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Schizophrenia etiology

Suzanne O Nolan, Taylor S Jefferson, Conner D Reynolds, Gregory D Smith, Andrew J Holley, Samantha L Hodges, Joaquin N Lugo
BACKGROUND: Loss of the Pten (phosphatase and tensin homolog) gene has been demonstrated to result in hyperactivation of the mammalian target of rapamycin (mTOR) pathway, a signaling pathway common to many disease etiologies, including tuberous sclerosis complex, Fragile X syndrome, and schizophrenia. Previous studies have focused on the impact of hyperactivation of the mTOR pathway in hippocampus and cortex and behaviors among those structures, but little is known about the relationship of Pten and mTOR signaling in the development and function of the cerebellum...
March 12, 2019: CNS & Neurological Disorders Drug Targets
Dengtang Liu, Haixin Cen, Kaida Jiang, Yifeng Xu
Schizophrenia is a severe mental disorder and its etiology and pathological mechanism are unknown. This article mainly introduces the progress of biological studies of schizophrenia in China in 2017, including neuroimaging, genetics, and immunology studies. It also introduces the research progress of high-risk psychotic syndrome and physiotherapy.
June 25, 2018: Shanghai Archives of Psychiatry
Steven J Girdler, Jamie E Confino, Mary E Woesner
Schizophrenia is a mental disorder that is characterized by progressive cognitive impairment in areas of attention, working memory, and executive functioning. Although no clear etiology of schizophrenia has been discovered, many factors have been identified that contribute to the development of the disease, such as neurotransmitter alterations, decreased synaptic plasticity, and diminished hippocampal volume. Historically, antipsychotic medications have targeted biochemical alterations in the brains of patients with schizophrenia but have been ineffective in alleviating cognitive and hippocampal deficits...
February 15, 2019: Psychopharmacology Bulletin
Ho Namkung, Brian J Lee, Akira Sawa
Supported by technological advances and collaborative efforts, psychiatric genetics has provided robust genetic findings in the past decade, particularly through genome-wide association studies (GWASs). However, translating these genetic findings into biological mechanisms and new therapies has been enormously challenging because of the complexity of their interpretation. Furthermore, the heterogeneity among patients with the same diagnosis, such as schizophrenia or major depressive disorder, challenges the biological validity of existing categorical approaches in clinical nosology, which is further complicated by the pleiotropic nature of many genetic variants across multiple disorders...
March 8, 2019: Cold Spring Harbor Symposia on Quantitative Biology
Katelyn R Ward, Robert E Featherstone, Melissa J Naschek, Olga Melnychenko, Anamika Banerjee, Janice Yi, Raymond L Gifford, Karin E Borgmann-Winter, Michael W Salter, Chang-Gyu Hahn, Steven J Siegel
Much evidence suggests that hypofunction of the N-methyl-d-aspartate glutamate receptor (NMDAR) may contribute broadly towards a subset of molecular, cognitive and behavioral abnormalities common among psychiatric and developmental diseases. However, little is known about the specific molecular changes that lead to NMDAR dysfunction. As such, personalized approaches to remediating NMDAR dysfunction based on a specific etiology remains a challenge. Sarcoma tyrosine kinase (Src) serves as a hub for multiple signaling mechanisms affecting GluN2 phosphorylation and can be disrupted by convergent alterations of various signaling pathways...
February 28, 2019: Progress in Neuro-psychopharmacology & Biological Psychiatry
Sherlly Xie, Håkan Karlsson, Christina Dalman, Linnea Widman, Dheeraj Rai, Renee M Gardner, Cecilia Magnusson, Diana E Schendel, Craig J Newschaffer, Brian K Lee
Importance: Familial aggregation of mental and neurological disorders is often observed in autism spectrum disorders (ASD), but reports have generally focused on single disorders and are limited to first-degree relatives. Objectives: To examine family history of mental and neurological disorders among first- to fourth-degree relatives and risk of ASD with and without intellectual disability (ID) in index persons. Design, Setting, and Participants: In this population-based cohort study, 567 436 index persons were identified from the Stockholm Youth Cohort, an ongoing longitudinal register-linkage cohort study of the total population aged 0 to 17 years residing in Stockholm County, Sweden...
March 1, 2019: JAMA Network Open
Denise Harold, Siobhan Connolly, Brien P Riley, Kenneth S Kendler, Shane E McCarthy, William R McCombie, Alex Richards, Michael J Owen, Michael C O'Donovan, James Walters, Gary Donohoe, Michael Gill, Aiden Corvin, Derek W Morris
Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions...
February 23, 2019: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Guillermina Tellez-Merlo, Julio Cesar Morales-Medina, Israel Camacho-Ábrego, Ismael Juárez-Díaz, Patricia Aguilar-Alonso, Fidel de la Cruz, Tommaso Iannitti, Gonzalo Flores
Schizophrenia is a severe mental disorder with numerous etiological susceptibilities. Maternal infection is a key risk factor for schizophrenia. Prenatal lipopolysaccharide (LPS) infection stimulates cytokine production that affects brain development. In the present study, we aimed to investigate the effect of prenatal LPS injection at gestational day (GD) 14-16 on behavioral paradigms, and neuronal morphology in the prefrontal cortex (PFC), basolateral amygdala (BLA), nucleus Accumbens (NAcc) and ventral hippocampus (VH) at two critical ages of development, pre-pubertal (postnatal day 35, PD35) and post-pubertal (PD60) age in male rats...
February 20, 2019: Neuroscience
Elizabeth C Davenport, Blanka R Szulc, James Drew, James Taylor, Toby Morgan, Nathalie F Higgs, Guillermo López-Doménech, Josef T Kittler
Altered excitatory/inhibitory (E/I) balance is implicated in neuropsychiatric and neurodevelopmental disorders, but the underlying genetic etiology remains poorly understood. Copy number variations in CYFIP1 are associated with autism, schizophrenia, and intellectual disability, but its role in regulating synaptic inhibition or E/I balance remains unclear. We show that CYFIP1, and the paralog CYFIP2, are enriched at inhibitory postsynaptic sites. While CYFIP1 or CYFIP2 upregulation increases excitatory synapse number and the frequency of miniature excitatory postsynaptic currents (mEPSCs), it has the opposite effect at inhibitory synapses, decreasing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs)...
February 19, 2019: Cell Reports
Sophie E Legge, James Tr Walters
Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7...
February 15, 2019: Pharmacogenomics
Markus M Nöthen, Franziska Degenhardt, Andreas J Forstner
A long-established hypothesis is that genetic factors contribute to the development of psychiatric diseases, including common illnesses such as schizophrenia and the affective disorders; however, reliable molecular identification of these factors represents a far more recent innovation. This has been rendered possible by technological advances in the individual characterization of the human genome and the combining of large genetic datasets at the international level. For the first time, the results of genome-wide analyses provide researchers with systematic insights into disease-relevant biological mechanisms...
February 2019: Der Nervenarzt
Melissa Quintero, Danijela Stanisic, Guilherme Cruz, João G M Pontes, Tássia Brena Barroso Carneiro Costa, Ljubica Tasic
Psychiatric disorders are some of the most impairing human diseases. Among them, bipolar disorder and schizophrenia are the most common. Both have complicated diagnostics due to their phenotypic, biological, and genetic heterogeneity, unknown etiology, and the underlying biological pathways, and molecular mechanisms are still not completely understood. Given the multifactorial complexity of these disorders, identification and implementation of metabolic biomarkers would assist in their early detection and diagnosis and facilitate disease monitoring and treatment responses...
2019: Advances in Experimental Medicine and Biology
Aamir Fahira, Zhiqiang Li, Ning Liu, Yongyong Shi
Recent genome-wide association study (GWAS) identified 12 independent loci for Attention-deficit hyperactivity disorder (ADHD). However, the causal genes expression and pathways of ADHD is still vague. We integrated GWAS, eQTL and genes expression data to find the causal genes, genes expression, and genes prioritization in the different brain tissues and whole blood cells. Overall 47 genes were prioritized, the most promising genes were LSG1, HYAL3, PIDD, PNPLA2, BLOC1S2, PLK1S1, CALN1, KAT2B, CTNNB1 and WDR11...
February 6, 2019: Behavioural Brain Research
Felipe V Gomes, Xiyu Zhu, Anthony A Grace
Schizophrenia is a neurodevelopmental disorder with genetic predisposition, and stress has long been linked to its etiology. While stress affects all stages of the illness, increasing evidence suggests that stress during critical periods of development may be particularly detrimental, increasing individual's vulnerability to psychosis. To thoroughly understand the potential causative role of stress, our group has been focusing on the prenatal methylazoxymethanol acetate (MAM) rodent model, and discovered that MAM offspring display abnormal stress reactivity and heightened anxiety prepubertally, prior to the manifestation of a hyperdopaminergic state...
January 30, 2019: Schizophrenia Research
Ian Robertson, Amy Cheung, Xiaoduo Fan
In patients with schizophrenia, insomnia is a common yet often overlooked comorbidity. With sleep disturbances inextricably linked to increased severity of schizophrenia and worsening clinical outcomes, insomnia is an important therapeutic target within this patient population. Thus, through a review of the current literature, this paper reiterates the important etiological link between these two conditions, while evaluating the safety, efficacy, and limitations of current therapeutic options for the treatment of comorbid insomnia in schizophrenia...
January 29, 2019: Progress in Neuro-psychopharmacology & Biological Psychiatry
Yong-Ping Liu, Mei Ding, Xi-Cen Zhang, Yi Liu, Jin-Feng Xuan, Jia-Xin Xing, Xi Xia, Jun Yao, Bao-Jie Wang
BACKGROUND: Schizophrenia is a severe neurodevelopmental disorder with a complex genetic and environmental etiology. Abnormal glutamate ionotropic N-methyl-D-aspartate receptor (NMDA) type subunit 1 (NR1) may be a potential cause of schizophrenia. METHODS: We conducted a case-control study to investigate the association between the GRIN1 gene, which encodes the NR1 subunit, and the risk of schizophrenia in a northern Chinese Han population using Sanger DNA sequencing...
January 31, 2019: BMC Medical Genetics
Jacob N Miller, Donald W Black
BACKGROUND: Schizoaffective disorder (SAD) is a chronic, potentially disabling psychotic disorder common in clinical settings. SAD often has been used as a diagnosis for individuals having an admixture of mood and psychotic symptoms whose diagnosis is uncertain. Its hallmark is the presence of symptoms of a major mood episode (either a depressive or manic episode) concurrent with symptoms characteristic of schizophrenia, such as delusions, hallucinations, or disorganized speech. METHODS: A literature search in PubMed and Google Scholar was conducted to identify articles on SAD...
February 2019: Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists
Pavel Katsel, Panos Roussos, Peter Fam, Sonia Khan, Weilun Tan, Tetsuro Hirose, Shinichi Nakagawa, Mikhail V Pletnikov, Vahram Haroutunian
Oligodendrocyte (OLG)-related abnormalities have been broadly observed in schizophrenia (SZ); however, the etiology of these abnormalities remains unknown. As SZ is broadly believed to be a developmental disorder, the etiology of the myelin abnormalities in SZ may be related to OLG fate specification during development. Noncoding RNAs (ncRNAs) are an important part of multifaceted transcriptional complexes participating in neurogenic commitment and regulation of postmitotic cell function. The long ncRNA, NEAT1, is a structural component of paraspeckles (subnuclear bodies in interchromatin regions) that may control activity of developmental enhancers of OLG fate specification...
January 29, 2019: NPJ Schizophrenia
Mark L Sowers, Jessica Di Re, Paul A Wadsworth, Alexander S Shavkunov, Cheryl Lichti, Kangling Zhang, Fernanda Laezza
Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14 -/- mice recapitulate the salient endophenotypes of synaptic dysfunction and behaviors that are associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the Fgf14 -/- model may provide a valuable tool to interrogate pathways related to disease mechanisms...
January 23, 2019: Proteomes
Antonia Tsavou, David Curtis
BACKGROUND: Several lines of evidence support the hypothesis that impaired functioning of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) might be involved in the etiology of schizophrenia. NMDAR is activated by phosphorylation by Fyn, and there is also some evidence to suggest that abnormalities in Fyn functionality could also be involved in susceptibility to schizophrenia. In a recent weighted burden analysis of exome-sequenced schizophrenia cases and controls, we noted modest statistical evidence for an enrichment of rare, functional variants in FYN, GRIN1, and GRIN2B in schizophrenia cases...
January 16, 2019: Psychiatric Genetics
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