abstract: Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.
Disrupted-in-Schizophrenia (DISC1) Functions Presynaptically at Glutamatergic Synapses  [PDF]
Brady J. Maher, Joseph J. LoTurco
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034053
Abstract: The pathophysiology of schizophrenia is believed to involve defects in synaptic transmission, and the function of many schizophrenia-associated genes, including DISC1, have been linked to synaptic function at glutamatergic synapses. Here we develop a rodent model via in utero electroporation to assay the presynaptic function of DISC1 at glutamatergic synapses. We used a combination of mosaic transgene expression, RNAi knockdown and optogenetics to restrict both genetic manipulation and synaptic stimulation of glutamatergic neurons presynaptic to other layer 2/3 neocortical pyramidal neurons that were then targeted for whole-cell patch-clamp recording. We show that expression of the DISC1 c-terminal truncation variant that is associated with Schizophrenia alters the frequency of mEPSCs and the kinetics of evoked glutamate release. In addition, we show that expression level of DISC1 is correlated with the probability of glutamate release such that increased DISC1 expression results in paired-pulse depression and RNAi knockdown of DISC1 produces paired-pulse facilitation. Overall, our results support a direct presynaptic function for the schizophrenia-associated gene, DISC1.
DISC1基因过表达对星形胶质细胞质膜伸展的影响  [PDF]
第三军医大学学报 , 2013,
Abstract: 目的构建精神分裂症断裂基因1(Disrupted-In-Schizophrenia1,DISC1)蛋白表达质粒,检测其过表达后对星形胶质细胞(Astrocytes,ASTs)质膜伸展的影响。方法针对小鼠DISC1基因mRNA编码序列,设计合成可扩增全长引物;以小鼠脑白质cDNA为模板进行PCR扩增,构建全长表达质粒,命名为pEGFP-n1-DISC1。分别将过表达组pEGFP-n1-DISC1和空载体对照组pEGFP-n1电转染原代培养ASTs,以Westernblot及免疫荧光染色检测DISC1-GFP融合蛋白的表达,利用Image-ProPlus5.0软件分析对照组与DISC1过表达组星形胶质细胞质膜伸展面积的大小。结果成功从cDNA中扩增出DISC1编码序列并插入pEGFP-n1载体,双酶切和测序结果证实,DISC1蛋白编码序列插入载体,并能正确读码翻译。构建质粒转染ASTs60h后,可见DISC1-GFP融合蛋白表达;与对照组相比,DISC1过表达组ASTs的质膜伸展面积明显增加(P<0.05)。结论成功构建小鼠DISC1全长基因表达载体,DISC1基因过表达后可促使ASTs质膜伸展面积增加。
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