Brain Structure and Function

, Volume 213, Issue 1–2, pp 255–271 | Cite as

Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex

  • Carlo Colantuoni
  • Thomas M. Hyde
  • Shruti Mitkus
  • Andrew Joseph
  • Leah Sartorius
  • Claudia Aguirre
  • Johanna Creswell
  • Elizabeth Johnson
  • Amy Deep-Soboslay
  • Mary M. Herman
  • Barbara K. Lipska
  • Daniel R. Weinberger
  • Joel E. Kleinman
Original Article

Abstract

The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann’s area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18–67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at http://www.ncbi.nlm.nih.gov/geo/ (accession #: TBA).

Keywords

Aging Disease onset Schizophrenia Gene expression Susceptibility Postmortem Prefrontal cortex 

Notes

Acknowledgments

This research was supported by funding solely provided by the Intramural Research Program of the National Institute of Mental Health. The authors would also like to thank Llewellyn B. Bigelow, MD., Vesna Imamovic, Yeva Snitkovsky, and Jewell King for their contributions to the collection and diagnosis of the brain specimens used in this research, the Offices of the Chief Medical Examiner of Washington DC and of Northern Virginia, as well as families of the deceased whose donation of this tissue made this research possible.

Disclosure/Conflicts of interest statement

We, the authors declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

References

  1. Addington AM, Gornick M, Duckworth J, Sporn A, Gogtay N, Bobb A, Greenstein D, Lenane M, Gochman P, Baker N, Balkissoon R, Vakkalanka RK, Weinberger DR, Rapoport JL, Straub RE (2005) GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry 10(6):581–588PubMedCrossRefGoogle Scholar
  2. Albert KA, Hemmings HC Jr, Adamo AI, Potkin SG, Akbarian S, Sandman CA, Cotman CW, Bunney WE Jr, Greengard P (2002) Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia. Arch Gen Psychiatry 59(8):705–712PubMedCrossRefGoogle Scholar
  3. Alda M, Ahrens B, Lit W, Dvorakova M, Labelle A, Zvolsky P, Jones B (1996) Age of onset in familial and sporadic schizophrenia. Acta Psychiatr Scand 93(6):447–450PubMedCrossRefGoogle Scholar
  4. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215(3):403–410PubMedGoogle Scholar
  5. Angermeyer MC, Kuhn L (1988) Gender differences in age at onset of schizophrenia. An overview. Eur Arch Psychiatry Neurol Sci 237(6):351–364PubMedCrossRefGoogle Scholar
  6. Badner JA, Gershon ES (2002) Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 7(4):405–411PubMedCrossRefGoogle Scholar
  7. Barnea-Goraly N, Menon V, Eckert M, Tamm L, Bammer R, Karchemskiy A, Dant CC, Reiss AL (2005) White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study. Cereb Cortex 15(12):1848–1854PubMedCrossRefGoogle Scholar
  8. Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B, Camargo LM, Oliver KR, Beher D, Shearman MS, Whiting PJ (2004) Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci 25(1):42–55PubMedCrossRefGoogle Scholar
  9. Brzustowicz LM, Simone J, Mohseni P, Hayter JE, Hodgkinson KA, Chow EW, Bassett AS (2004) Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22. Am J Hum Genet 74(5):1057–1063PubMedCrossRefGoogle Scholar
  10. Buonanno A, Fischbach GD (2001) Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol 11:287–296PubMedCrossRefGoogle Scholar
  11. Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR (2005) Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 102(24):8627–8632PubMedCrossRefGoogle Scholar
  12. Cardno AG, Gottesman II (2000) Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 97(1):12–17PubMedCrossRefGoogle Scholar
  13. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75(5):807–821PubMedCrossRefGoogle Scholar
  14. Chen Q, He G, Chen Q, Wu S, Xu Y, Feng G, Li Y, Wang L, He L (2005) A case–control study of the relationship between the metabotropic glutamate receptor 3 gene and schizophrenia in the Chinese population. Schizophr Res 73(1):21–26PubMedCrossRefGoogle Scholar
  15. Chowdari KV, Mirnics K, Semwal P, Wood J, Lawrence E, Bhatia T, Deshpande SN, Thelma BK, Ferrell RE, Middleton FA, Devlin B, Levitt P, Lewis DA, Nimgaonkar VL (2002) Association and linkage analyses of RGS4 polymorphisms in schizophrenia. Hum Mol Genet 11(12):1373–1380PubMedCrossRefGoogle Scholar
  16. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard FP, Maurice K, Essioux L, Millasseau P, Grel P, Debailleul V, Simon AM, Caterina D, Dufaure I, Malekzadeh K, Belova M, Luan JJ, Bouillot M, Sambucy JL, Primas G, Saumier M, Boubkiri N, Martin-Saumier S, Nasroune M, Peixoto H, Delaye A, Pinchot V, Bastucci M, Guillou S, Chevillon M, Sainz-Fuertes R, Meguenni S, Aurich-Costa J, Cherif D, Gimalac A, Van Duijn C, Gauvreau D, Ouellette G, Fortier I, Raelson J, Sherbatich T, Riazanskaia N, Rogaev E, Raeymaekers P, Aerssens J, Konings F, Luyten W, Macciardi F, Sham PC, Straub RE, Weinberger DR, Cohen N, Cohen D (2002) Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 99(21):13675–13680PubMedCrossRefGoogle Scholar
  17. Colantuoni C, Henry G, Zeger S, Pevsner J (2002) SNOMAD (Standardization and NOrmalization of MicroArray Data): web-accessible gene expression data analysis. Bioinformatics 18(11):1540–1541PubMedCrossRefGoogle Scholar
  18. Corfas G, Roy K, Buxbaum JD (2004) Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci 7(6):575–580PubMedCrossRefGoogle Scholar
  19. Corvin AP, Morris DW, McGhee K, Schwaiger S, Scully P, Quinn J, Meagher D, Clair DS, Waddington JL, Gill M (2004) Confirmation and refinement of an “at-risk” haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus. Mol Psychiatry 9(2):208–213PubMedCrossRefGoogle Scholar
  20. DeLisi LE (1992) The significance of age of onset for schizophrenia. Schizophr Bull 18(2):209–215PubMedGoogle Scholar
  21. Dubertret C, Hanoun N, Ades J, Hamon M, Gorwood P (2005) Family-based association study of the 5-HT transporter gene and schizophrenia. Int J Neuropsychopharmacol 8(1):87–92PubMedCrossRefGoogle Scholar
  22. Eberwine J, Yeh H, Miyashiro K, Cao Y, Nair S, Finnell R, Zettel M, Coleman P (1992) Analysis of gene expression in single live neurons. Proc Natl Acad Sci USA 89(7):3010–3014PubMedCrossRefGoogle Scholar
  23. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98(12):6917–6922PubMedCrossRefGoogle Scholar
  24. Egan MF, Weinberger DR, Lu B (2003) Schizophrenia, III: brain-derived neurotropic factor and genetic risk. Am J Psychiatry 160(7):1242PubMedCrossRefGoogle Scholar
  25. Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, Mattay VS, Bertolino A, Hyde TM, Shannon-Weickert C, Akil M, Crook J, Vakkalanka RK, Balkissoon R, Gibbs RA, Kleinman JE, Weinberger DR (2004) Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc Natl Acad Sci USA 101(34):12604–12609PubMedCrossRefGoogle Scholar
  26. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36(2):131–137PubMedCrossRefGoogle Scholar
  27. Falcon-Perez JM, Starcevic M, Gautam R, Dell’Angelica EC (2002) BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules. J Biol Chem 277(31):28191–28199PubMedCrossRefGoogle Scholar
  28. Freedman R, Leonard S, Gault JM, Hopkins J, Cloninger CR, Kaufmann CA, Tsuang MT, Farone SV, Malaspina D, Svrakic DM, Sanders A, Gejman P (2001) Linkage disequilibrium for schizophrenia at the chromosome 15q13–14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J Med Genet 105(1):20–22PubMedCrossRefGoogle Scholar
  29. Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y (2003) Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia. Psychiatr Genet 13(2):71–76PubMedCrossRefGoogle Scholar
  30. Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M, Tonegawa S (2003) Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci USA 100(15):8993–8998PubMedCrossRefGoogle Scholar
  31. Gottesman II, Shields J (1967) A polygenic theory of schizophrenia. Proc Natl Acad Sci USA 58(1):199–205PubMedCrossRefGoogle Scholar
  32. Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD, Haroutunian V, Fienberg AA (2001) Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 98:4746–4751PubMedCrossRefGoogle Scholar
  33. Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J, Parker A, Martin R, Levitzky S, Partonen T, Meyer J, Lonnqvist J, Peltonen L, Ekelund J (2003) Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 12(23):3151–3159PubMedCrossRefGoogle Scholar
  34. Hafner H, an der Heiden W (1997) Epidemiology of schizophrenia. Can J Psychiatry 42(2):139–151PubMedGoogle Scholar
  35. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23(17):6690–6694PubMedGoogle Scholar
  36. Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10(1):40–68PubMedCrossRefGoogle Scholar
  37. Hoogendoorn B, Coleman SL, Guy CA, Smith SK, O’Donovan MC, Buckland PR (2004) Functional analysis of polymorphisms in the promoter regions of genes on 22q11. Hum Mutat 24(1):35–42PubMedCrossRefGoogle Scholar
  38. Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y, Inada T, Ozaki N (2004) Association of AKT1 with schizophrenia confirmed in a Japanese population. Biol Psychiatry 56(9):698–700PubMedCrossRefGoogle Scholar
  39. Jayaswal SK, Adityanjee, Khandelwal SK (1988): Age of onset of schizophrenia. Br J Psychiatry. 152:428Google Scholar
  40. Kety SS, Rosenthal D, Wender PH, Schulsinger F, Jacobsen B (1976) Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic. Behav Genet 6:219–225PubMedCrossRefGoogle Scholar
  41. Korostishevsky M, Kaganovich M, Cholostoy A, Ashkenazi M, Ratner Y, Dahary D, Bernstein J, Bening-Abu-Shach U, Ben-Asher E, Lancet D, Ritsner M, Navon R (2004) Is the G72/G30 locus associated with schizophrenia? Single nucleotide polymorphisms, haplotypes, and gene expression analysis. Biol Psychiatry 56(3):169–176PubMedCrossRefGoogle Scholar
  42. Korostishevsky M, Kremer I, Kaganovich M, Cholostoy A, Murad I, Muhaheed M, Bannoura I, Rietschel M, Dobrusin M, Bening-Abu-Shach U, Belmaker RH, Maier W, Ebstein RP, Navon R (2005) Transmission disequilibrium and haplotype analyses of the G72/G30 locus: suggestive linkage to schizophrenia in Palestinian Arabs living in the North of Israel. Am J Med Genet B Neuropsychiatr Genet 141:91–95Google Scholar
  43. Kuhn K, Baker SC, Chudin E, Lieu MH, Oeser S, Bennett H, Rigault P, Barker D, McDaniel TK, Chee MS (2004) A novel, high-performance random array platform for quantitative gene expression profiling. Genome Res 14(11):2347–2356PubMedCrossRefGoogle Scholar
  44. Kunugi H, Vallada HP, Sham PC, Hoda F, Arranz MJ, Li T, Nanko S, Murray RM, McGuffin P, Owen M, Gill M, Collier DA (1997) Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 7(3):97–101PubMedCrossRefGoogle Scholar
  45. Larsen TK, McGlashan TH, Moe LC (1996) First-episode schizophrenia: I. Early course parameters. Schizophr Bull 122(2):241–256Google Scholar
  46. Lauriat TL, Dracheva S, Chin B, Schmeidler J, McInnes LA, Haroutunian V (2005) Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain. Neuroscience 137:843–851PubMedCrossRefGoogle Scholar
  47. Lazar NL, Rajakumar N, Cain DP (2008) Injections of NGF into neonatal frontal cortex decrease social interaction as adults: a rat model of schizophrenia. Schizophr Bull 34:127–136PubMedCrossRefGoogle Scholar
  48. Leung A, Chue P (2000) Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand Suppl 401:3–38PubMedCrossRefGoogle Scholar
  49. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV, Brzustowicz LM, Kaufmann CA, Garver DL, Gurling HM, Lindholm E, Coon H, Moises HW, Byerley W, Shaw SH, Mesen A, Sherrington R, O’Neill FA, Walsh D, Kendler KS, Ekelund J, Paunio T, Lonnqvist J, Peltonen L, O’Donovan MC, Owen MJ, Wildenauer DB, Maier W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy-Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet 73(1):34–48PubMedCrossRefGoogle Scholar
  50. Li T, Sham PC, Vallada H, Xie T, Tang X, Murray RM, Liu X, Collier DA (1996) Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatr Genet 6(3):131–133PubMedCrossRefGoogle Scholar
  51. Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC, Collier DA (2000) Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 5(1):77–84PubMedCrossRefGoogle Scholar
  52. Li W, Zhang Q, Oiso N, Novak EK, Gautam R, O’Brien EP, Tinsley CL, Blake DJ, Spritz RA, Copeland NG, Jenkins NA, Amato D, Roe BA, Starcevic M, Dell’Angelica EC, Elliott RW, Mishra V, Kingsmore SF, Paylor RE, Swank RT (2003) Hermansky–Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nat Genet 35(1):84–89PubMedCrossRefGoogle Scholar
  53. Li T, Ma X, Sham PC, Sun X, Hu X, Wang Q, Meng H, Deng W, Liu X, Murray RM, Collier DA (2004) Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population. Am J Med Genet B Neuropsychiatr Genet 129(1):13–15CrossRefGoogle Scholar
  54. Lipska BK, Mitkus S, Caruso M, Hyde TM, Chen J, Vakkalanka R, Straub RE, Weinberger DR, Kleinman JE (2006) RGS4 mRNA expression in postmortem human cortex is associated with COMT val158met genotype and COMT enzyme activity. Hum Mol Genet 15:2804–2812PubMedCrossRefGoogle Scholar
  55. Mallory FB (1961) Pathological technique. Hafner, New York, pp 158–180Google Scholar
  56. Marti SB, Cichon S, Propping P, Nothen M (2002) Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Am J Med Genet 114(1):46–50PubMedCrossRefGoogle Scholar
  57. Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310(5751):1187–1191PubMedCrossRefGoogle Scholar
  58. Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P (2001) Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry 6(3):293–301PubMedCrossRefGoogle Scholar
  59. Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, Fujita T, Kuroda S, Katayama T, Tohyama M (2003) Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 8(7):685–694PubMedCrossRefGoogle Scholar
  60. Morris JA, Kandpal G, Ma L, Austin CP (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. Hum Mol Genet 12(13):1591–1608PubMedCrossRefGoogle Scholar
  61. Morris DW, Rodgers A, McGhee KA, Schwaiger S, Scully P, Quinn J, Meagher D, Waddington JL, Gill M, Corvin AP (2004) Confirming RGS4 as a susceptibility gene for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 125(1):50–53CrossRefGoogle Scholar
  62. Nicodemus KK, Kolachana BS, Vakkalanka R, Straub RE, Giegling I, Egan MF, Rujescu D, Weinberger DR (2006) Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Hum Genet 120(6):889–906PubMedCrossRefGoogle Scholar
  63. Norton N, Moskvina V, Morris DW, Bray NJ, Zammit S, Williams NM, Williams HJ, Preece AC, Dwyer S, Wilkinson JC, Spurlock G, Kirov G, Buckland P, Waddington JL, Gill M, Corvin AP, Owen MJ, O’donovan MC (2005) Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. Am J Med Genet B Neuropsychiatr Genet 141:96–101Google Scholar
  64. Numakawa T, Yagasaki Y, Ishimoto T, Okada T, Suzuki T, Iwata N, Ozaki N, Taguchi T, Tatsumi M, Kamijima K, Straub RE, Weinberger DR, Kunugi H, Hashimoto R (2004) Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 13(21):2699–2708PubMedCrossRefGoogle Scholar
  65. Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC (1998) Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Brain Res Mol Brain Res 56(1–2):207–217PubMedCrossRefGoogle Scholar
  66. Ohnuma T, Tessler S, Arai H, Faull RL, McKenna PJ, Emson PC (2000) Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus. Brain Res Mol Brain Res 85(1–2):24–31PubMedCrossRefGoogle Scholar
  67. Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K, Okawa M, Yamada N, Hatten ME, Snyder SH, Ross CA, Sawa A (2003) Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA 100(1):289–294PubMedCrossRefGoogle Scholar
  68. Paus T, Zijdenbos A, Worsley K, Collins DL, Blumenthal J, Giedd JN, Rapoport JL, Evans AC (1999) Structural maturation of neural pathways in children and adolescents: in vivo study. Science 283(5409):1908–1911PubMedCrossRefGoogle Scholar
  69. Perlman WR, Tomaskovic-Crook E, Montague DM, Webster MJ, Rubinow DR, Kleinman JE, Weickert CS (2005) Alteration in estrogen receptor alpha mRNA levels in frontal cortex and hippocampus of patients with major mental illness. Biol Psychiatry 58:812–824PubMedCrossRefGoogle Scholar
  70. Prophet EB, Mills B, Arrington JB, Sobin LH (1992) Laboratory methods in histotechnology. American Registry of Pathology, Washington DCGoogle Scholar
  71. Rajakumar N, Leung LS, Ma J, Rajakumar B, Rushlow W (2004) Altered neurotrophin receptor function in the developing prefrontal cortex leads to adult-onset dopaminergic hyperresponsivity and impaired prepulse inhibition of acoustic startle. Biol Psychiatry 55:797–803PubMedCrossRefGoogle Scholar
  72. Rajkowska G, Goldman-Rakic PS (1995) Cytoarchitectonic definition of prefrontal areas in the normal human cortex: I. Remapping of areas 9 and 46 using quantitative criteria. Cereb Cortex 5:307–322PubMedCrossRefGoogle Scholar
  73. Schwab SG, Hoefgen B, Hanses C, Hassenbach MB, Albus M, Lerer B, Trixler M, Maier W, Wildenauer DB (2005) Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families. Biol Psychiatry 58(6):446–450PubMedCrossRefGoogle Scholar
  74. Schwab SG, Knapp M, Mondabon S, Hallmayer J, Borrmann-Hassenbach M, Albus M, Lerer B, Rietschel M, Trixler M, Maier W, Wildenauer DB (2003) Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. Am J Hum Genet 72(1):185–190PubMedCrossRefGoogle Scholar
  75. Schumacher J, Jamra RA, Freudenberg J, Becker T, Ohlraun S, Otte AC, Tullius M, Kovalenko S, Bogaert AV, Maier W, Rietschel M, Propping P, Nothen MM, Cichon S (2004) Examination of G72 and d-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. Mol Psychiatry 9(2):203–207PubMedCrossRefGoogle Scholar
  76. Semendeferi K, Armstrong E, Schleicher A, Zilles K, Van Hoesen GW (2001) Prefrontal cortex in humans and apes: a comparative study of area 10. Am J Phys Anthropol 114:224–241PubMedCrossRefGoogle Scholar
  77. Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A, Reznik I, Spivak B, Grisaru N, Karp L, Schiffer R, Kotler M, Strous RD, Swartz-Vanetik M, Knobler HY, Shinar E, Beckmann JS, Yakir B, Risch N, Zak NB, Darvasi A (2002) A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71(6):1296–1302PubMedCrossRefGoogle Scholar
  78. Smith RE, Haroutunian V, Davis KL, Meador-Woodruff JH (2001) Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia. Am J Psychiatry 158(9):1393–1399PubMedCrossRefGoogle Scholar
  79. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans HJ (1990) Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336(8706):13–16PubMedCrossRefGoogle Scholar
  80. Starcevic M, Dell’Angelica EC (2004) Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1). J Biol Chem 279(27):28393–401PubMedCrossRefGoogle Scholar
  81. Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E, Gunnarsdottir S, Walker N, Petursson H, Crombie C, Ingason A, Gulcher JR, Stefansson K, St Clair D (2002) Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 72(1):83–87PubMedCrossRefGoogle Scholar
  82. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K (2003) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71(4):877–892CrossRefGoogle Scholar
  83. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV, Harris-Kerr C, Wormley B, Sadek H, Kadambi B, Cesare AJ, Gibberman A, Wang X, O’Neill FA, Walsh D, Kendler KS (2002) Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 71:337–348PubMedCrossRefGoogle Scholar
  84. Straub RE, Lipska BK, Egan MF, Goldberg TE, Callicott JH, Mayhew MB, Vakkalanka RK, Kolachana BS, Kleinman JE, Weinberger DR (2007) Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol Psychiatry 12:854–869PubMedCrossRefGoogle Scholar
  85. 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
  86. Tamminga CA (1997) Gender and schizophrenia. J Clin Psychiatry 58(Suppl 15):33–37PubMedGoogle Scholar
  87. Tang JX, Chen WY, He G, Zhou J, Gu NF, Feng GY, He L (2004) Polymorphisms within 5′ end of the Neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population. Mol Psychiatry 9(1):11–12PubMedCrossRefGoogle Scholar
  88. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, Starkey M, Webster MJ, Yolken RH, Bahn S (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362:798–805PubMedCrossRefGoogle Scholar
  89. Webster MJ, Weickert CS, Herman MM, Kleinman JE (2002) BDNF mRNA expression during postnatal development, maturation and aging of the human prefrontal cortex. Dev Brain Res 139:139–150CrossRefGoogle Scholar
  90. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44(7):660–669PubMedGoogle Scholar
  91. Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, McCreadie RG, Buckland P, Sharkey V, Chowdari KV, Zammit S, Nimgaonkar V, Kirov G, Owen MJ, O’Donovan MC (2004) Support for RGS4 as a susceptibility gene for schizophrenia. Biol Psychiatry 55(2):192–195PubMedCrossRefGoogle Scholar
  92. Woo TU, Crowell AL (2005) Targeting synapses and myelin in the prevention of schizophrenia. Schizophr Res 73(2–3):193–207PubMedCrossRefGoogle Scholar
  93. Xu J, Pato MT, Torre CD, Medeiros H, Carvalho C, Basile VS, Bauer A, Dourado A, Valente J, Soares MJ, Macedo AA, Coelho I, Ferreira CP, Azevedo MH, Macciardi F, Kennedy JL, Pato CN (2001) Evidence for linkage disequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families. Am J Med Genet 105(8):669–674PubMedCrossRefGoogle Scholar
  94. Yamada K, Nakamura K, Minabe Y, Iwayama-Shigeno Y, Takao H, Toyota T, Hattori E, Takei N, Sekine Y, Suzuki K, Iwata Y, Miyoshi K, Honda A, Baba K, Katayama T, Tohyama M, Mori N, Yoshikawa T (2004) Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts. Biol Psychiatry 56(9):683–690PubMedCrossRefGoogle Scholar
  95. Yang JZ, Si TM, Ruan Y, Ling YS, Han YH, Wang XL, Zhou M, Zhang HY, Kong QM, Liu C, Zhang DR, Yu YQ, Liu SZ, Ju GZ, Shu L, Ma DL, Zhang D (2003) Association study of neuregulin 1 gene with schizophrenia. Mol Psychiatry 8(7):706–709PubMedCrossRefGoogle Scholar
  96. Zheng Y, Li H, Qin W, Chen W, Duan Y, Xiao Y, Li C, Zhang J, Li X, Feng G, He L (2005) Association of the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase gene with schizophrenia in the Chinese Han population. Biochem Biophys Res Commun 328(4):809–815PubMedCrossRefGoogle Scholar
  97. Zou F, Li C, Duan S, Zheng Y, Gu N, Feng G, Xing Y, Shi J, He L (2005) A family-based study of the association between the G72/G30 genes and schizophrenia in the Chinese population. Schizophr Res 73(2–3):257–261PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Carlo Colantuoni
    • 1
    • 2
    • 3
  • Thomas M. Hyde
    • 1
  • Shruti Mitkus
    • 1
  • Andrew Joseph
    • 1
  • Leah Sartorius
    • 1
  • Claudia Aguirre
    • 1
  • Johanna Creswell
    • 1
  • Elizabeth Johnson
    • 2
  • Amy Deep-Soboslay
    • 1
  • Mary M. Herman
    • 1
  • Barbara K. Lipska
    • 1
  • Daniel R. Weinberger
    • 1
  • Joel E. Kleinman
    • 1
  1. 1.Clinical Brain Disorders BranchGenes Cognition and Psychosis Program, IRP, NIMH, NIHBethesdaUSA
  2. 2.Department of BiostatisticsJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  3. 3.BaltimoreUSA

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