Numerous studies have examined gene expression profiles in post-mortem human brain samples from individuals with schizophrenia compared with healthy controls, to gain insight into the molecular mechanisms of the disease. Although some findings have been replicated across studies, there is a general lack of consensus on which genes or pathways are affected. It has been unclear if these differences are due to the underlying cohorts or methodological considerations. Here, we present the most comprehensive analysis to date of expression patterns in the prefrontal cortex of schizophrenic, compared with unaffected controls. Using data from seven independent studies, we assembled a data set of 153 affected and 153 control individuals. Remarkably, we identified expression differences in the brains of schizophrenics that are validated by up to seven laboratories using independent cohorts. Our combined analysis revealed a signature of 39 probes that are upregulated in schizophrenia and 86 that are downregulated. Some of these genes were previously identified in studies that were not included in our analysis, while others are novel to our analysis. In particular, we observe gene expression changes associated with various aspects of neuronal communication and alterations of processes affected as a consequence of changes in synaptic functioning. A gene network analysis predicted previously unidentified functional relationships among the signature genes. Our results provide evidence for a common underlying expression signature in this heterogeneous disorder.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Jablensky A . Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci 2000; 250: 274–285.
Iwamoto K, Kato T . Gene expression profiling in schizophrenia and related mental disorders. Neuroscientist 2006; 12: 349–361.
Mirnics K, Levitt P, Lewis DA . Critical appraisal of DNA microarrays in psychiatric genomics. Biol Psychiatry 2006; 60: 163–176.
Pongrac J, Middleton FA, Lewis DA, Levitt P, Mirnics K . Gene expression profiling with DNA microarrays: advancing our understanding of psychiatric disorders. Neurochem Res 2002; 27: 1049–1063.
Altar CA, Jurata LW, Charles V, Lemire A, Liu P, Bukhman Y et al. Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry 2005; 58: 85–96.
Iwamoto K, Bundo M, Kato T . Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet 2005; 14: 241–253.
Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P . Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 2002; 22: 2718–2729.
Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P . Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000; 28: 53–67.
Arion D, Unger T, Lewis DA, Levitt P, Mirnics K . Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol Psychiatry 2007; 62: 711–721.
Aston C, Jiang L, Sokolov BP . Microarray analysis of postmortem temporal cortex from patients with schizophrenia. J Neurosci Res 2004; 77: 858–866.
Dracheva S, Davis KL, Chin B, Woo DA, Schmeidler J, Haroutunian V . Myelin-associated mRNA and protein expression deficits in the anterior cingulate cortex and hippocampus in elderly schizophrenia patients. Neurobiol Dis 2006; 21: 531–540.
Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 2001; 98: 4746–4751.
Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 2008; 40: 827–834.
Mathieson I, Munafo MR, Flint J . Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia. Mol Psychiatry 2011. Epub 2011/04/13.
O’Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.
Mistry M, Pavlidis P . A cross-laboratory comparison of expression profiling data from normal human postmortem brain. Neuroscience 2010; 167: 384–395.
Torkamani A, Dean B, Schork NJ, Thomas EA . Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. Genome Res 2010; 20: 403–412.
Choi KH, Higgs BW, Wendland JR, Song J, McMahon FJ, Webster MJ . Gene expression and genetic variation data implicate PCLO in bipolar disorder. Biol Psychiatry 2011; 69: 353–359.
Liu C, Cheng L, Badner JA, Zhang D, Craig DW, Redman M et al. Whole-genome association mapping of gene expression in the human prefrontal cortex. Mol Psychiatry 2010; 15: 779–784.
Barnes M, Freudenberg J, Thompson S, Aronow B, Pavlidis P . Experimental comparison and cross-validation of the Affymetrix and Illumina gene expression analysis platforms. Nucleic Acids Res 2005; 33: 5914–5923.
Baum AE, Hamshere M, Green E, Cichon S, Rietschel M, Noethen MM et al. Meta-analysis of two genome-wide association studies of bipolar disorder reveals important points of agreement. Mol Psychiatry 2008; 13: 466–467.
Choi KH, Elashoff M, Higgs BW, Song J, Kim S, Sabunciyan S et al. Putative psychosis genes in the prefrontal cortex: combined analysis of gene expression microarrays. BMC Psychiatry 2008; 8: 87.
Liu Y, Blackwood DH, Caesar S, de Geus EJ, Farmer A, Ferreira MA et al. Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Mol Psychiatry 2011; 16: 2–4.
Dawany NB, Tozeren A . Asymmetric microarray data produces gene lists highly predictive of research literature on multiple cancer types. BMC Bioinform 2010; 11: 483.
Leek JT, Storey JD . Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 2007; 3: 1724–1735.
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc Natl Acad Sci USA 2004; 101: 9309–9314.
de Magalhaes JP, Curado J, Church GM . Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 2009; 25: 875–881.
Elashoff M, Higgs BW, Yolken RH, Knable MB, Weis S, Webster MJ . et al. Meta-analysis of 12 genomic studies in bipolar disorder. J Mol Neurosci 2007; 31: 221–243.
Maycox PR, Kelly F, Taylor A, Bates S, Reid J, Logendra R et al. Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function. Mol Psychiatry 2009; 14: 1083–1094.
Garbett K, Gal-Chis R, Gaszner G, Lewis DA, Mirnics K . Transcriptome alterations in the prefrontal cortex of subjects with schizophrenia who committed suicide. Neuropsychopharmacol Hung 2008; 10: 9–14.
Katsel P, Davis KL, Gorman JM, Haroutunian V . Variations in differential gene expression patterns across multiple brain regions in schizophrenia. Schizophr Res 2005; 77: 241–252.
Bolstad BM, Irizarry RA, Astrand M, Speed TP . A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 2003; 19: 185–193.
Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP . Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 2003; 31: e15.
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003; 4: 249–264.
Kent WJ . BLAT–the BLAST-like alignment tool. Genome Res 2002; 12: 656–664.
Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al. Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet 2000; 25: 25–29. .
Gillis J, Mistry M, Pavlidis P . Gene function analysis in complex data sets using ErmineJ. Nat Protoc 2010; 5: 1148–1159.
Lee HK, Braynen W, Keshav K, Pavlidis P . ErmineJ: tool for functional analysis of gene expression data sets. BMC Bioinform 2005; 6: 269.
Chatr-aryamontri A, Ceol A, Palazzi LM, Nardelli G, Schneider MV, Castagnoli L et al. MINT: the molecular INTeraction database. Nucleic Acids Res 2007; 35 (Database issue): D572–D574.
Chua HN, Sung WK, Wong L . Exploiting indirect neighbours and topological weight to predict protein function from protein-protein interactions. Bioinformatics 2006; 22: 1623–1630.
Gilbert D . Biomolecular interaction network database. Brief Bioinform 2005; 6: 194–198.
Lynn DJ, Winsor GL, Chan C, Richard N, Laird MR, Barsky A et al. InnateDB: facilitating systems-level analyses of the mammalian innate immune response. Mol Syst Biol 2008; 4: 218.
Prasad TS, Kandasamy K, Pandey A . Human protein reference database and human proteinpedia as discovery tools for systems biology. Methods Mol Biol 2009; 577: 67–79.
Razick S, Magklaras G, Donaldson IM . iRefIndex: a consolidated protein interaction database with provenance. BMC Bioinform 2008; 9: 405.
Dijkstra EW . A note on two problems in connexion with graphs. Numerische Mathematik 1959; 1: 269–271.
Glatt SJ, Everall IP, Kremen WS, Corbeil J, Sasik R, Khanlou N et al. Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia. Proc Natl Acad Sci USA 2005; 102: 15533–15538.
Zhou X, Kao MC, Wong WH . Transitive functional annotation by shortest-path analysis of gene expression data. Proc Natl Acad Sci USA 2002; 99: 12783–12788.
Oldham MC, Konopka G, Iwamoto K, Langfelder P, Kato T, Horvath S et al. Functional organization of the transcriptome in human brain. Nature Neurosci 2008; 11: 1271–1282.
Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 2008; 28: 264–278.
Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 2004; 9: 684–697, 43.
Narayan S, Tang B, Head SR, Gilmartin TJ, Sutcliffe JG, Dean B et al. Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res 2008; 1239: 235–248.
Saetre P, Emilsson L, Axelsson E, Kreuger J, Lindholm E, Jazin E . Inflammation-related genes up-regulated in schizophrenia brains. BMC Psychiatry 2007; 7: 46.
Park E, Iaccarino C, Lee J, Kwon I, Baik SM, Kim M et al. Regulatory roles of hnRNP M and Nova-1 in the alternative splicing of the dopamine D2 receptor pre-mRNA. J Biol Chem 2011; 286: 25301–25308.
Eyles DW, McGrath JJ, Reynolds GP . Neuronal calcium-binding proteins and schizophrenia. Schizophr Res 2002; 57: 27–34. .
Manji HK . G proteins: implications for psychiatry. Am J Psychiatry 1992; 149: 746–760.
Schwab SG, Hallmayer J, Lerer B, Albus M, Borrmann M, Honig S et al. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis. Am J Hum Genet 1998; 63: 1139–1152.
Oliver S . Guilt-by-association goes global. Nature 2000; 403: 601–603.
Thomas EA . Molecular profiling of antipsychotic drug function: convergent mechanisms in the pathology and treatment of psychiatric disorders. Mol Neurobiol 2006; 34: 109–128.
We would like to thank the groups and institutions who made their data available, including Dr Karoly Mirnics (Vanderbilt), Dr Vahram Haroutunian (Mt Sinai), the SMRI and the Harvard Brain bank. This study would not have been possible without their generosity. This work was supported by a Grant from the National Institutes of Health to PP (GM076990). MM was partly supported by the MIND Foundation of BC for Schizophrenia Research. JG is partly supported by CIHR and the Michael Smith Foundation for Health Research. PP is also supported by a career award from the Michael Smith Foundation for Health Research, a CIHR New Investigator award, and the Canadian Foundation for Innovation.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
About this article
Cite this article
Mistry, M., Gillis, J. & Pavlidis, P. Genome-wide expression profiling of schizophrenia using a large combined cohort. Mol Psychiatry 18, 215–225 (2013). https://doi.org/10.1038/mp.2011.172
- gene expression
- post-mortem brain
- prefrontal cortex
Journal of Neural Transmission (2022)
Highlighting the gaps in hazard and risk assessment of unregulated Endocrine Active Substances in surface waters: retinoids as a European case study
Environmental Sciences Europe (2021)
Bioinformatics analysis of long non-coding RNA-associated competing endogenous RNA network in schizophrenia
Scientific Reports (2021)
Proteome Analysis of PC12 Cells Reveals Alterations in Translation Regulation and Actin Signaling Induced by Clozapine
Neurochemical Research (2021)
Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia
Nature Neuroscience (2019)