Re-analysis of Bipolar Disorder and Schizophrenia Gene Expression Complements the Kraepelinian Dichotomy

  • Kui Qian
  • Antonio Di Lieto
  • Jukka Corander
  • Petri Auvinen
  • Dario GrecoEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 736)


The differential diagnosis of schizophrenia (SZ) and bipolar disorder (BD) is based solely on clinical features and upon a subset of overlapping symptoms. Within the last years, an increasing amount of clinical, epidemiological and genetic data suggested inconsistent with the Kraepelinian dichotomy. We performed re-analysis of genome-wide gene expression data obtained from postmortem prefrontal cortex (PEC) of both BD and SZ patients with matched controls from four independent microarray experiments. We found 2,577 and 477 genes specifically altered in BD and SZ, respectively. Of these, 164 genes were shared between the syndromes. We identified genes of the transcriptional and post-transcriptional machineries altered in BD and genes of the development changed in SZ. Our results showed that the genomic expression profile of BD and SZ had some similarity but still could be well-distinguished by suitable statistical test.


Bipolar Disorder Bayesian Model Average Bayesian Model Average Entrez Gene Database Stanley Medical Research Institute 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study has been funded by the Institute of Biotechnology, University of Helsinki (Finland), and by the Academy of Finland (PA). DG was funded by the Paulon Säätiö (Finland). The work of JC was supported by the grant no. 121301 from Academy of Finland. The authors are deeply grateful to Prof. Eero Castrén and Dr Iiris Hovatta for critical comments on the manuscript.


  1. 1.
    American Psychiatric Association Task Force on DSM-IV (2000) Diagnostic and statistical manual of mental disorders: DSM-IV-TR, 4th edn. American Psychiatric Association, Washington, pp xxxvii, 943Google Scholar
  2. 2.
    Consortium WTCC (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678CrossRefGoogle Scholar
  3. 3.
    Sullivan PF, Kendler KS, Neale MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60(12):1187–1192PubMedCrossRefGoogle Scholar
  4. 4.
    Craddock N, O’Donovan MC, Owen MJ (2006) Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull 32(1):9–16PubMedCrossRefGoogle Scholar
  5. 5.
    Consortium IS (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455(7210):237–241CrossRefGoogle Scholar
  6. 6.
    Lichtenstein P et al (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373(9659):234–239PubMedCrossRefGoogle Scholar
  7. 7.
    Purcell SM et al (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256):748–752PubMedGoogle Scholar
  8. 8.
    Stefansson H et al (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455(7210):232–236PubMedCrossRefGoogle Scholar
  9. 9.
    Hunsberger JG et al (2009) micrornas in mental health: from biological underpinnings to potential therapies. Neuromol Med 11(3):173–182CrossRefGoogle Scholar
  10. 10.
    Burmeister M, McInnis MG, Zollner S (2008) Psychiatric genetics: progress amid controversy. Nat Rev Genet 9(7):527–540PubMedCrossRefGoogle Scholar
  11. 11.
    Mirnics K et al (2000) Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28(1):53–67PubMedCrossRefGoogle Scholar
  12. 12.
    Ryan MM et al (2006) Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes. Mol Psychiatry 11(10):965–978PubMedCrossRefGoogle Scholar
  13. 13.
    Nakatani N et al (2006) Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation. Hum Mol Genet 15(12):1949–1962PubMedCrossRefGoogle Scholar
  14. 14.
    Tkachev D et al (2007) Further evidence for altered myelin biosynthesis and glutamatergic dysfunction in schizophrenia. Int J Neuropsychopharmacol 10(4):557–563PubMedCrossRefGoogle Scholar
  15. 15.
    Benes FM et al (2005) The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia. Mol Psychiatry 11(3):241–251CrossRefGoogle Scholar
  16. 16.
    Iwamoto K, Bundo M, Kato T (2005) 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 14(2):241–253PubMedCrossRefGoogle Scholar
  17. 17.
    Tkachev D et al (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362(9386):798–805PubMedCrossRefGoogle Scholar
  18. 18.
    Iwamoto K et al (2004) Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry 9(4): 406–416PubMedCrossRefGoogle Scholar
  19. 19.
    Prabakaran S et al (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9(7):684–697, 643Google Scholar
  20. 20.
    Hashimoto T et al (2008) Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 13(2):147–161PubMedCrossRefGoogle Scholar
  21. 21.
    Larsson O, Wennmalm K, Sandberg R (2006) Comparative microarray analysis. OMICS 10(3):381–397PubMedCrossRefGoogle Scholar
  22. 22.
    Greco D et al (2008) Physiology, pathology and relatedness of human tissues from gene expression meta-analysis. PLoS One 3(4):e1880PubMedCrossRefGoogle Scholar
  23. 23.
    Parman C, Halling C (2009) affyQCReport: a package to generate QC reports for affymetrix array dataGoogle Scholar
  24. 24.
    Bolstad BM et al (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19(2):185–193PubMedCrossRefGoogle Scholar
  25. 25.
    Irizarry RA et al (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4(2):249–264PubMedCrossRefGoogle Scholar
  26. 26.
    Gautier L et al (2004) affy – analysis of Affymetrix genechip data at the probe level. Bioinformatics 20(3):307–315PubMedCrossRefGoogle Scholar
  27. 27.
    Goeman JJ et al (2004) A global test for groups of genes: testing association with a clinical outcome. Bioinformatics 20(1):93–99PubMedCrossRefGoogle Scholar
  28. 28.
    Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W (eds) Bioinformatics and computational biology solutions using R and bioconductor. New York: Springer, pp 397–420CrossRefGoogle Scholar
  29. 29.
    Huang da W, Sherman BT, Lempicki RA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37(1):1–13CrossRefGoogle Scholar
  30. 30.
    Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57CrossRefGoogle Scholar
  31. 31.
    Zhang B, Kirov S, Snoddy J (2005) webgestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res 33(Web Server issue):W741–748Google Scholar
  32. 32.
    Yeung KY, Bumgarner RE, Raftery AE (2005) Bayesian model averaging: development of an improved multi-class, gene selection and classification tool for microarray data. Bioinformatics 21(10):2394–2402PubMedCrossRefGoogle Scholar
  33. 33.
    Maglott D et al (2007) Entrez gene: gene-centered information at NCBI. Nucleic Acids Res 35(Database issue):D26–31Google Scholar
  34. 34.
    Choi KH et al (2008) Putative psychosis genes in the prefrontal cortex: combined analysis of gene expression microarrays. BMC Psychiatry 8:87PubMedCrossRefGoogle Scholar
  35. 35.
    Pedersen CB, Mortensen PB, Cantor-Graae E (2011) Do risk factors for schizophrenia predispose to emigration? Schizophr Res 127(1–3):229–234PubMedCrossRefGoogle Scholar
  36. 36.
    Fatjo-Vilas M et al (2011) Dysbindin-1 gene contributes differentially to early- and adult-onset forms of functional psychosis. Am J Med Genet B Neuropsychiatr Genet 156(3):322–333CrossRefGoogle Scholar
  37. 37.
    Gruber O et al (2011) A systematic experimental neuropsychological investigation of the functional integrity of working memory circuits in major depression. Eur Arch Psychiatry Clin Neurosci 261:179–184PubMedCrossRefGoogle Scholar
  38. 38.
    McIntosh BJ et al (2011) Performance-based assessment of functional skills in severe mental illness: results of a large-scale study in China. J Psychiatr Res:45(8):1089–1094Google Scholar
  39. 39.
    Mueser KT et al (2010) Neurocognition and social skill in older persons with schizophrenia and major mood disorders: An analysis of gender and diagnosis effects. J Neurolinguistics 23(3):297–317PubMedCrossRefGoogle Scholar
  40. 40.
    Pedersen CB, Mortensen PB, Cantor-Graae E Do risk factors for schizophrenia predispose to emigration? Schizophr Res 127(1–3):229–234Google Scholar
  41. 41.
    Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry 62(11):1310–1316PubMedCrossRefGoogle Scholar
  42. 42.
    Rollins B et al (2009) Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PLoS One 4(3):e4913PubMedCrossRefGoogle Scholar
  43. 43.
    Nasrallah HA, Brecher M, Paulsson B (2006) Placebo-level incidence of extrapyramidal symptoms (EPS) with quetiapine in controlled studies of patients with bipolar mania. Bipolar Disord 8(5 Pt 1):467–474PubMedCrossRefGoogle Scholar
  44. 44.
    Lewis R, Bagnall AM, Leitner M (2005) Sertindole for schizophrenia. Cochrane Database Syst Rev (3):CD001715. Review. PMID: 16034864 [PubMed - indexed for MEDLINE]Google Scholar
  45. 45.
    Thompson Ray M et al (2011) Decreased BDNF, trkb-TK + and GAD(67) mrna expression in the hippocampus of individuals with schizophrenia and mood disorders. J Psychiatry Neurosci 36(1):100048Google Scholar
  46. 46.
    Wang JF et al (2009) Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disord 11(5):523–529PubMedCrossRefGoogle Scholar
  47. 47.
    Pounds SB (2006) Estimation and control of multiple testing error rates for microarray studies. Brief Bioinform 7(1):25–36PubMedCrossRefGoogle Scholar
  48. 48.
    Moreau MP et al (2011) Altered microrna expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder. Biol Psychiatry 69(2):188–193PubMedCrossRefGoogle Scholar
  49. 49.
    Kim AH et al (2010) microrna expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr Res 124(1–3):183–191PubMedCrossRefGoogle Scholar
  50. 50.
    Dinan TG (2010) micrornas as a target for novel antipsychotics: a systematic review of an emerging field. Int J Neuropsychopharmacol 13(3):395–404PubMedCrossRefGoogle Scholar
  51. 51.
    Gershon ES, Alliey-Rodriguez N, Liu C (2011) After GWAS: searching for genetic risk for Schizophrenia and bipolar disorder. Am J Psychiatry 168(3):253–256PubMedCrossRefGoogle Scholar
  52. 52.
    Souza BR et al (2011) Downregulation of the camp/PKA pathway in PC12 cells overexpressing NCS-1. Cell Mol Neurobiol 31(1):135–143PubMedCrossRefGoogle Scholar
  53. 53.
    Yuan P et al (2010) Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord 124(1–2):164–169PubMedCrossRefGoogle Scholar
  54. 54.
    Yuan P et al Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord 124(1–2):164–169Google Scholar
  55. 55.
    Kakiuchi C et al (2007) Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder. Neurosci Lett 417(3):316–321PubMedCrossRefGoogle Scholar
  56. 56.
    Ubhi K, Price J (2005) Expression of POU-domain transcription factor, Oct-6, in schizophrenia, bipolar disorder and major depression. BMC Psychiatry 5:38PubMedCrossRefGoogle Scholar
  57. 57.
    Iwayama Y et al (2010) Association analyses between brain-expressed fatty-acid binding protein (FABP) genes and schizophrenia and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 153B(2):484–493PubMedGoogle Scholar
  58. 58.
    Quinones MP, Kaddurah-Daouk R (2009) Metabolomics tools for identifying biomarkers for neuropsychiatric diseases. Neurobiol Dis 35(2):165–176PubMedCrossRefGoogle Scholar
  59. 59.
    Adibhatla RM, Hatcher JF (2010) Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12(1): 125–169PubMedCrossRefGoogle Scholar
  60. 60.
    Shedden K et al (2008) Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 14(8):822–827PubMedCrossRefGoogle Scholar
  61. 61.
    van’t Veer LJ, Bernards R (2008) Enabling personalized cancer medicine through analysis of gene-expression patterns. Nature 452(7187):564–570Google Scholar
  62. 62.
    Lee SC et al (2009) Post-treatment tumor gene expression signatures are more predictive of treatment outcomes than baseline signatures in breast cancer. Pharmacogenet Genomics 19(11):833–842PubMedCrossRefGoogle Scholar
  63. 63.
    Zaas AK et al (2010) Blood gene expression signatures predict invasive candidiasis. Sci Transl Med 2(21):21ra17Google Scholar
  64. 64.
    Morozova O, Hirst M, Marra MA (2009) Applications of new sequencing technologies for transcriptome analysis. Annu Rev Genomics Hum Genet 10:135–151PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Kui Qian
    • 1
  • Antonio Di Lieto
    • 2
  • Jukka Corander
    • 3
  • Petri Auvinen
    • 1
  • Dario Greco
    • 4
    Email author
  1. 1.Institute of BiotechnologyUniversity of HelsinkiHelsinkiFinland
  2. 2.Neuroscience CentreUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of Mathematics and StatisticsUniversity of HelsinkiHelsinkiFinland
  4. 4.Department of Bioscience and NutritionKarolinska InstitutetStockholmSweden

Personalised recommendations