title: Blood transcriptomic comparison of individuals with and without autism spectrum disorder: A combined-samples mega-analysis.
abstract: Blood-based microarray studies comparing individuals affected with autism spectrum disorder (ASD) and typically developing individuals help characterize differences in circulating immune cell functions and offer potential biomarker signal. We sought to combine the subject-level data from previously published studies by mega-analysis to increase the statistical power. We identified studies that compared ex vivo blood or lymphocytes from ASD-affected individuals and unrelated comparison subjects using Affymetrix or Illumina array platforms. Raw microarray data and clinical meta-data were obtained from seven studies, totaling 626 affected and 447 comparison subjects. Microarray data were processed using uniform methods. Covariate-controlled mixed-effect linear models were used to identify gene transcripts and co-expression network modules that were significantly associated with diagnostic status. Permutation-based gene-set analysis was used to identify functionally related sets of genes that were over- and under-expressed among ASD samples. Our results were consistent with diminished interferon-, EGF-, PDGF-, PI3K-AKT-mTOR-, and RAS-MAPK-signaling cascades, and increased ribosomal translation and NK-cell related activity in ASD. We explored evidence for sex-differences in the ASD-related transcriptomic signature. We also demonstrated that machine-learning classifiers using blood transcriptome data perform with moderate accuracy when data are combined across studies. Comparing our results with those from blood-based studies of protein biomarkers (e.g., cytokines and trophic factors), we propose that ASD may feature decoupling between certain circulating signaling proteins (higher in ASD samples) and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples). These findings provide insight into ASD-related transcriptional differences in circulating immune cells. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, New York.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Tylee
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, New York.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Hess
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, New York.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Quinn
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, New York.
authors.forename: Rahul
authors.initials: R
authors.lastname: Barve
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, New York.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhang-James
authors.affiliation: Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, New York.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Neurology, UC Davis School of Medicine, Sacramento, California.
authors.forename: Boryana S
authors.initials: BS
authors.lastname: Stamova
authors.affiliation: Department of Neurology, UC Davis School of Medicine, Sacramento, California.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Sharp
authors.affiliation: Department of Public Health Sciences and UC Davis MIND Institute, School of Medicine, Davis, California.
authors.forename: Irva
authors.initials: I
authors.lastname: Hertz-Picciotto
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, New York.|K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Department of Pediatrics, Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sek Won
authors.initials: SW
authors.lastname: Kong
authors.affiliation: Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, New York.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Glatt
mesh_terms: D000067877:Autism Spectrum Disorder / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D059467:Transcriptome / Q000235:genetics*
chemical_list: D015415:Biomarkers
keywords: gene expression; immune system; machine learning; microarray