title: Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia.
abstract: The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders. In an attempt to summarize existing studies of schizophrenia cases and non-related comparison subjects, we performed two mega-analyses of a combined set of microarray data from postmortem prefrontal cortices (n=315) and from ex-vivo blood tissues (n=578). We adjusted regression models per gene to remove non-significant covariates, providing best-estimates of transcripts dysregulated in schizophrenia. We also examined dysregulation of functionally related gene sets and gene co-expression modules, and assessed enrichment of cell types and genetic risk factors. The identities of the most significantly dysregulated genes were largely distinct for each tissue, but the findings indicated common emergent biological functions (e.g. immunity) and regulatory factors (e.g., predicted targets of transcription factors and miRNA species across tissues). Our network-based analyses converged upon similar patterns of heightened innate immune gene expression in both brain and blood in schizophrenia. We also constructed generalizable machine-learning classifiers using the blood-based microarray data. Our study provides an informative atlas for future pathophysiologic and biomarker studies of schizophrenia.
authors.affiliation: Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Syracuse, NY, USA; Departments of Psychiatry and Behavioral Sciences & Neuroscience and Physiology, Syracuse, NY, USA; SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Hess
authors.affiliation: Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Syracuse, NY, USA; Departments of Psychiatry and Behavioral Sciences & Neuroscience and Physiology, Syracuse, NY, USA; SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Tylee
authors.affiliation: Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Syracuse, NY, USA; Departments of Psychiatry and Behavioral Sciences & Neuroscience and Physiology, Syracuse, NY, USA; SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Barve
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA; MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: de Jong
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA; Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.affiliation: School of Medicine & Public Health, The University of Newcastle, Callaghan, Newcastle, Australia; Department of Anatomy, Faculty of Medical Sciences, University of Sri Jayawardenepura, Nugegoda, Sri Lanka; Schizophrenia Research Institute, Sydney, New South Wales, Australia; Faculty of Medicine, Sir John Kotelawala Defence University, Ratmalana, Sri Lanka.
authors.forename: Nishantha
authors.initials: N
authors.lastname: Kumarasinghe
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; School of Biomedical Sciences & Pharmacy, Faculty of Health, The University of Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, Australia; Centre for Translational Neuroscience & Mental Health, University of Newcastle, Callaghan, Newcastle, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Tooney
authors.affiliation: School of Medicine & Public Health, The University of Newcastle, Callaghan, Newcastle, Australia; Schizophrenia Research Institute, Sydney, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, Australia; Centre for Translational Neuroscience & Mental Health, University of Newcastle, Callaghan, Newcastle, Australia.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schall
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; School of Biomedical Sciences & Pharmacy, Faculty of Health, The University of Newcastle, New South Wales, Australia; Centre for Translational Neuroscience & Mental Health, University of Newcastle, Callaghan, Newcastle, Australia.
authors.forename: Erin
authors.initials: E
authors.lastname: Gardiner
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; School of Biomedical Sciences & Pharmacy, Faculty of Health, The University of Newcastle, New South Wales, Australia; Centre for Translational Neuroscience & Mental Health, University of Newcastle, Callaghan, Newcastle, Australia.
authors.forename: Natalie Jane
authors.initials: NJ
authors.lastname: Beveridge
authors.affiliation: School of Biomedical Sciences & Pharmacy, Faculty of Health, The University of Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Department of Anatomy, Faculty of Medical Sciences, University of Sri Jayawardenepura, Nugegoda, Sri Lanka.
authors.forename: Surangi
authors.initials: S
authors.lastname: Yasawardene
authors.affiliation: Department of Anatomy, Faculty of Medical Sciences, University of Sri Jayawardenepura, Nugegoda, Sri Lanka.
authors.forename: Antionette
authors.initials: A
authors.lastname: Perera
authors.affiliation: Department of Anatomy, Faculty of Medical Sciences, University of Sri Jayawardenepura, Nugegoda, Sri Lanka.
authors.forename: Jayan
authors.initials: J
authors.lastname: Mendis
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; School of Psychiatry, University of New South Wales, Kensington, New South Wales, Australia.
authors.forename: Vaughan
authors.initials: V
authors.lastname: Carr
authors.affiliation: School of Medicine & Public Health, The University of Newcastle, Callaghan, Newcastle, Australia; Hunter Medical Research Institute, Newcastle, Australia; Centre for Translational Neuroscience & Mental Health, University of Newcastle, Callaghan, Newcastle, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Kelly
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; School of Biomedical Sciences & Pharmacy, Faculty of Health, The University of Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, Australia; Centre for Translational Neuroscience & Mental Health, University of Newcastle, Callaghan, Newcastle, Australia.
authors.forename: Murray
authors.initials: M
authors.lastname: Cairns
authors.affiliation: Center for Behavioral Genomics, Department of Psychiatry, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA; Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, USA.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Syracuse, NY, USA; Departments of Psychiatry and Behavioral Sciences & Neuroscience and Physiology, Syracuse, NY, USA; SUNY Upstate Medical University, Syracuse, NY, USA. Electronic address: stephen.glatt@psychgenelab.com.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Glatt
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D000069550:Machine Learning; D046228:Microarray Analysis; D015233:Models, Statistical; D017397:Prefrontal Cortex / Q000378:metabolism*; D011618:Psychotic Disorders / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D015415:Biomarkers
keywords: Blood; Brain; Gene expression; Innate immunity; Random forests; Schizophrenia; Support vector machine; Transcriptome