Progress in defining the biological causes of schizophrenia

Benjamin Pickard

doi:10.1017/S1462399411001955

Progress in defining the biological causes of schizophrenia

Published online by Cambridge University Press: 28 July 2011

Benjamin Pickard

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Benjamin Pickard*: Affiliation:
Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, Glasgow, UK.
*: *Corresponding author: Benjamin Pickard, Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. E-mail: benjamin.pickard@strath.ac.uk

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Abstract

Schizophrenia is a common mental illness resulting from a complex interplay of genetic and environmental risk factors. Establishing its primary molecular and cellular aetiopathologies has proved difficult. However, this is a vital step towards the rational development of useful disease biomarkers and new therapeutic strategies. The advent and large-scale application of genomic, transcriptomic, proteomic and metabolomic technologies are generating data sets required to achieve this goal. This discovery phase, typified by its objective and hypothesis-free approach, is described in the first part of the review. The accumulating biological information, when viewed as a whole, reveals a number of biological process and subcellular locations that contribute to schizophrenia causation. The data also show that each technique targets different aspects of central nervous system function in the disease state. In the second part of the review, key schizophrenia candidate genes are discussed more fully. Two higher-order processes – adult neurogenesis and inflammation – that appear to have pathological relevance are also described in detail. Finally, three areas where progress would have a large impact on schizophrenia biology are discussed: deducing the causes of schizophrenia in the individual, explaining the phenomenon of cross-disorder risk factors, and distinguishing causative disease factors from those that are reactive or compensatory.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 13 , March 2011 , e25

DOI: https://doi.org/10.1017/S1462399411001955 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2011

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References

1Liddle, P.F. (1987) The symptoms of chronic schizophrenia. A re-examination of the positive-negative dichotomy. British Journal of Psychiatry 151, 145-151CrossRef Google Scholar PubMed

2Karam, C.S. et al. (2010) Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends in Pharmacological Sciences 31, 381-390CrossRef Google Scholar PubMed

3Meyer-Lindenberg, A. (2010) From maps to mechanisms through neuroimaging of schizophrenia. Nature 468, 194-202CrossRef Google Scholar PubMed

4Segal, D. et al. (2007) Oligodendrocyte pathophysiology: a new view of schizophrenia. International Journal of Neuropsychopharmacology 10, 503-511CrossRef Google Scholar PubMed

5Arnold, S.E. (1999) Neurodevelopmental abnormalities in schizophrenia: insights from neuropathology. Development and Psychopathology 11, 439-456CrossRef Google Scholar PubMed

6Kety, S.S. (1988) Schizophrenic illness in the families of schizophrenic adoptees: findings from the Danish national sample. Schizophrenia Bulletin 14, 217-222CrossRef Google Scholar PubMed

7Kendler, K.S. (1983) Overview: a current perspective on twin studies of schizophrenia. American Journal of Psychiatry 140, 1413-1425Google Scholar PubMed

8Risch, N. (1990) Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genetic Epidemiology 7, 3-16; discussion 17–45CrossRef Google Scholar PubMed

9Gottesman, I.I. (1991) Schizophrenia Genesis: The Origins of Madness, Freeman, New YorkGoogle Scholar

10Bodmer, W. and Bonilla, C. (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nature Genetics 40, 695-701CrossRef Google Scholar PubMed

11Lichtenstein, P. et al. (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234-239CrossRef Google Scholar PubMed

12Williams, H.J. et al. (2011) Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries. Human Molecular Genetics 20, 387-391CrossRef Google Scholar PubMed

13Craddock, N. and Owen, M.J. (2005) The beginning of the end for the Kraepelinian dichotomy. British Journal of Psychiatry 186, 364-366CrossRef Google Scholar PubMed

14Huang, J. et al. (2010) Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression. American Journal of Psychiatry 167, 1254-1263CrossRef Google Scholar PubMed

15Faraone, S.V., Taylor, L. and Tsuang, M.T. (2002) The molecular genetics of schizophrenia: an emerging consensus. Expert Reviews in Molecular Medicine 4, 1-13CrossRef Google Scholar PubMed

16Harrison, P.J. and Weinberger, D.R. (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Molecular Psychiatry 10, 40-68; image 45CrossRef Google Scholar PubMed

17Ross, C.A. et al. (2006) Neurobiology of schizophrenia. Neuron 52, 139-153CrossRef Google Scholar PubMed

18Carter, C.J. (2006) Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability. Schizophrenia Research 86, 1-14CrossRef Google Scholar PubMed

19Jarskog, L.F., Miyamoto, S. and Lieberman, J.A. (2007) Schizophrenia: new pathological insights and therapies. Annual Review of Medicine 58, 49-61CrossRef Google Scholar PubMed

20Hayashi-Takagi, A. and Sawa, A. (2010) Disturbed synaptic connectivity in schizophrenia: convergence of genetic risk factors during neurodevelopment. Brain Research Bulletin 83, 140-146CrossRef Google Scholar PubMed

21Bray, N.J. et al. (2010) The neurobiology of schizophrenia: new leads and avenues for treatment. Current Opinion in Neurobiology 20, 810-815CrossRef Google Scholar PubMed

22Kirov, G. et al. (2009) A genome-wide association study in 574 schizophrenia trios using DNA pooling. Molecular Psychiatry 14, 796-803CrossRef Google Scholar PubMed

23O'Donovan, M.C. et al. (2008) Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nature Genetics 40, 1053-1055CrossRef Google Scholar PubMed

24Lencz, T. et al. (2007) Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Molecular Psychiatry 12, 572-580CrossRef Google Scholar PubMed

25Purcell, S.M. et al. (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748-752Google Scholar PubMed

26Stefansson, H. et al. (2009) Common variants conferring risk of schizophrenia. Nature 460, 744-747CrossRef Google Scholar PubMed

27Shi, J. et al. (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753-757CrossRef Google Scholar PubMed

28Ikeda, M. et al. (2010) Genome-wide association study of schizophrenia in a Japanese population. Biological PsychiatryGoogle Scholar

29Athanasiu, L. et al. (2010) Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. Journal of Psychiatric Research 44, 748-753CrossRef Google Scholar

30Chen, X. et al. (2010) GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia. Molecular Psychiatry, 2010 September 14 [Epub ahead of print]Google Scholar PubMed

31Wang, Z. et al. (2006) A review and re-evaluation of an association between the NOTCH4 locus and schizophrenia. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 141B, 902-906CrossRef Google Scholar PubMed

32Sha, L. et al. (2011) SOX11 target genes: implications for neurogenesis and neuropsychiatric illness. Acta NeuropsychiatricaGoogle Scholar

33Wang, K., Li, M. and Hakonarson, H. (2010) Analysing biological pathways in genome-wide association studies. Nature Reviews. Genetics 11, 843-854CrossRef Google Scholar PubMed

34Jia, P. et al. (2010) Common variants conferring risk of schizophrenia: a pathway analysis of GWAS data. Schizophrenia Research 122, 38-42CrossRef Google Scholar PubMed

35O'Dushlaine, C. et al. (2011) Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Molecular Psychiatry 16, 286-292CrossRef Google Scholar PubMed

36Redon, R. et al. (2006) Global variation in copy number in the human genome. Nature 444, 444-454CrossRef Google Scholar PubMed

37Lee, C. and Scherer, S.W. (2010) The clinical context of copy number variation in the human genome. Expert Reviews in Molecular Medicine 12, e8CrossRef Google Scholar PubMed

38Conrad, D.F. et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature 464, 704-712CrossRef Google Scholar PubMed

39Grozeva, D. et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Archives of General Psychiatry 67, 318-327CrossRef Google Scholar

40Tam, G.W. et al. (2009) The role of DNA copy number variation in schizophrenia. Biological Psychiatry 66, 1005-1012CrossRef Google Scholar PubMed

41Bassett, A.S., Scherer, S.W. and Brzustowicz, L.M. (2010) Copy number variations in schizophrenia: critical review and new perspectives on concepts of genetics and disease. American Journal of Psychiatry 167, 899-914CrossRef Google Scholar PubMed

42Sebat, J., Levy, D.L. and McCarthy, S.E. (2009) Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends in Genetics 25, 528-535CrossRef Google Scholar PubMed

43Weiss, L.A. et al. (2008) Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 358, 667-675CrossRef Google Scholar PubMed

44Moreno-De-Luca, D. et al. (2010) Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. American Journal of Human Genetics 87, 618-630CrossRef Google Scholar PubMed

45Magri, C. et al. (2010) New copy number variations in schizophrenia. PLoS One 5, e13422CrossRef Google Scholar PubMed

46Mulle, J.G. et al. Microdeletions of 3q29 confer high risk for schizophrenia. American Journal of Human Genetics 87, 229-236CrossRef Google Scholar

47Karayiorgou, M., Simon, T.J. and Gogos, J.A. (2010) 22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia. Nature Reviews. Neuroscience 11, 402-416CrossRef Google Scholar PubMed

48Ingason, A. et al. (2010) Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Molecular Psychiatry 16, 17-25CrossRef Google Scholar

49International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237-241CrossRef Google Scholar

50Stefansson, H. et al. (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455, 232-236CrossRef Google Scholar PubMed

51Walsh, T. et al. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539-543CrossRef Google Scholar PubMed

52McCarthy, S.E. et al. (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics 41, 1223-1227CrossRef Google Scholar PubMed

53Levinson, D.F. et al. (2011) Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. American Journal of PsychiatryCrossRef Google Scholar PubMed

54Vacic, V. et al. (2011) Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. NatureGoogle Scholar PubMed

55Girirajan, S. et al. (2010) A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics 42, 203-209CrossRef Google Scholar PubMed

56Doody, G.A. et al. (1998) ‘Pfropfschizophrenie’ revisited. Schizophrenia in people with mild learning disability. British Journal of Psychiatry 173, 145-153CrossRef Google Scholar PubMed

57Zhang, D. et al. (2009) Singleton deletions throughout the genome increase risk of bipolar disorder. Molecular Psychiatry 14, 376-380CrossRef Google Scholar PubMed

58Priebe, L. et al. (2011) Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder. Molecular Psychiatry, 2011 March 5 [Epub ahead of print]Google Scholar PubMed

59Muir, W.J., Pickard, B.S. and Blackwood, D.H. (2006) Chromosomal abnormalities and psychosis. British Journal of Psychiatry 188, 501-503CrossRef Google Scholar PubMed

60Chubb, J.E. et al. (2008) The DISC locus in psychiatric illness. Molecular Psychiatry 13, 36-64CrossRef Google Scholar PubMed

61Millar, J.K. et al. (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Human Molecular Genetics 9, 1415-1423CrossRef Google Scholar PubMed

62Muir, W.J., Pickard, B.S. and Blackwood, D.H. (2008) Disrupted-in-schizophrenia-1. Current Psychiatry Reports 10, 140-147CrossRef Google Scholar PubMed

63St Clair, D. et al. (1990) Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336, 13-16CrossRef Google Scholar PubMed

64Gornick, M.C. et al. (2005) Dysbindin (DTNBP1, 6p22.3) is associated with childhood-onset psychosis and endophenotypes measured by the Premorbid Adjustment Scale (PAS). Journal of Autism and Developmental Disorders 35, 831-838CrossRef Google Scholar PubMed

65Blackwood, D.H. et al. (2001) Schizophrenia and affective disorders–cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. American Journal of Human Genetics 69, 428-433CrossRef Google Scholar PubMed

66Millar, J.K. et al. (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310, 1187-1191CrossRef Google Scholar PubMed

67Ozeki, Y. et al. (2011) A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: altered l-serine level associated with disruption of PSAT1 gene expression. Neuroscience Research 69, 154-160CrossRef Google Scholar PubMed

68Pickard, B.S. et al. (2008) A common variant in the 3′UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder. Proceedings of the National Academy of Sciences of the United States of America 105, 14940-14945CrossRef Google Scholar

69Pickard, B.S. et al. (2006) Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. Molecular Psychiatry 11, 847-857CrossRef Google Scholar PubMed

70Whalley, H.C. et al. (2009) A GRIK4 variant conferring protection against bipolar disorder modulates hippocampal function. Molecular Psychiatry 14, 467-468CrossRef Google Scholar PubMed

71Knight, H.M. et al. (2009) A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. American Journal of Human Genetics 85, 833-846CrossRef Google Scholar PubMed

72Kamnasaran, D. et al. (2003) Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. Journal of Medical Genetics 40, 325-332CrossRef Google Scholar

73Pickard, B.S. et al. (2009) Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder. Molecular Psychiatry 14, 874-884CrossRef Google Scholar PubMed

74Pickard, B.S. et al. (2005) Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 136B, 26-32CrossRef Google Scholar PubMed

75Ferreira, M.A. et al. (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nature Genetics 40, 1056-1058CrossRef Google Scholar PubMed

76Li, Y. et al. (2010) Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nature Genetics 42, 969-972CrossRef Google Scholar PubMed

77Bilguvar, K. et al. (2010) Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467, 207-210CrossRef Google Scholar PubMed

78Song, W. et al. (2008) Identification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia. Biochemical and Biophysical Research Communications 367, 700-706CrossRef Google Scholar PubMed

79Tarabeux, J. et al. (2010) De novo truncating mutation in Kinesin 17 associated with schizophrenia. Biological Psychiatry 68, 649-656CrossRef Google Scholar PubMed

80Datta, S.R. et al. (2010) A threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia. Molecular Psychiatry 15, 615-628CrossRef Google Scholar PubMed

81Dwyer, S. et al. (2011) Investigation of rare non-synonymous variants at ABCA13 in schizophrenia and bipolar disorder. Molecular Psychiatry, 2011 February 1 [Epub ahead of print]CrossRef Google Scholar PubMed

82Porter, R.H., Eastwood, S.L. and Harrison, P.J. (1997) Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia. Brain Research 751, 217-231CrossRef Google Scholar PubMed

83Sokolov, B.P. (1998) Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of “neuroleptic-free” schizophrenics: evidence on reversible up-regulation by typical neuroleptics. Journal of Neurochemistry 71, 2454-2464CrossRef Google Scholar PubMed

84Meador-Woodruff, J.H., Davis, K.L. and Haroutunian, V. (2001) Abnormal kainate receptor expression in prefrontal cortex in schizophrenia. Neuropsychopharmacology 24, 545-552CrossRef Google Scholar PubMed

85Singh, I. and Rose, N. (2009) Biomarkers in psychiatry. Nature 460, 202-207CrossRef Google Scholar PubMed

86Schwarz, E. and Bahn, S. (2008) Biomarker discovery in psychiatric disorders. Electrophoresis 29, 2884-2890CrossRef Google Scholar PubMed

87Altar, C.A., Vawter, M.P. and Ginsberg, S.D. (2009) Target identification for CNS diseases by transcriptional profiling. Neuropsychopharmacology 34, 18-54CrossRef Google Scholar PubMed

88Middleton, F.A. et al. (2002) Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. Journal of Neuroscience 22, 2718-2729CrossRef Google Scholar PubMed

89Horvath, S., Janka, Z. and Mirnics, K. (2011) Analyzing schizophrenia by DNA microarrays. Biological Psychiatry 69, 157-162CrossRef Google Scholar PubMed

90Lewis, D.A. and Mirnics, K. (2006) Transcriptome alterations in schizophrenia: disturbing the functional architecture of the dorsolateral prefrontal cortex. Progress in Brain Research 158, 141-152CrossRef Google Scholar PubMed

91Mirnics, K., Levitt, P. and Lewis, D.A. (2006) Critical appraisal of DNA microarrays in psychiatric genomics. Biological Psychiatry 60, 163-176CrossRef Google Scholar PubMed

92Iwamoto, K. and Kato, T. (2006) Gene expression profiling in schizophrenia and related mental disorders. Neuroscientist 12, 349-361CrossRef Google Scholar PubMed

93Arion, D. et al. (2007) Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biological Psychiatry 62, 711-721CrossRef Google Scholar PubMed

94Hashimoto, T. et al. (2008) Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Molecular Psychiatry 13, 147-161CrossRef Google Scholar PubMed

95Matigian, N.A. et al. (2008) Fibroblast and lymphoblast gene expression profiles in schizophrenia: are non-neural cells informative? PLoS One 3, e2412CrossRef Google Scholar PubMed

96Sullivan, P.F., Fan, C. and Perou, C.M. (2006) Evaluating the comparability of gene expression in blood and brain. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 141B, 261-268CrossRef Google Scholar PubMed

97Takahashi, M. et al. (2010) Diagnostic classification of schizophrenia by neural network analysis of blood-based gene expression signatures. Schizophrenia Research 119, 210-218CrossRef Google Scholar PubMed

98Middleton, F.A. et al. (2005) Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 136B, 12-25CrossRef Google Scholar PubMed

99Duncan, C.E., Chetcuti, A.F. and Schofield, P.R. (2008) Coregulation of genes in the mouse brain following treatment with clozapine, haloperidol, or olanzapine implicates altered potassium channel subunit expression in the mechanism of antipsychotic drug action. Psychiatric Genetics 18, 226-239CrossRef Google Scholar PubMed

100Sivagnanasundaram, S. et al. (2007) Differential gene expression in the hippocampus of the Df1/+ mice: a model for 22q11.2 deletion syndrome and schizophrenia. Brain Research 1139, 48-59CrossRef Google Scholar

101Polymeropoulos, M.H. et al. (2009) Common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol supports a key role of lipid homeostasis in schizophrenia. Schizophrenia Research 108, 134-142CrossRef Google Scholar PubMed

102Xu, B., Karayiorgou, M. and Gogos, J.A. (2010) MicroRNAs in psychiatric and neurodevelopmental disorders. Brain Research 1338, 78-88CrossRef Google Scholar PubMed

103Forero, D.A. et al. (2010) miRNA genes and the brain: implications for psychiatric disorders. Human Mutation 31, 1195-1204CrossRef Google Scholar PubMed

104Schwarz, E. and Bahn, S. (2008) Cerebrospinal fluid: identification of diagnostic markers for schizophrenia. Expert Review of Molecular Diagnostics 8, 209-216CrossRef Google Scholar PubMed

105English, J.A. et al. (2011) The neuroproteomics of schizophrenia. Biological Psychiatry 69, 163-172CrossRef Google Scholar PubMed

106Levin, Y. et al. (2010) Global proteomic profiling reveals altered proteomic signature in schizophrenia serum. Molecular Psychiatry 15, 1088-1100CrossRef Google Scholar PubMed

107Martins-de-Souza, D. et al. (2010) Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential biomarkers candidates for schizophrenia. Journal of Psychiatric Research 44, 1176-1189CrossRef Google Scholar PubMed

108Martins-de-Souza, D. et al. (2009) Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation. BMC Psychiatry 9, 17CrossRef Google Scholar PubMed

109Johnston-Wilson, N.L. et al. (2000) Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Molecular Psychiatry 5, 142-149CrossRef Google Scholar PubMed

110English, J.A. et al. (2009) 2-D DIGE analysis implicates cytoskeletal abnormalities in psychiatric disease. Proteomics 9, 3368-3382CrossRef Google Scholar PubMed

111Herberth, M. et al. (2010) Impaired glycolytic response in peripheral blood mononuclear cells of first-onset antipsychotic-naive schizophrenia patients. Molecular Psychiatry, 2010 June 29 [Epub ahead of print]Google Scholar PubMed

112Huang, J.T. et al. (2007) CSF metabolic and proteomic profiles in patients prodromal for psychosis. PLoS One 2, e756CrossRef Google Scholar PubMed

113Huang, J.T. et al. (2006) Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis. PLoS Med 3, e428CrossRef Google Scholar PubMed

114Malberg, J.E. and Monteggia, L.M. (2008) VGF, a new player in antidepressant action? Science Signalling 1, e19Google Scholar PubMed

115Thakker-Varia, S. et al. (2007) The neuropeptide VGF produces antidepressant-like behavioral effects and enhances proliferation in the hippocampus. Journal of Neuroscience 27, 12156-12167CrossRef Google Scholar PubMed

116Hunsberger, J.G. et al. (2007) Antidepressant actions of the exercise-regulated gene VGF. Nature Medicine 13, 1476-1482CrossRef Google Scholar PubMed

117Bartolomucci, A. et al. (2007) The role of the vgf gene and VGF-derived peptides in nutrition and metabolism. Genes and Nutrition 2, 169-180CrossRef Google Scholar PubMed

118Sha, L. et al. (2011) Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3. Molecular Psychiatry, 2011 June 28 [Epub ahead of print]Google Scholar PubMed

119Nicholson, J.K. and Lindon, J.C. (2008) Systems biology: metabonomics. Nature 455, 1054-1056CrossRef Google Scholar PubMed

120Quinones, M.P. and Kaddurah-Daouk, R. (2009) Metabolomics tools for identifying biomarkers for neuropsychiatric diseases. Neurobiology of Disease 35, 165-176CrossRef Google Scholar PubMed

121Kaddurah-Daouk, R. and Krishnan, K.R. (2009) Metabolomics: a global biochemical approach to the study of central nervous system diseases. Neuropsychopharmacology 34, 173-186CrossRef Google Scholar

122Kaddurah-Daouk, R. et al. (2007) Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Molecular Psychiatry 12, 934-945CrossRef Google Scholar PubMed

123Kale, A. et al. (2008) Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from never-medicated first-episode psychotic patients. Schizophrenia Research 98, 295-301CrossRef Google Scholar PubMed

124Ross, B.M. (2003) Phospholipid and eicosanoid signaling disturbances in schizophrenia. Prostaglandins, Leukotrienes, and Essential Fatty Acids 69, 407-412CrossRef Google Scholar PubMed

125Berger, G.E., Smesny, S. and Amminger, G.P. (2006) Bioactive lipids in schizophrenia. International Review of Psychiatry 18, 85-98CrossRef Google Scholar PubMed

126Do, K.Q. et al. (2009) Redox dysregulation, neurodevelopment, and schizophrenia. Current Opinion in Neurobiology 19, 220-230CrossRef Google Scholar PubMed

127Yao, J.K. and Keshavan, M.S. (2011) Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. Antioxidants and Redox Signaling, 2011 May 4 [Epub ahead of print]CrossRef Google Scholar PubMed

128Wang, J.F. et al. (2009) Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disorder 11, 523-529CrossRef Google Scholar

129Do, K.Q. et al. (2000) Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. European Journal of Neuroscience 12, 3721-3728CrossRef Google Scholar PubMed

130Yao, J.K., Leonard, S. and Reddy, R. (2006) Altered glutathione redox state in schizophrenia. Disease Markers 22, 83-93CrossRef Google Scholar PubMed

131Rodriguez-Santiago, B. et al. (2010) Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia. Molecular Psychiatry 15, 1023-1033CrossRef Google Scholar PubMed

132Holmes, E. et al. (2006) Metabolic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Medicine 3, e327CrossRef Google Scholar PubMed

133Clay, H.B., Sillivan, S. and Konradi, C. (2011) Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. International Journal of Developmental NeuroscienceCrossRef Google Scholar

134Scaglia, F. (2010) The role of mitochondrial dysfunction in psychiatric disease. Developmental Disabilities Research Reviews 16, 136-143CrossRef Google Scholar PubMed

135Dixon, L. et al. (2000) Prevalence and correlates of diabetes in national schizophrenia samples. Schizophrenia Bulletin 26, 903-912CrossRef Google Scholar PubMed

136Kohen, D. (2004) Diabetes mellitus and schizophrenia: historical perspective. British Journal of Psychiatry 47, S64-S66CrossRef Google Scholar PubMed

137Rollins, B. et al. (2009) Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PLoS One 4, e4913CrossRef Google Scholar PubMed

138Millar, J.K. et al. (2005) Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Molecular and Cellular Neurosciences 30, 477-484CrossRef Google Scholar PubMed

139James, R. et al. (2004) Disrupted in schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria. Molecular and Cellular Neurosciences 26, 112-122CrossRef Google Scholar PubMed

140Park, Y.U. et al. (2010) Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin. Proceedings of the National Academy of Sciences of the United States of America 107, 17785-17790CrossRef Google Scholar PubMed

141Straub, R.E. et al. (2002) Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. American Journal of Human Genetics 71, 337-348CrossRef Google Scholar PubMed

142Stefansson, H. et al. (2002) Neuregulin 1 and susceptibility to schizophrenia. American Journal of Human Genetics 71, 877-892CrossRef Google Scholar PubMed

143Guo, A.Y. et al. (2009) The dystrobrevin-binding protein 1 gene: features and networks. Molecular Psychiatry 14, 18-29CrossRef Google Scholar PubMed

144Buonanno, A. (2010) The neuregulin signaling pathway and schizophrenia: from genes to synapses and neural circuits. Brain Research Bulletin 83, 122-131CrossRef Google Scholar PubMed

145Banerjee, A. et al. (2010) Neuregulin 1-erbB4 pathway in schizophrenia: from genes to an interactome. Brain Research Bulletin 83, 132-139CrossRef Google Scholar

146Brandon, N.J. et al. (2009) Understanding the role of DISC1 in psychiatric disease and during normal development. Journal of Neuroscience 29, 12768-12775CrossRef Google Scholar PubMed

147Camargo, L.M. et al. (2007) Disrupted in schizophrenia 1 interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular Psychiatry 12, 74-86CrossRef Google Scholar

148Hattori, T. et al. (2007) A novel DISC1-interacting partner DISC1-binding zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth. Molecular Psychiatry 12, 398-407CrossRef Google Scholar PubMed

149Millar, J.K., Christie, S. and Porteous, D.J. (2003) Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochemical and Biophysical Research Communications 311, 1019-1025CrossRef Google Scholar

150Miyoshi, K. et al. (2004) DISC1 localizes to the centrosome by binding to kendrin. Biochemical and Biophysical Research Communications 317, 1195-1199CrossRef Google Scholar

151Miyoshi, K. et al. (2003) Disrupted-in-schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Molecular Psychiatry 8, 685-694CrossRef Google Scholar PubMed

152Morris, J.A. et al. (2003) DISC1 (Disrupted-in-schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Human Molecular Genetics 12, 1591-1608CrossRef Google Scholar PubMed

153Ogawa, F., Kasai, M. and Akiyama, T. (2005) A functional link between disrupted-in-schizophrenia 1 and the eukaryotic translation initiation factor 3. Biochemical and Biophysical Research Communications 338, 771-776CrossRef Google Scholar PubMed

154Ozeki, Y. et al. (2003) Disrupted-in-schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proceedings of the National Academy of Sciences of the United States of America 100, 289-294CrossRef Google Scholar PubMed

155Hayashi-Takagi, A. et al. (2010) Disrupted-in-schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nature Neuroscience 13, 327-332CrossRef Google Scholar PubMed

156Hirohashi, Y. et al. (2006) Centrosomal proteins Nde1 and Su48 form a complex regulated by phosphorylation. Oncogene 25, 6048-6055CrossRef Google Scholar

157Wang, Q. et al. (2006) Characterization of Su48, a centrosome protein essential for cell division. Proceedings of the National Academy of Sciences of the United States of America 103, 6512-6517CrossRef Google Scholar PubMed

158Kamiya, A. et al. (2008) Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses. Archives of General Psychiatry 65, 996-1006CrossRef Google Scholar

159Fukuda, T. et al. (2010) CAMDI, a novel disrupted in schizophrenia 1 (DISC1)-binding protein, is required for radial migration. Journal of Biological Chemistry 285, 40554-40561CrossRef Google Scholar PubMed

160Enomoto, A. et al. (2009) Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. Neuron 63, 774-787CrossRef Google Scholar PubMed

161Kim, J.Y. et al. (2009) DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron 63, 761-773CrossRef Google Scholar

162Bradshaw, N.J. et al. (2008) DISC1, PDE4B, and NDE1 at the centrosome and synapse. Biochemical and Biophysical Research Communications 377, 1091-1096CrossRef Google Scholar PubMed

163Brandon, N.J. et al. (2004) Disrupted in schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Molecular and Cellular Neurosciences 25, 42-55CrossRef Google Scholar

164Taya, S. et al. (2007) DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. Journal of Neuroscience 27, 15-26CrossRef Google Scholar PubMed

165Singh, K.K. et al. (2010) Dixdc1 is a critical regulator of DISC1 and embryonic cortical development. Neuron 67, 33-48CrossRef Google Scholar PubMed

166Toro, R. et al. (2010) Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends in Genetics 26, 363-372CrossRef Google Scholar PubMed

167van de Lagemaat, L.N. and Grant, S.G. (2010) Genome variation and complexity in the autism spectrum. Neuron 67, 8-10CrossRef Google Scholar PubMed

168Krabbendam, L. and van Os, J. (2005) Schizophrenia and urbanicity: a major environmental influence–conditional on genetic risk. Schizophrenia Bulletin 31, 795-799CrossRef Google Scholar

169van den Pol, A.N. (2009) Viral infection leading to brain dysfunction: more prevalent than appreciated? Neuron 64, 17-20CrossRef Google Scholar PubMed

170Yolken, R.H., Dickerson, F.B. and Fuller Torrey, E. (2009) Toxoplasma and schizophrenia. Parasite Immunology 31, 706-715CrossRef Google Scholar PubMed

171Henriquez, S.A. et al. (2009) Neuropsychiatric disease and Toxoplasma gondii infection. Neuroimmunomodulation 16, 122-133CrossRef Google Scholar PubMed

172Watanabe, Y., Someya, T. and Nawa, H. (2010) Cytokine hypothesis of schizophrenia pathogenesis: evidence from human studies and animal models. Psychiatry and Clinical Neurosciences 64, 217-230CrossRef Google Scholar PubMed

173Laan, W. et al. (2010) Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry 71, 520-527CrossRef Google Scholar PubMed

174Baranzini, S.E. (2009) The genetics of autoimmune diseases: a networked perspective. Current Opinion in Immunology 21, 596-605CrossRef Google Scholar PubMed

175Abazyan, B. et al. (2010) Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biological Psychiatry 68, 1172-1181CrossRef Google Scholar PubMed

176Ayhan, Y. et al. (2010) Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders. Molecular PsychiatryGoogle Scholar PubMed

177Ibi, D. et al. (2010) Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. Behavioural Brain Research 206, 32-37CrossRef Google Scholar PubMed

178Barrett, J.C. et al. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genetics 40, 955-962CrossRef Google Scholar PubMed

179Turnbull, C. et al. (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nature Genetics 42, 504-507CrossRef Google Scholar PubMed

180Boulanger, L.M. (2009) Immune proteins in brain development and synaptic plasticity. Neuron 64, 93-109CrossRef Google Scholar PubMed

181Kolluri, N. et al. (2005) Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. American Journal of Psychiatry 162, 1200-1202CrossRef Google Scholar PubMed

182Sweet, R.A. et al. (2009) Reduced dendritic spine density in auditory cortex of subjects with schizophrenia. Neuropsychopharmacology 34, 374-389CrossRef Google Scholar PubMed

183Glantz, L.A. and Lewis, D.A. (2001) Dendritic spine density in schizophrenia and depression. Archives of General Psychiatry 58, 203CrossRef Google Scholar PubMed

184Kempermann, G., Krebs, J. and Fabel, K. (2008) The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Current Opinion in Psychiatry 21, 290-295CrossRef Google Scholar PubMed

185Toro, C.T. and Deakin, J.F. (2007) Adult neurogenesis and schizophrenia: a window on abnormal early brain development? Schizophrenia Research 90, 1-14CrossRef Google Scholar PubMed

186Reif, A. et al. (2006) Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Molecular PsychiatryCrossRef Google Scholar PubMed

187Deng, W., Aimone, J.B. and Gage, F.H. (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nature Reviews. Neuroscience 11, 339-350CrossRef Google Scholar PubMed

188Marlatt, M.W. and Lucassen, P.J. (2010) Neurogenesis and Alzheimer's disease: biology and pathophysiology in mice and men. Current Alzheimer Research 7, 113-125CrossRef Google Scholar PubMed

189Vandenbosch, R. et al. (2009) Adult neurogenesis and the diseased brain. Current Medicinal Chemistry 16, 652-666CrossRef Google Scholar PubMed

190Kaneko, N. and Sawamoto, K. (2009) Adult neurogenesis and its alteration under pathological conditions. Neuroscience Research 63, 155-164CrossRef Google Scholar PubMed

191Sailor, K.A., Ming, G.L. and Song, H. (2006) Neurogenesis as a potential therapeutic strategy for neurodegenerative diseases. Expert Opinion on Biological Therapy 6, 879-890CrossRef Google Scholar PubMed

192Steiner, B., Wolf, S. and Kempermann, G. (2006) Adult neurogenesis and neurodegenerative disease. Regenerative Medicine 1, 15-28CrossRef Google Scholar PubMed

193Hikida, T. et al. (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proceedings of the National Academy of Sciences of the United States of America 104, 14501-14506CrossRef Google Scholar PubMed

194Kvajo, M. et al. (2008) A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proceedings of the National Academy of Sciences of the United States of America 105, 7076-7081CrossRef Google Scholar PubMed

195Pletnikov, M.V. et al. (2008) Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Molecular Psychiatry 13, 173-186, 115CrossRef Google Scholar PubMed

196Pletnikov, M.V. et al. (2008) Enlargement of the lateral ventricles in mutant DISC1 transgenic mice. Molecular Psychiatry 13, 115CrossRef Google Scholar PubMed

197Shen, S. et al. (2008) Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. Journal of Neuroscience 28, 10893-10904CrossRef Google Scholar PubMed

198Fournier, N.M., Caruncho, H.J. and Kalynchuk, L.E. (2009) Decreased levels of disrupted-in-schizophrenia 1 (DISC1) are associated with expansion of the dentate granule cell layer in normal and kindled rats. Neuroscience Letters 455, 134-139CrossRef Google Scholar PubMed

199Meyer, K.D. and Morris, J.A. (2009) Disc1 regulates granule cell migration in the developing hippocampus. Human Molecular GeneticsCrossRef Google Scholar PubMed

200Ming, G.L. and Song, H. (2009) DISC1 partners with GSK3beta in neurogenesis. Cell 136, 990-992CrossRef Google Scholar PubMed

201Duan, X. et al. (2007) Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130, 1146-1158CrossRef Google Scholar PubMed

202Pieper, A.A. et al. (2005) The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. Proceedings of the National Academy of Sciences of the United States of America 102, 14052-14057CrossRef Google Scholar PubMed

203Brunskill, E.W. et al. (2005) Abnormal neurodevelopment, neurosignaling and behaviour in Npas3-deficient mice. European Journal of Neuroscience 22, 1265-1276CrossRef Google Scholar PubMed

204Erbel-Sieler, C. et al. (2004) Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors. Proceedings of the National Academy of Sciences of the United States of America 101, 13648-13653CrossRef Google Scholar PubMed

205Pieper, A.A. et al. (2010) Discovery of a proneurogenic, neuroprotective chemical. Cell 142, 39-51CrossRef Google Scholar PubMed

206Nica, A.C. et al. (2010) Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genetics 6, e1000895CrossRef Google Scholar PubMed

207Nica, A.C. and Dermitzakis, E.T. (2008) Using gene expression to investigate the genetic basis of complex disorders. Human Molecular Genetics 17, R129-R134CrossRef Google Scholar PubMed

208Geschwind, D.H. and Konopka, G. (2009) Neuroscience in the era of functional genomics and systems biology. Nature 461, 908-915CrossRef Google Scholar PubMed

209Veyrieras, J.B. et al. (2008) High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genetics 4, e1000214CrossRef Google Scholar PubMed

210Gilad, Y., Rifkin, S.A. and Pritchard, J.K. (2008) Revealing the architecture of gene regulation: the promise of eQTL studies. Trends in Genetics 24, 408-415CrossRef Google Scholar PubMed

211Hennah, W. and Porteous, D. (2009) The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS One 4, e4906CrossRef Google Scholar PubMed

212Richards, A.L. et al. (2011) Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain. Molecular Psychiatry, 2011 February 22 [Epub ahead of print]Google Scholar PubMed

213Chamberlain, S.J., Li, X.J. and Lalande, M. (2008) Induced pluripotent stem (iPS) cells as in vitro models of human neurogenetic disorders. Neurogenetics 9, 227-235CrossRef Google Scholar PubMed

214Brennand, K.J. et al. (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221-225CrossRef Google Scholar PubMed

215Chiang, C.H. et al. (2011) Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Molecular Psychiatry 16, 358-360CrossRef Google Scholar PubMed

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Progress in defining the biological causes of schizophrenia

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Progress in defining the biological causes of schizophrenia

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