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| Open AccessD-serine reconstitutes synaptic and intrinsic inhibitory control of pyramidal neurons in a neurodevelopmental mouse model for schizophrenia
Modulation of NMDA receptors via D-serine has been investigated as therapeutic strategy in schizophrenia. Here the authors show that D-serine rescues synaptic and intrinsic inhibitory control of cingulate pyramidal neurons, via modulation of parvalbumin neuron excitability, in a mouse model of neurodevelopmental cognitive dysfunction.
- Xiao-Qin Zhang
- , Le Xu
- & Hao-Wei Shen
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Article
| Open AccessThe genetic relationships between brain structure and schizophrenia
Schizophrenia is considered a brain disorder. Here, authors show genetic overlap between brain structure and schizophrenia that was strongest in the hubs of structural covariance networks and concentrated three chromosomal regions.
- Eva-Maria Stauffer
- , Richard A. I. Bethlehem
- & Edward T. Bullmore
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| Open AccessAltered corollary discharge signaling in the auditory cortex of a mouse model of schizophrenia predisposition
Schizophrenia patients are impaired in attenuating responses to self-generated sensory input. Here, the authors reveal the same sensory deficit and reduced corollary discharge signaling in mice carrying a major genetic risk factor for schizophrenia.
- Brian P. Rummell
- , Solmaz Bikas
- & Torfi Sigurdsson
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| Open AccessHuman forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways
Identifying schizophrenia risk genes is essential for illuminating the disease etiology. Here, authors prioritized Propionyl-CoA Carboxylase Subunit Beta (PCCB) as a schizophrenia-associated gene, and linked PCCB to GABAergic pathways using human forebrain organoids-based transcriptomic and metabolomic analysis.
- Wendiao Zhang
- , Ming Zhang
- & Qingtuan Meng
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| Open AccessSchizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
Copy number deletions in 2p16.3 locus (NRXN1) in individuals significantly increase risk for schizophrenia. Here, authors show, at single cell level, genetic background-specific effects that culminate in synaptic dysfunction using iPSC-derived brain organoid model.
- Rebecca Sebastian
- , Kang Jin
- & ChangHui Pak
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Article
| Open AccessRegional clozapine, ECT and lithium usage inversely associated with excess suicide rates in male adolescents
There are conflicting results on the effectiveness of pharmacologic interventions for suicide prevention in adolescence. Here, the authors show, in a retrospective registry study from Sweden during 2016–2020, that regional utilization rates of clozapine, electroconvulsive therapy and lithium in 15–19-year-olds were associated with lower excess suicide death rates in male adolescents
- Adrian E. Desai Boström
- , Peter Andersson
- & Jussi Jokinen
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Article
| Open AccessRescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub
The 16p11.2 duplication confers risk for autism and schizophrenia, but the disease mechanisms are unknown. Here, the authors use proteomics to show dysregulation of synaptic and epilepsy-associated protein networks in the cortex of model mice, and demonstrate that correcting Prrt2 gene dosage rescues circuit hypersynchrony and behavioural phenotypes.
- Marc P. Forrest
- , Marc Dos Santos
- & Peter Penzes
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Article
| Open AccessFunctional geometry of the cortex encodes dimensions of consciousness
Dimensions of consciousness such as wakefulness or awareness are well established but have not been mapped to the brain. Here, the authors show that dimensions of consciousness are encoded in the functional geometry of the cortex.
- Zirui Huang
- , George A. Mashour
- & Anthony G. Hudetz
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Article
| Open AccessDerivation and utility of schizophrenia polygenic risk associated multimodal MRI frontotemporal network
Schizophrenia is highly heritable and characterized by widespread brain abnormalities. Here, the authors identify schizophrenia polygenic risk associated multimodal frontotemporal network that can serve as a transdiagnostic brain signature specific to schizophrenia.
- Shile Qi
- , Jing Sui
- & Vince D. Calhoun
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Article
| Open AccessAn in vitro model of neuronal ensembles
Advances in 3D neuronal cultures have allowed unprecedented access to the mechanisms underlying brain diseases. This work describes the novel Modular Neuronal Network (MoNNet) system, which enables more complex studies of cortical neuronal ensemble dynamics.
- M. Angeles Rabadan
- , Estanislao Daniel De La Cruz
- & Raju Tomer
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Article
| Open AccessChromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia
Schizophrenia (SZ) is a severe psychiatric disorder; unfortunately, only ~1/3 of patients respond favorably to treatment. Here, the authors reveal hyperacetylation of histone H2A.Z in SZ neurons and postmortem SZ human brain tissues. They further show BRD4 is a reader of hyperacetylated H2A.Z and treatment with bromodomain inhibitor JQ1 largely rescues abnormal gene expression associated with SZ.
- Lorna A. Farrelly
- , Shuangping Zheng
- & Ian Maze
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Article
| Open AccessSchizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats
The effects of SAP97 mutations associated with schizophrenia on synaptic function are unclear. Here, the authors show that schizophrenia-related SAP97 mutations enhance glutamatergic synapse strength in the dentate gyrus, impairing contextual episodic memory in rats.
- Yuni Kay
- , Linda Tsan
- & Bruce E. Herring
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Article
| Open AccessTranscriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants
Coordinated programs of gene expression drive brain development. Here, the authors use human embryonic stem cells and foetal cortical tissue as well as available GWAS statistics and analysis of genetic variants associated with neuropsychiatric disorders and cognition revealing a convergence on transcriptional programs regulating excitatory cortical neurogenesis.
- Bret Sanders
- , Daniel D’Andrea
- & Eunju Shin
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Article
| Open AccessPolygenic contribution to the relationship of loneliness and social isolation with schizophrenia
Loneliness and social isolation (LNL-ISO) are associated with schizophrenia. Here the authors demonstrate the role of shared heritability, bidirectional causal relationships and significant differences by sex, illustrating the genomic footprint of social isolation on schizophrenia.
- Álvaro Andreu-Bernabeu
- , Covadonga M. Díaz-Caneja
- & Javier González-Peñas
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Article
| Open AccessAssociations between patterns in comorbid diagnostic trajectories of individuals with schizophrenia and etiological factors
Schizophrenia is a complex disorder where individuals experience different symptoms and outcomes that can be captured by patterns in other diagnoses. Here the authors use computational approaches to summarize these patterns and suggest they are associated with genetic and environmental exposure.
- Morten Dybdahl Krebs
- , Gonçalo Espregueira Themudo
- & Wesley K. Thompson
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| Open AccessSchizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations
Overlapping genes have been implicated in schizophrenia and neurodevelopmental disorders. Here, the authors overlap de novo variants in the two types of disorders and find variants in these genes with the same functional effect and in some cases the same specific variants.
- Elliott Rees
- , Hugo D. J. Creeth
- & Michael C. O’Donovan
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Article
| Open AccessGenome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk
The authors provide a comprehensive, single base resolution view of association between genetic variation and DNA methylation in human brain. They also show that heritability attributed to schizophrenia GWAS-associated variants reflects the epigenetic plasticity of the brain.
- Kira A. Perzel Mandell
- , Nicholas J. Eagles
- & Andrew E. Jaffe
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Article
| Open AccessHistamine H1 receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice
Social impairment and anhedonia are common negative symptoms in patients with schizophrenia. Here, the authors show that the histamine H1 receptor in cholinergic neurons in the basal forebrain has a critical role in sensorimotor gating, social behaviour, and anhedonia-like behaviour in mice.
- Li Cheng
- , Cenglin Xu
- & Zhong Chen
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| Open AccessOverexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition
The molecular and cellular mechanisms of cortical disinhibition as a common feature of many psychiatric diseases are not fully understood. The authors identify an interaction between NRG1 and Nav1.1 sodium channel as a mechanism of how NRG1 modulates the excitability of GABAergic interneurons.
- Yao-Yi Wang
- , Bing Zhao
- & Dong-Min Yin
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Article
| Open AccessPCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia
The role of ciliary/centriolar components in the postnatal brain is unclear. Here, the authors show via ablation of Pcm1 in mice that degenerative ciliary/centriolar phenotypes induce neuroanatomical and behavioral changes. Sequencing of PCM1 in human cohorts and zebrafish in vivo complementation suggests PCM1 mutations can contribute to schizophrenia.
- Tanner O. Monroe
- , Melanie E. Garrett
- & Nicholas Katsanis
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| Open AccessCommon schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons
Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits.
- Mads E. Hauberg
- , Jordi Creus-Muncunill
- & Panos Roussos
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Article
| Open AccessA shared genetic contribution to breast cancer and schizophrenia
Schizophrenia has been associated with increased risk of breast cancer, yet the risk of schizophrenia following breast cancer is unclear. Here, the authors show a bidirectional association between breast cancer and schizophrenia in Sweden and a shared genetic contribution to both diseases.
- Donghao Lu
- , Jie Song
- & Unnur A. Valdimarsdóttir
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Article
| Open AccessReduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia
Stein, Barbosa et al. show that anti-NMDAR encephalitis and schizophrenia are characterized by reduced serial dependence in spatial working memory. Cortical network simulations show that this can be parsimoniously explained by a reduction in NMDAR-dependent short-term synaptic potentiation in these diseases.
- Heike Stein
- , Joao Barbosa
- & Albert Compte
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| Open AccessTopoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity
Topoisomerase 3β (Top3β) solves topological stress in DNA or RNA metabolism and its mutations are linked to mental disorders. Here, the authors describe transcriptional and behavioural impairments in Top3β-knockout mice and show that these are linked to impaired neurogenesis and synaptic plasticity.
- Yuyoung Joo
- , Yutong Xue
- & Weidong Wang
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Article
| Open AccessEEG microstates are a candidate endophenotype for schizophrenia
EEG microstate abnormalities have been reported in patients with schizophrenia. Here the authors demonstrate that patients and their siblings show similar microstate abnormalities compared to healthy controls.
- Janir Ramos da Cruz
- , Ophélie Favrod
- & Michael H. Herzog
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Article
| Open AccessTranscriptional and imaging-genetic association of cortical interneurons, brain function, and schizophrenia risk
Interneuron subtypes have distinct properties and spatial distributions. Here, the authors show that the molecular-genetic basis of cortical resting-state brain function is shaped by distributions of interneuron-related transcripts and may capture individual differences in schizophrenia risk.
- Kevin M. Anderson
- , Meghan A. Collins
- & Avram J. Holmes
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| Open AccessInterneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia
Dysfunction of GABAergic neurons in the prefrontal cortex has been reported in schizophrenia. Here, the authors use the apomorphine-susceptible rat, which displays some schizophrenia-like behaviors, and show that interneurons in the medial prefrontal cortex are hypomyelinated, which may contribute to this behavioral phenotype.
- Dorien A. Maas
- , Vivian D. Eijsink
- & Gerard J. M. Martens
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Article
| Open AccessIncreased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia
Common variants identified by large-scale genomewide association studies cannot account fully account for the heritability of schizophrenia (SCZ). Here, the authors report high-coverage whole-genome sequencing of 1162 SCZ cases and 936 controls and explore the contribution of different types of variants to SCZ.
- Matthew Halvorsen
- , Ruth Huh
- & Jin P. Szatkiewicz
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| Open AccessMetagenome-wide association of gut microbiome features for schizophrenia
Gut microbiome has been linked to neurogenerative diseases. Here, the authors present a metagenome-wide association study of schizophrenia (SZ) in human cohorts and identify SZ-associated specific gut-brain functional modules and pathways including SCFAs and neurotransmitters.
- Feng Zhu
- , Yanmei Ju
- & Xiancang Ma
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Article
| Open AccessSchizophrenia-related microdeletion causes defective ciliary motility and brain ventricle enlargement via microRNA-dependent mechanisms in mice
Schizophrenia is associated with brain ventricular enlargement. Here, the authors show in mice that 22q11 deletion, which is associated with schizophrenia, causes ventricular enlargement and motility abnormalities in cilia lining ventricle walls via a microRNA mechanism.
- Tae-Yeon Eom
- , Seung Baek Han
- & Stanislav S. Zakharenko
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Article
| Open AccessSynaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats
Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis. Here, using [11C]UCB-J PET, the authors show for the first time in vivo that levels of the synaptic marker protein SV2A are reduced in schizophrenia and unaffected by antipsychotic treatment in a rat model.
- Ellis Chika Onwordi
- , Els F. Halff
- & Oliver D. Howes
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| Open AccessReduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging
Post-mortem studies have suggested a possible reduction in mu-opioid receptor (MOR) density in people with schizophrenia. Here, the authors examined MOR in living patients with schizophrenia using PET imaging, and found local reductions of MOR compared to controls.
- Abhishekh H. Ashok
- , Jim Myers
- & Oliver D. Howes
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| Open AccessDiurnal rhythms in gene expression in the prefrontal cortex in schizophrenia
Sleep disturbance is common in psychiatric disease, and this may contribute to altered circadian rhythm in gene expression. Here the authors show that rhythms in gene expression in the dorsolateral prefrontal cortex in schizophrenia are different to that seen in healthy controls.
- Marianne L. Seney
- , Kelly Cahill
- & Colleen A. McClung
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| Open AccessThe autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour
In humans, copy-number variants of the CYFIP1 gene have been associated with autism spectrum disorders and schizophrenia. Here, the authors characterize Cyfip1-heterozygous mice, revealing that they display deficits in brain white matter structure and functional connectivity along with abnormal behaviours.
- Nuria Domínguez-Iturza
- , Adrian C. Lo
- & Claudia Bagni
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| Open AccessModulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner
Region-specific increases in hippocampal activity have been reported in schizophrenia patients, yet there are little known about how these circuit levels changes modulate behavioral deficits. Here authors found that that over-expression of the a5 subunit of the GABAA receptor increased tonic GABA currents and normalized aberrant pyramidal cell activity in the ventral hippocampus which had distinct disease symptom outcomes depending on the pathway targeted
- J. J. Donegan
- , A. M. Boley
- & D. J. Lodge
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| Open AccessFunctional genomics reveal gene regulatory mechanisms underlying schizophrenia risk
We know a large number of risk SNPs for schizophrenia, but little about how these SNPs contribute to the disorder. Here, the authors use functional genomics to identify risk SNPs that disrupt transcription factor binding and validate the regulatory effects of the transcription factor binding-disrupting SNPs.
- Yongxia Huo
- , Shiwu Li
- & Xiong-Jian Luo
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Article
| Open AccessEvaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia
Chromatin accessibility may be altered in disease states. Here the authors carry out ATAC-seq on a large number of samples of dorsolateral prefrontal cortex from individuals with schizophrenia, and healthy controls.
- Julien Bryois
- , Melanie E. Garrett
- & Gregory E. Crawford
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Article
| Open AccessGenome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia
Educational attainment and schizophrenia have a negative phenotypic relationship but show positive genetic correlation. Here, the authors study genetic dependence between the two traits and find that multiple genes have pleiotropic effects on both without a systematic pattern of sign concordance.
- V. Bansal
- , M. Mitjans
- & P. D. Koellinger
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Article
| Open AccessMultimodal neuromarkers in schizophrenia via cognition-guided MRI fusion
Cognitive impairment is a feature of many psychiatric diseases. Here the authors aimed to identify multimodal neuromarkers that can be used to quantify and predict cognitive performance in individuals with schizophrenia using three different features of MRI and three independent cohorts.
- Jing Sui
- , Shile Qi
- & Vince D. Calhoun
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Article
| Open AccessImpaired recruitment of dopamine neurons during working memory in mice with striatal D2 receptor overexpression
Disrupted dopamine neuron firing is thought to contribute to cognitive dysfunction in psychiatric disorders. Here the authors show that mice overexpressing D2R in the striatum, commonly seen in schizophrenia, are also impaired in recruitment of dopamine neurons during working memory performance.
- Sevil Duvarci
- , Eleanor H. Simpson
- & Torfi Sigurdsson
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Article
| Open AccessVariations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment
Patients with schizophrenia show varied response to antipsychotics. Here, the authors demonstrate in patients under antipsychotics treatment that a haplotype associated with lower dysbindin-1 expression correlated with better executive functions, providing further mechanistic support from mouse models.
- Diego Scheggia
- , Rosa Mastrogiacomo
- & Francesco Papaleo
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Article
| Open AccessComprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes
More than 100 risk loci for schizophrenia have been identified by genome-wide association studies. Here, the authors apply an integrative genomic approach to prioritize risk genes and validate GLT8D1 and CSNK2B as candidate causal genes by in vitro studies in neural stem cells.
- Cui-Ping Yang
- , Xiaoyan Li
- & Xiong-Jian Luo
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Article
| Open AccessTranscriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains
Induced pluripotent stem cell (hiPSC)-based models have inherent variations in their cellular and molecular output and readouts. Here, Hoffman and colleagues devise a method to account for gene expression variations in hiPSC-derived neurons from patients with childhood-onset schizophrenia.
- Gabriel E. Hoffman
- , Brigham J. Hartley
- & Kristen J. Brennand
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Article
| Open AccessHippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task
Theta- and gamma-frequency oscillatory synchrony correlates with spatial working memory performance. Here the authors report increases in theta-gamma cross-frequency coupling as a compensatory mechism associated with better working memory performance in models of cognitive dysfunction in mice.
- Makoto Tamura
- , Timothy J. Spellman
- & Joshua A. Gordon
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Article
| Open AccessGenetic correlation between amyotrophic lateral sclerosis and schizophrenia
Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.
- Russell L. McLaughlin
- , Dick Schijven
- & Michael C. O’Donovan
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Article
| Open AccessExperimental evidence for circular inference in schizophrenia
Schizophrenia is a mental disorder characterized by hallucinations and delusions. Here the authors report a novel probabilistic inference task in which compared to healthy subjects, schizophrenia patients show greater degree of circular inference that matches the severity of their clinical symptoms.
- Renaud Jardri
- , Sandrine Duverne
- & Sophie Denève
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| Open AccessThe TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
Dysregulation of microRNAs has been implicated in neurodevelopmental disorders, including schizophrenia. Here the authors show that the TLX-miR-219 cascade regulates the proliferation of neural stem cells during normal development, and this pathway is dysregulated in a schizophrenia iPSC model.
- Kiyohito Murai
- , Guoqiang Sun
- & Yanhong Shi
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Article
| Open AccessGenome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank
Here, Richa Saxena and colleagues perform a genome-wide association study (GWAS) of self-reported morningness/eveningness preference in the UKBiobank cohort, and identify new genetic loci that contribute to a person's chronotype.
- Jacqueline M. Lane
- , Irma Vlasac
- & Richa Saxena
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Article
| Open AccessGenome-wide burden of deleterious coding variants increased in schizophrenia
Schizophrenia is a complex disorder with high heritability but poorly understood genetics. Here Olde Loohuis et al.compare schizophrenia patients to unaffected individuals and identify an increased individual burden of rare deleterious mutations in patients.
- Loes M. Olde Loohuis
- , Jacob A. S. Vorstman
- & Roel A. Ophoff