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Schizophrenia Bioinformatics

Germano Orrù, Mauro Giovanni Carta, Alessia Bramanti
Background: Several studies have shown that the Single Nucleotide Polymorphism (SNP) in the CACAN1C gene, rs1006737, is related to different mood disorder illnesses, such as bipolar disorder and schizophrenia. Current day molecular procedures for allele detection of this gene can be very expensive and time consuming. Hence, a sensitive and specific molecular procedure for detecting these mutations in a large number of subjects is desirable, especially for research groups who have no complex laboratory equipment...
2018: Clinical Practice and Epidemiology in Mental Health: CP & EMH
Fernando J Sialana, An-Li Wang, Benedetta Fazari, Martina Kristofova, Roman Smidak, Svenja V Trossbach, Carsten Korth, Joseph P Huston, Maria A de Souza Silva, Gert Lubec
Disrupted-in-schizophrenia 1 (DISC1) is a key protein involved in behavioral processes and various mental disorders, including schizophrenia and major depression. A transgenic rat overexpressing non-mutant human DISC1, modeling aberrant proteostasis of the DISC1 protein, displays behavioral, biochemical and anatomical deficits consistent with aspects of mental disorders, including changes in the dorsal striatum, an anatomical region critical in the development of behavioral disorders. Herein, dorsal striatum of 10 transgenic DISC1 (tgDISC1) and 10 wild type (WT) littermate control rats was used for synaptosomal preparations and for performing liquid chromatography-tandem mass spectrometry (LC-MS)-based quantitative proteomics, using isobaric labeling (TMT10plex)...
2018: Frontiers in Molecular Neuroscience
Rana Adnan Tahir, Sheikh Arslan Sehgal
BACKGROUND: Synapsin II regulates neurotransmitter release from mature nerve terminals and plays important role in the formation of new nerve terminals. The associations of SYN II are identified in various studies that are linked to the onset of Schizophrenia. Schizophrenia is characterized by abnormal behavior like obsession, dampening of emotions and auditory hallucination. METHODS: The bioinformatics approaches were utilized for structural modeling and docking analyses of SYN II followed by pharmacophore generation to identify potent inhibitors...
February 12, 2018: Combinatorial Chemistry & High Throughput Screening
Jessica D Tenenbaum, Krithika Bhuvaneshwar, Jane P Gagliardi, Kate Fultz Hollis, Peilin Jia, Liang Ma, Radhakrishnan Nagarajan, Gopalkumar Rakesh, Vignesh Subbian, Shyam Visweswaran, Zhongming Zhao, Leon Rozenblit
Mental illness is increasingly recognized as both a significant cost to society and a significant area of opportunity for biological breakthrough. As -omics and imaging technologies enable researchers to probe molecular and physiological underpinnings of multiple diseases, opportunities arise to explore the biological basis for behavioral health and disease. From individual investigators to large international consortia, researchers have generated rich data sets in the area of mental health, including genomic, transcriptomic, metabolomic, proteomic, clinical and imaging resources...
November 27, 2017: Briefings in Bioinformatics
Yeunkum Lee, Jae Ryun Ryu, Hyojin Kang, Yoonhee Kim, Shinhyun Kim, Yinhua Zhang, Chunmei Jin, Hyo Min Cho, Won-Ki Kim, Woong Sun, Kihoon Han
Variants of the SHANK3 gene, which encodes a core scaffold protein of the postsynaptic density of excitatory synapses, have been causally associated with numerous brain disorders. Shank3 proteins directly bind zinc ions through their C-terminal sterile α motif domain, which enhances the multimerization and synaptic localization of Shank3, to regulate excitatory synaptic strength. However, no studies have explored whether zinc affects the protein interactions of Shank3, which might contribute to the synaptic changes observed after zinc application...
December 16, 2017: Biochemical and Biophysical Research Communications
Kristen Therese Thomas, Bart Russell Anderson, Niraj Shah, Stephanie Elaine Zimmer, Daniel Hawkins, Arielle Nicole Valdez, Qiaochu Gu, Gary Jonathan Bassell
Genomic studies have repeatedly associated variants in the gene encoding the microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling...
July 5, 2017: Cell Reports
Jing Li, Wangshu Zhang, Hui Yang, Daniel P Howrigan, Brent Wilkinson, Tade Souaiaia, Oleg V Evgrafov, Giulio Genovese, Veronica A Clementel, Jennifer C Tudor, Ted Abel, James A Knowles, Benjamin M Neale, Kai Wang, Fengzhu Sun, Marcelo P Coba
The postsynaptic density (PSD) contains a collection of scaffold proteins used for assembling synaptic signaling complexes. However, it is not known how the core-scaffold machinery associates in protein-interaction networks or how proteins encoded by genes involved in complex brain disorders are distributed through spatiotemporal protein complexes. Here using immunopurification, proteomics and bioinformatics, we isolated 2,876 proteins across 41 in vivo interactomes and determined their protein domain composition, correlation to gene expression levels and developmental integration to the PSD...
August 2017: Nature Neuroscience
Glenn A Doyle, Richard C Crist, Emre T Karatas, Matthew J Hammond, Adam D Ewing, Thomas N Ferraro, Chang-Gyu Hahn, Wade H Berrettini
Whereas some rare genetic variants convey high risk for schizophrenia (SZ), common alleles conveying even moderate risk remain elusive. Long interspersed element-1s (L1) are mobile retrotransposons comprising ~17% of the human genome. L1 retrotransposition can cause somatic mosaicism during neurodevelopment by insertional mutagenesis. We hypothesized that, compared to controls, patients diagnosed with schizophrenia (PDS) may have increased numbers of deleterious L1 insertions, perhaps occurring de novo, in brain-expressed genes of dorsolateral prefrontal cortex (DLPFC) neurons...
December 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Lisha Shao, Binyan Lu, Zhexing Wen, Shaolei Teng, Lingling Wang, Yi Zhao, Liyuan Wang, Koko Ishizuka, Xiufeng Xu, Akira Sawa, Hongjun Song, Guoli Ming, Yi Zhong
Although the genetic contribution is under debate, biological studies in multiple mouse models have suggested that the Disrupted-in-Schizophrenia-1 (DISC1) protein may contribute to susceptibility to psychiatric disorders. In the present study, we took the advantages of the Drosophila model to dissect the molecular pathways that can be affected by DISC1 in the context of pathology-related phenotypes. We found that three pathways that include the homologs of Drosophila Dys, Trio, and Shot were downregulated by introducing a C-terminal truncated mutant DISC1...
July 15, 2017: Human Molecular Genetics
Yeunkum Lee, Hyojin Kang, Bokyoung Lee, Yinhua Zhang, Yoonhee Kim, Shinhyun Kim, Won-Ki Kim, Kihoon Han
Recent molecular genetic studies have identified 100s of risk genes for various neurodevelopmental and neuropsychiatric disorders. As the number of risk genes increases, it is becoming clear that different mutations of a single gene could cause different types of disorders. One of the best examples of such a gene is SHANK3, which encodes a core scaffold protein of the neuronal excitatory post-synapse. Deletions, duplications, and point mutations of SHANK3 are associated with autism spectrum disorders, intellectual disability, schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder...
2017: Frontiers in Molecular Neuroscience
Julio Rodríguez-López, Beatriz Sobrino, Jorge Amigo, Noa Carrera, Julio Brenlla, Santiago Agra, Eduardo Paz, Ángel Carracedo, Mario Páramo, Manuel Arrojo, Javier Costas
Copy number variants (CNVs) conferring risk of schizophrenia present incomplete penetrance, suggesting the existence of second genetic hits. Identification of second hits may help to find genes with rare variants of susceptibility to schizophrenia. The aim of this work was to search for second hits of moderate/high risk in schizophrenia carriers of risk CNVs and resequencing of the relevant genes in additional samples. To this end, ten patients with risk CNVs at cytobands 15q11.2, 15q11.2-13.1, 16p11.2, or 16p13...
April 18, 2017: European Archives of Psychiatry and Clinical Neuroscience
Emma Reble, Christina A Castellani, Melkaye G Melka, Richard O'Reilly, Shiva M Singh
OBJECTIVES: Monozygotic twins with near-identical genotypes and discordance for complex diseases represent an exceptional resource to ascertain disease etiology. This strategy has been particularly effective with the availability of high-resolution complete individual genome sequencing. The challenge is using effective approaches to identify relevant differences that may cause or contribute toward disease discordance. PARTICIPANTS AND METHODS: This study carried out a VarScan2 bioinformatic analysis and a pathway analysis on whole-genome sequences from two sets of monozygotic twins...
April 2017: Psychiatric Genetics
S Liu, F Zhang, Y Y Shugart, L Yang, X Li, Z Liu, N Sun, C Yang, X Guo, J Shi, L Wang, L Cheng, K Zhang, T Yang, Y Xu
To date, diagnosis of schizophrenia is still based on clinical interviews and careful observations, which is subjective and variable, and can lead to misdiagnosis and/or delay in diagnosis. As early intervention in schizophrenia is important in improving outcomes, objective tests that can be used for schizophrenia diagnosis or treatment monitoring are thus in great need. MicroRNAs (miRNAs) negatively regulate target gene expression and their biogenesis is tightly controlled by various factors including transcription factors (TFs)...
January 10, 2017: Translational Psychiatry
Hon-Cheong So, Pak C Sham
Motivation: It is hoped that advances in our knowledge in disease genomics will contribute to personalized medicine such as individualized preventive strategies or early diagnoses of diseases. With the growth of genome-wide association studies (GWAS) in the past decade, how far have we reached this goal? In this study we explored the predictive ability of polygenic risk scores (PRSs) derived from GWAS for a range of complex disease and traits. Results: We first proposed a new approach to evaluate predictive performances of PRS at arbitrary P -value thresholds...
March 15, 2017: Bioinformatics
Ellen S Ovenden, Britt I Drögemöller, Lize van der Merwe, Bonginkosi Chiliza, Laila Asmal, Robin A Emsley, Louise Warnich
AIM: Noncoding variation has demonstrated regulatory effects on disease treatment outcomes. This study investigated the potential functionality of previously implicated noncoding variants on schizophrenia treatment response. MATERIALS & METHODS: Predicted regulatory potential of variation identified from antipsychotic response genome-wide association studies was determined. Prioritized variants were assessed for association(s) with treatment outcomes in a South African first episode schizophrenia cohort (n = 103)...
January 2017: Pharmacogenomics
Olympia Gianfrancesco, Alix Warburton, David A Collier, Vivien J Bubb, John P Quinn
Genome-wide association studies (GWAS) have identified a locus on chromosome 1p21.3 to be highly associated with schizophrenia. A microRNA, MIR137, within this locus has been proposed as the gene causally associated with schizophrenia, due to its known role as a regulator of neuronal development and function. However, the involvement of other genes within this region, including DPYD (dihydropyrimidine dehydrogenase), is also plausible. In this communication, we describe a previously uncharacterised, brain-expressed RNA, EU358092, within the schizophrenia-associated region at 1p21...
June 2017: Schizophrenia Research
M Föcking, P Dicker, L M Lopez, M Hryniewiecka, K Wynne, J A English, G Cagney, D R Cotter
The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders such as schizophrenia and bipolar disorder. We enriched for this anatomical structure in the anterior cingulate cortex of 16 bipolar disorder samples and 20 controls from the Stanley Medical Research Institute. Unbiased shotgun proteomics incorporating label-free quantitation was used to identify differentially expressed proteins. Quantitative investigation of the PSD identified 2033 proteins, among which 288 were found to be differentially expressed...
November 29, 2016: Translational Psychiatry
Xingchun Gao, Yajing Mi, Na Guo, Zhifang Hu, Fengrui Hu, Dou Liu, Lei Gao, Xingchun Gou, Weilin Jin
Glioblastoma(GBM) is one of the most common and aggressive malignant primary tumors of the central nervous system and mitochondria have been proposed to participate in GBM tumorigenesis. Previous studies have identified a potential role of Disrupted in Schizophrenia 1 (DISC1), a multi-compartmentalized protein, in mitochondria. But whether DISC1 could regulate GBM tumorigenesis via mitochondria is still unknown. We determined the expression level of DISC1 by both bioinformatics analysis and tissue analysis, and found that DISC1 was highly expressed in GBM...
December 27, 2016: Oncotarget
William T Carrick, Brandi Burks, Murray J Cairns, Jannet Kocerha
Dopaminergic neurotransmission mediates a majority of the vital central nervous system functions. Disruption of these synaptic events provokes a multitude of neurological pathologies, including Parkinson's, schizophrenia, depression, and addiction. Growing evidence supports a key role for noncoding RNA (ncRNA) regulation in the synapse. This review will discuss the role of both short and long ncRNAs in dopamine signaling, including bioinformatic examination of the pathways they target. Specifically, we focus on the contribution of ncRNAs to dopaminergic dysfunction in neurodegenerative as well as psychiatric disease...
2016: Frontiers in Molecular Biosciences
Seong-Tshool Hong
The human intestine contains a massive and complex microbial community called gut microbiota. A typical human carries 100 trillion microbes in his/her body which is 10 times greater than the number of their host cells, i.e. whole number of human cells. A combined microbial genome constituting gut microbiota is well excess our own human genome. The microbial composition of gut microbiotata and its role on diseases became a booming area of research, presenting a new paradigm of opportunities for modern medicines...
September 2016: Journal of Hypertension
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