Publications by authors named "David A Collier"

166 Publications

Genetic underpinnings of sociability in the general population.

Neuropsychopharmacology 2021 08 30;46(9):1627-1634. Epub 2021 May 30.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Levels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits-loneliness and social anxiety-but not with bipolar disorder or Alzheimer's disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability.
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http://dx.doi.org/10.1038/s41386-021-01044-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280100PMC
August 2021

HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry.

Transl Psychiatry 2021 04 12;11(1):214. Epub 2021 Apr 12.

Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm and 1500/mm were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
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http://dx.doi.org/10.1038/s41398-021-01322-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042025PMC
April 2021

Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects.

Alzheimers Dement (N Y) 2020 24;6(1):e12078. Epub 2020 Aug 24.

College of Medicine and Health University of Exeter Medical School University of Exeter Exeter UK.

Background: Stroke/thromboembolic events, infections, and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events.

Methods: Whole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone, and volinanserin using RNA sequencing. Bioinformatic analysis was performed that scored the association between antipsychotic signatures and expression data from 415,252 samples in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) repository.

Results: Atherosclerosis, venous thromboembolism, and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (eg, brain derived neurotrophic factor [BDNF], platelet derived growth factor receptor [PDGFR]-beta, tumor necrosis factor [TNF], transforming growth factor [TGF]-beta, selenoamino acid metabolism, and influenza infection).

Conclusions: These findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.
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http://dx.doi.org/10.1002/trc2.12078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443741PMC
August 2020

Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.

Cell Rep 2020 07;32(2):107908

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.
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http://dx.doi.org/10.1016/j.celrep.2020.107908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428328PMC
July 2020

Transcriptional Signatures of Tau and Amyloid Neuropathology.

Cell Rep 2020 02;30(6):2040-2054.e5

Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK. Electronic address:

Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of β-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology.
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http://dx.doi.org/10.1016/j.celrep.2020.01.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016505PMC
February 2020

TractaViewer: a genome-wide tool for preliminary assessment of therapeutic target druggability.

Bioinformatics 2019 11;35(21):4509-4510

Eli Lilly & Co. Ltd, Erl Wood Manor, Windlesham, UK.

Summary: We present software to characterize and rank potential therapeutic (drug) targets with data from public databases and present it in a user-friendly format. By understanding potential obstacles to drug development through the gathering and understanding of this information, combined with robust approaches to target validation to generate therapeutic hypotheses, this approach may provide high quality targets, leading the process of drug development to become more efficient and cost-effective.

Availability And Implementation: The information we gather on potential targets concerns small-molecule druggability (ligandability), suitability for large-molecule approaches (e.g. antibodies) or new modalities (e.g. antisense oligonucleotides, siRNA or PROTAC), feasibility (availability of resources such as assays and biological knowledge) and potential safety risks (adverse tissue-wise expression, deleterious phenotypes). This information can be termed 'tractability'. We provide visualization tools to understand its components. TractaViewer is available from https://github.com/NeilPearson-Lilly/TractaViewer.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz270DOI Listing
November 2019

Associations between childhood maltreatment and inflammatory markers.

BJPsych Open 2019 Jan;5(1):e3

Honorary Lecturer and Medical Research Council Postdoctoral Fellow, Social,Genetic and Developmental Psychiatry Centre, King's College London,UK.

Background: Childhood maltreatment is one of the strongest predictors of adulthood depression and alterations to circulating levels of inflammatory markers is one putative mechanism mediating risk or resilience.AimsTo determine the effects of childhood maltreatment on circulating levels of 41 inflammatory markers in healthy individuals and those with a major depressive disorder (MDD) diagnosis.

Method: We investigated the association of childhood maltreatment with levels of 41 inflammatory markers in two groups, 164 patients with MDD and 301 controls, using multiplex electrochemiluminescence methods applied to blood serum.

Results: Childhood maltreatment was not associated with altered inflammatory markers in either group after multiple testing correction. Body mass index (BMI) exerted strong effects on interleukin-6 and C-reactive protein levels in those with MDD.

Conclusions: Childhood maltreatment did not exert effects on inflammatory marker levels in either the participants with MDD or the control group in our study. Our results instead highlight the more pertinent influence of BMI.Declaration of interestD.A.C. and H.W. work for Eli Lilly Inc. R.N. has received speaker fees from Sunovion, Jansen and Lundbeck. G.B. has received consultancy fees and funding from Eli Lilly. R.H.M.-W. has received consultancy fees or has a financial relationship with AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Ferrer, Janssen-Cilag, Lundbeck, MyTomorrows, Otsuka, Pfizer, Pulse, Roche, Servier, SPIMACO and Sunovian. I.M.A. has received consultancy fees or has a financial relationship with Alkermes, Lundbeck, Lundbeck/Otsuka, and Servier. S.W. has sat on an advisory board for Sunovion, Allergan and has received speaker fees from Astra Zeneca. A.H.Y. has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. A.J.C. has received honoraria for speaking from Astra Zeneca, honoraria for consulting with Allergan, Livanova and Lundbeck and research grant support from Lundbeck.
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http://dx.doi.org/10.1192/bjo.2018.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343120PMC
January 2019

A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia.

Mol Psychiatry 2019 03 15;24(3):328-337. Epub 2019 Jan 15.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (β = -0.9, P = 4.21 × 10), a known regulatory variant in the atypical chemokine receptor 1 (ACKR1) gene. Individuals homozygous for the C allele at rs2814778 were significantly more likely to develop neutropenia and have to stop clozapine treatment (OR = 20.4, P = 3.44 × 10). This genotype, also termed "Duffy-null", has previously been shown to be associated with lower neutrophil levels in those of African ancestry. Our results indicate the relevance of the rs2814778 genotype for those taking clozapine and its potential as a pharmacogenetic test, dependent on the outcome of additional safety studies, to assist decision making in the initiation and on-going management of clozapine treatment.
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http://dx.doi.org/10.1038/s41380-018-0335-7DOI Listing
March 2019

Genome-wide RNAseq study of the molecular mechanisms underlying microglia activation in response to pathological tau perturbation in the rTg4510 tau transgenic animal model.

Mol Neurodegener 2018 12 17;13(1):65. Epub 2018 Dec 17.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.

Background: Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer's disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks.

Methods: Microglia cells were isolated from rTg4510 tau transgenic mice and gene expression was profiled using RNA sequencing. Four age groups of mice (2-, 4-, 6-, and 8-months) were analyzed to capture longitudinal gene expression changes that correspond to varying levels of pathology, from minimal tau accumulation to massive neuronal loss. Statistical and system biology approaches were used to analyze the genes and pathways that underlie microglia activation. Differentially expressed genes were compared to human brain co-expression networks.

Results: Statistical analysis of RNAseq data indicated that more than 4000 genes were differentially expressed in rTg4510 microglia compared to wild type microglia, with the majority of gene expression changes occurring between 2- and 4-months of age. These genes belong to four major clusters based on their temporal expression pattern. Genes involved in innate immunity were continuously up-regulated, whereas genes involved in the glutamatergic synapse were down-regulated. Up-regulated innate inflammatory pathways included NF-κB signaling, cytokine-cytokine receptor interaction, lysosome, oxidative phosphorylation, and phagosome. NF-κB and cytokine signaling were among the earliest pathways activated, likely driven by the RELA, STAT1 and STAT6 transcription factors. The expression of many AD associated genes such as APOE and TREM2 was also altered in rTg4510 microglia cells. Differentially expressed genes in rTg4510 microglia were enriched in human neurodegenerative disease associated pathways, including Alzheimer's, Parkinson's, and Huntington's diseases, and highly overlapped with the microglia and endothelial modules of human brain transcriptional co-expression networks.

Conclusion: This study revealed temporal transcriptome alterations in microglia cells in response to pathological tau perturbation and provides insight into the molecular changes underlying microglia activation during tau mediated neurodegeneration.
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http://dx.doi.org/10.1186/s13024-018-0296-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296031PMC
December 2018

Author Correction: Expression-based drug screening of neural progenitor cells from individuals with schizophrenia.

Nat Commun 2018 11 19;9(1):4926. Epub 2018 Nov 19.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

In the originally published version of this Article, the affiliation details for Eric E. Schadt and Radoslav Savic incorrectly omitted 'Sema4, a Mount Sinai venture, Stamford, Connecticut, USA'. This has been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07326-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242834PMC
November 2018

Expression-based drug screening of neural progenitor cells from individuals with schizophrenia.

Nat Commun 2018 10 24;9(1):4412. Epub 2018 Oct 24.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs. CCL) and/or a diagnosis (SZ vs. control)-dependent manner. Overall, we describe a proof-of-concept application of transcriptomic drug screening to hiPSC-based models, demonstrating that the drug-induced gene expression differences observed with patient-derived hiPSC NPCs are enriched for SZ biology, thereby revealing a major advantage of incorporating cell type and patient-specific platforms in drug discovery.
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http://dx.doi.org/10.1038/s41467-018-06515-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200740PMC
October 2018

Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain.

Neurobiol Aging 2018 09 17;69:151-166. Epub 2018 May 17.

Department of Biostatistics and Health Informatics, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, UK.

Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell-type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity. We primarily discovered changes in an endothelial gene-enriched subnetwork at 4 months, including a shift toward a more central role for the amyloid precursor protein gene, coupled with widespread disruption of other cell-type subnetworks, including a subnetwork with neuronal identity. We reveal an unexpected potential role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signaling hub, suggesting an underlying link between immune response and vascular disease in dementia.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075941PMC
September 2018

Conference Report: Psychiatric Genomics Consortium Meeting: Pathways to Drugs, London, March 2017.

Biol Psychiatry 2018 09 8;84(6):e49-e50. Epub 2018 Feb 8.

Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London; United Kingdom National Institute for Health Research Biomedical Research Centre for Mental Health, South London and Maudsley Hospital, London. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2018.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984980PMC
September 2018

Regulatory characterisation of the schizophrenia-associated CACNA1C proximal promoter and the potential role for the transcription factor EZH2 in schizophrenia aetiology.

Schizophr Res 2018 09 28;199:168-175. Epub 2018 Feb 28.

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK. Electronic address:

Genomic wide association studies identified the CACNA1C locus as genetically associated with both schizophrenia and bipolar affective disorder. CACNA1C encodes Cav1.2, one of four subunits of L-type voltage gated calcium channels. Variation resides in non-coding regions of CACNA1C which interact with the promoter and are validated expression quantitative trait loci. Using reporter gene constructs we demonstrate the CACNA1C promoter is a major mediator of inducible regulation of CACNA1C activity in the SH-SY5Y neuroblastoma cell line. Exposure of SH-SY5Y cells to lithium and cocaine modulated both the endogenous CACNA1C gene and the promoter in reporter gene constructs. Deletion analysis of the promoter demonstrated the actions of both lithium and cocaine were mediated by the proximal promoter. Initial interrogation of ENCODE ChIP-seq data over the CACNA1C promoter indicated binding of the transcription factor 'Enhancer of zeste homolog 2' (EZH2), which was consistent with our data that overexpression of EZH2 repressed CACNA1C promoter reporter gene expression. Array data from the Human Brain Transcriptome demonstrated that EZH2 was highly expressed across the developing brain, but subsequently maintained at low levels after birth and adulthood. RNA-seq data obtained from PD_NGSAtlas, a reference database for epigenomic and transcriptomic data for psychiatric disorders, demonstrated a 3-fold increase in EZH2 expression in the anterior cingulate cortex of individuals with schizophrenia compared to controls. We propose that EZH2 may contribute to schizophrenia risk at two distinct time points either through disruption in development leading to neurodevelopmental changes, or through anomalous reactivation of expression in the adult brain.
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http://dx.doi.org/10.1016/j.schres.2018.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179964PMC
September 2018

Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.

Nat Genet 2018 03 26;50(3):381-389. Epub 2018 Feb 26.

Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
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http://dx.doi.org/10.1038/s41588-018-0059-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918692PMC
March 2018

Genetics of schizophrenia: A consensus paper of the WFSBP Task Force on Genetics.

World J Biol Psychiatry 2017 10 23;18(7):492-505. Epub 2017 Jan 23.

a Department of Psychiatry, Psychotherapy, and Psychosomatics , Martin Luther University of Halle-Wittenberg , Halle , Germany.

Objectives: Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes.

Methods: This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing.

Results: A large, new body of evidence on genetics of schizophrenia has accumulated over recent years. Many new robustly associated genetic loci have been detected. Furthermore, there is consensus that at least a dozen microdeletions and microduplications contribute to the disease. Genetic overlap between schizophrenia, other psychiatric disorders, and neurodevelopmental syndromes raised new questions regarding the current classification of psychiatric and neurodevelopmental diseases.

Conclusions: Future studies will address especially the functional characterisation of genetic variants. This will hopefully open the doors to our understanding of the pathophysiology of schizophrenia and other related diseases. Complementary, integrated systems biology approaches to genomics, transcriptomics, proteomics and metabolomics may also play crucial roles in enabling a precision medicine approach to the treatment of individual patients.
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http://dx.doi.org/10.1080/15622975.2016.1268715DOI Listing
October 2017

Aberrant spontaneous neural activity and correlation with evoked-brain potentials in first-episode, treatment-naïve patients with deficit and non-deficit schizophrenia.

Psychiatry Res Neuroimaging 2017 Mar 5;261:9-19. Epub 2017 Jan 5.

The Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address:

The goals of the study were to analyze spontaneous neural activity between deficit and non-deficit schizophrenia (DS, NDS) using resting-state fMRI, and to investigate the correlation of fMRI with clinical features and evoked brain potentials. The amplitude of low frequency fluctuation (ALFF) was measured in 41 DS participants, 42 NDS participants, and 42 healthy controls. ALFF in the bilateral cerebellum posterior lobe was significantly decreased in patients, while ALFF in the right fusiform gyrus and the bilateral putamen was significantly increased. In schizophrenia patients, ALFF in the right putamen positively correlated with excited/activation on Positive and Negative Syndrome Scale (PANSS-EXC/ACT). In DS patients, ALFF in the right insula was significantly increased than in controls and positively correlated with S2-P50 amplitude of sensory gating P50. ALFF in the left cerebellum posterior lobe negatively correlated with negative symptoms and withdrawn on PANSS (PANSS-NS, PANSS-WIT), ALFF in the right putamen positively correlated with PANSS-WIT. In NDS patients, ALFF in the middle temporal gyrus decreased than in controls and negatively correlated with P3b subcomponent of P300 latency. ALFF in the left cerebellum posterior lobe negatively correlated with PANSS-EXC/ACT. The middle temporal gyrus in NDS or the right insula in DS may show spatiotemporal defects.
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http://dx.doi.org/10.1016/j.pscychresns.2017.01.001DOI Listing
March 2017

Probing the Association between Early Evolutionary Markers and Schizophrenia.

PLoS One 2017 12;12(1):e0169227. Epub 2017 Jan 12.

NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Schizophrenia is suggested to be a by-product of the evolution in humans, a compromise for our language, creative thinking and cognitive abilities, and thus, essentially, a human disorder. The time of its origin during the course of human evolution remains unclear. Here we investigate several markers of early human evolution and their relationship to the genetic risk of schizophrenia. We tested the schizophrenia evolutionary hypothesis by analyzing genome-wide association studies of schizophrenia and other human phenotypes in a statistical framework suited for polygenic architectures. We analyzed evolutionary proxy measures: human accelerated regions, segmental duplications, and ohnologs, representing various time periods of human evolution for overlap with the human genomic loci associated with schizophrenia. Polygenic enrichment plots suggest a higher prevalence of schizophrenia associations in human accelerated regions, segmental duplications and ohnologs. However, the enrichment is mostly accounted for by linkage disequilibrium, especially with functional elements like introns and untranslated regions. Our results did not provide clear evidence that markers of early human evolution are more likely associated with schizophrenia. While SNPs associated with schizophrenia are enriched in HAR, Ohno and SD regions, the enrichment seems to be mediated by affiliation to known genomic enrichment categories. Taken together with previous results, these findings suggest that schizophrenia risk may have mainly developed more recently in human evolution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169227PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231388PMC
August 2017

Genome-Wide Association of Heroin Dependence in Han Chinese.

PLoS One 2016 9;11(12):e0167388. Epub 2016 Dec 9.

Institute of Psychiatry, Psychology and Neuroscience, MRC SGDP Centre, King's College London, United Kingdom.

Drug addiction is a costly and recurring healthcare problem, necessitating a need to understand risk factors and mechanisms of addiction, and to identify new biomarkers. To date, genome-wide association studies (GWAS) for heroin addiction have been limited; moreover they have been restricted to examining samples of European and African-American origin due to difficulty of recruiting samples from other populations. This is the first study to test a Han Chinese population; we performed a GWAS on a homogeneous sample of 370 Han Chinese subjects diagnosed with heroin dependence using the DSM-IV criteria and 134 ethnically matched controls. Analysis using the diagnostic criteria of heroin dependence yielded suggestive evidence for association between variants in the genes CCDC42 (coiled coil domain 42; p = 2.8x10-7) and BRSK2 (BR serine/threonine 2; p = 4.110-6). In addition, we found evidence for risk variants within the ARHGEF10 (Rho guanine nucleotide exchange factor 10) gene on chromosome 8 and variants in a region on chromosome 20q13, which is gene-poor but has a concentration of mRNAs and predicted miRNAs. Gene-based association analysis identified genome-wide significant association between variants in CCDC42 and heroin addiction. Additionally, when we investigated shared risk variants between heroin addiction and risk of other addiction-related and psychiatric phenotypes using polygenic risk scores, we found a suggestive relationship with variants predicting tobacco addiction, and a significant relationship with variants predicting schizophrenia. Our genome wide association study of heroin dependence provides data in a novel sample, with functionally plausible results and evidence of genetic data of value to the field.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167388PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147879PMC
July 2017

Novel brain expressed RNA identified at the MIR137 schizophrenia-associated locus.

Schizophr Res 2017 06 29;184:109-115. Epub 2016 Nov 29.

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK. Electronic address:

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 1p21.3. As we observed for MIR137, EU358092 expression was modulated in response to psychoactive drug treatment in the human SH-SY5Y neuroblastoma cell line. Bioinformatic analysis of publically available CNS expression data indicates that MIR137 and EU358092 are often co-expressed in vivo. A potential regulatory domain for expression of EU358092 is identified by bioinformatic analysis and its regulatory function is confirmed by reporter gene assays. These data suggest a potentially important role for EU358092 in the aetiology of schizophrenia, either individually or in combination with other genes at this locus.
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http://dx.doi.org/10.1016/j.schres.2016.11.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477099PMC
June 2017

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Nat Genet 2017 01 21;49(1):27-35. Epub 2016 Nov 21.

Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
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http://dx.doi.org/10.1038/ng.3725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737772PMC
January 2017

Translating genome-wide association findings into new therapeutics for psychiatry.

Nat Neurosci 2016 10;19(11):1392-1396

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Genome-wide association studies (GWAS) in psychiatry, once they reach sufficient sample size and power, have been enormously successful. The Psychiatric Genomics Consortium (PGC) aims for mega-analyses with sample sizes that will grow to >1 million individuals in the next 5 years. This should lead to hundreds of new findings for common genetic variants across nine psychiatric disorders studied by the PGC. The new targets discovered by GWAS have the potential to restart largely stalled psychiatric drug development pipelines, and the translation of GWAS findings into the clinic is a key aim of the recently funded phase 3 of the PGC. This is not without considerable technical challenges. These approaches complement the other main aim of GWAS studies, risk prediction approaches for improving detection, differential diagnosis, and clinical trial design. This paper outlines the motivations, technical and analytical issues, and the plans for translating PGC phase 3 findings into new therapeutics.
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http://dx.doi.org/10.1038/nn.4411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676453PMC
October 2016

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response.

World J Biol Psychiatry 2017 02 7;18(1):5-28. Epub 2016 Sep 7.

d Department of Psychiatry, Psychotherapy and Psychosomatics , Martin Luther University of Halle-Wittenberg , Halle , Germany.

Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.
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http://dx.doi.org/10.1080/15622975.2016.1208843DOI Listing
February 2017

Analysis of Intellectual Disability Copy Number Variants for Association With Schizophrenia.

JAMA Psychiatry 2016 09;73(9):963-969

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.

Importance: At least 11 rare copy number variants (CNVs) have been shown to be major risk factors for schizophrenia (SZ). These CNVs also increase the risk for other neurodevelopmental disorders, such as intellectual disability. It is possible that additional intellectual disability-associated CNVs increase the risk for SZ but have not yet been implicated in SZ because of previous studies being underpowered.

Objective: To examine whether additional CNVs implicated in intellectual disability represent novel SZ risk loci.

Design, Setting, And Participants: We used single-nucleotide polymorphism (SNP) array data to evaluate a set of 51 CNVs implicated in intellectual disability (excluding the known SZ loci) in a large data set of patients with SZ and healthy persons serving as controls recruited in a variety of settings. We analyzed a new sample of 6934 individuals with SZ and 8751 controls and combined those data with previously published large data sets for a total of 20 403 cases of SZ and 26 628 controls.

Main Outcomes And Measures: Burden analysis of CNVs implicated in intellectual disability (excluding known SZ CNVs) for association with SZ. Association of individual intellectual disability CNV loci with SZ.

Results: Of data on the 20 403 cases (6151 [30.15%] female) and 26 628 controls (14 252 [53.52%] female), 51 intellectual disability CNVs were analyzed. Collectively, intellectual disability CNVs were significantly enriched for SZ (P = 1.0 × 10-6; odds ratio [OR], 1.9 [95% CI, 1.46-2.49]). Of the 51 CNVs tested, 19 (37%) were more common in SZ cases; only 4 (8%) were more common in controls (no observations were made for the remaining 28 [55%] loci). One novel locus, deletion at 16p12.1, was significantly associated with SZ after correction for multiple testing (rate in SZ, 33 [0.16%]; rate in controls, 12 [0.05%]; corrected P = .017; OR, 3.3; 95% CI, 1.61-7.05), and 2 loci reached nominal levels of significance (deletions at 2q11.2: 6 [0.03%] vs 1 [0.004%]; OR, 9.3; 95% CI, 1.03-447.76; corrected P > .99; and duplications at 10q11.21q11.23: 5 [0.2%] vs 0 [0.03%]; OR, infinity; 95% CI, 1.26-infinity; corrected P = .71). Our new data set also provided independent support for the 11 SZ risk loci previously reported to be associated with the disorder and for the protective effect of 22q11.2 duplication.

Conclusions And Relevance: A large proportion of CNV loci implicated in intellectual disability are risk factors for SZ, but the available sample size precludes statistical confirmation for additional individual loci.
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http://dx.doi.org/10.1001/jamapsychiatry.2016.1831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014093PMC
September 2016

An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation.

Genome Biol 2016 08 30;17(1):176. Epub 2016 Aug 30.

University of Exeter Medical School, University of Exeter, Exeter, UK.

Background: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated.

Results: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease.

Conclusions: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
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http://dx.doi.org/10.1186/s13059-016-1041-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004279PMC
August 2016

Identification and Potential Regulatory Properties of Evolutionary Conserved Regions (ECRs) at the Schizophrenia-Associated MIR137 Locus.

J Mol Neurosci 2016 Oct 15;60(2):239-47. Epub 2016 Aug 15.

Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, L69 3BX, Liverpool, UK.

Genome-wide association studies (GWAS) have identified a region at chromosome 1p21.3, containing the microRNA MIR137, to be among the most significant associations for schizophrenia. However, the mechanism by which genetic variation at this locus increases risk of schizophrenia is unknown. Identifying key regulatory regions around MIR137 is crucial to understanding the potential role of this gene in the aetiology of psychiatric disorders. Through alignment of vertebrate genomes, we identified seven non-coding regions at the MIR137 locus with conservation comparable to exons (>70 %). Bioinformatic analysis using the Psychiatric Genomics Consortium GWAS dataset for schizophrenia showed five of the ECRs to have genome-wide significant SNPs in or adjacent to their sequence. Analysis of available datasets on chromatin marks and histone modification data showed that three of the ECRs were predicted to be functional in the human brain, and three in development. In vitro analysis of ECR activity using reporter gene assays showed that all seven of the selected ECRs displayed transcriptional regulatory activity in the SH-SY5Y neuroblastoma cell line. This data suggests a regulatory role in the developing and adult brain for these highly conserved regions at the MIR137 schizophrenia-associated locus and further that these domains could act individually or synergistically to regulate levels of MIR137 expression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026716PMC
http://dx.doi.org/10.1007/s12031-016-0812-xDOI Listing
October 2016

High-throughput DNA methylation analysis in anorexia nervosa confirms TNXB hypermethylation.

World J Biol Psychiatry 2018 04 1;19(3):187-199. Epub 2016 Jul 1.

c Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy , University Hospital Essen, University of Duisburg-Essen , Essen , Germany.

Objectives: Patients with anorexia nervosa (AN) are ideally suited to identify differentially methylated genes in response to starvation.

Methods: We examined high-throughput DNA methylation derived from whole blood of 47 females with AN, 47 lean females without AN and 100 population-based females to compare AN with both controls. To account for different cell type compositions, we applied two reference-free methods (FastLMM-EWASher, RefFreeEWAS) and searched for consensus CpG sites identified by both methods. We used a validation sample of five monozygotic AN-discordant twin pairs.

Results: Fifty-one consensus sites were identified in AN vs. lean and 81 in AN vs. population-based comparisons. These sites have not been reported in AN methylation analyses, but for the latter comparison 54/81 sites showed directionally consistent differential methylation effects in the AN-discordant twins. For a single nucleotide polymorphism rs923768 in CSGALNACT1 a nearby site was nominally associated with AN. At the gene level, we confirmed hypermethylated sites at TNXB. We found support for a locus at NR1H3 in the AN vs. lean control comparison, but the methylation direction was opposite to the one previously reported.

Conclusions: We confirm genes like TNXB previously described to comprise differentially methylated sites, and highlight further sites that might be specifically involved in AN starvation processes.
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http://dx.doi.org/10.1080/15622975.2016.1190033DOI Listing
April 2018

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia.

J Psychopharmacol 2016 08 14;30(8):826-30. Epub 2016 Jun 14.

MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, King's College London, London, UK.

Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development. We compiled 9389 gene sets (2496 with unique gene content) and interrogated gene-based p-values from the PGC2-SCZ analysis. Although no single drug exceeded experiment wide significance (corrected p<0.05), highly ranked gene-sets reaching suggestive significance including the dopamine receptor antagonists metoclopramide and trifluoperazine and the tyrosine kinase inhibitor neratinib. This is a proof of principle analysis showing the potential utility of GWAS data of schizophrenia for the direct identification of candidate drugs and molecules that show polypharmacy.
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http://dx.doi.org/10.1177/0269881116653109DOI Listing
August 2016

Ulk4 Regulates Neural Stem Cell Pool.

Stem Cells 2016 09 27;34(9):2318-31. Epub 2016 Jun 27.

Regenerative Medicine Institute, School of Medicine, National University of Ireland (NUI) Galway, Galway, Ireland.

The size of neural stem cell (NSC) pool at birth determines the starting point of adult neurogenesis. Aberrant neurogenesis is associated with major mental illness, in which ULK4 is proposed as a rare risk factor. Little is known about factors regulating the NSC pool, or function of the ULK4. Here, we showed that Ulk4(tm1a/tm1a) mice displayed a dramatically reduced NSC pool at birth. Ulk4 was expressed in a cell cycle-dependent manner and peaked in G2/M phases. Targeted disruption of the Ulk4 perturbed mid-neurogenesis and significantly reduced cerebral cortex in postnatal mice. Pathway analyses of dysregulated genes in Ulk4(tm1a/tm1a) mice revealed Ulk4 as a key regulator of cell cycle and NSC proliferation, partially through regulation of the Wnt signaling. In addition, we identified hemizygous deletion of ULK4 gene in 1.2/1,000 patients with pleiotropic symptoms including severe language delay and learning difficulties. ULK4, therefore, may significantly contribute to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Stem Cells 2016;34:2318-2331.
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http://dx.doi.org/10.1002/stem.2423DOI Listing
September 2016
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