Abstract
In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case–control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182–1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485–0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the ‘glutamate hypothesis’ of psychotic illness.
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References
MacIntyre DJ, Blackwood DH, Porteous DJ, Pickard BS, Muir WJ . Chromosomal abnormalities and mental illness. Mol Psychiatry 2003; 8: 275–287.
Nielsen J, Wohlert M . Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet 1991; 87: 81–83.
Pickard BS, Millar JK, Porteous DJ, Muir WJ, Blackwood DH . Cytogenetics and gene discovery in psychiatric disorders. Pharmacogenomics J 2005; 5: 81–88.
Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ . Schizophrenia and affective disorders – cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 2001; 69: 428–433.
St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 1990; 336: 13–16.
Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423.
Millar JK, Christie S, Anderson S, Lawson D, Hsiao-Wei Loh D, Devon RS et al. Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry 2001; 6: 173–178.
Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001; 10: 1611–1617.
Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J et al. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 2003; 12: 3151–3159.
Gejman PV, Martinez M, Cao Q, Friedman E, Berrettini WH, Goldin LR et al. Linkage analysis of fifty-seven microsatellite loci to bipolar disorder. Neuropsychopharmacology 1993; 9: 31–40.
Hwu HG, Liu CM, Fann CS, Ou-Yang WC, Lee SF . Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry 2003; 8: 445–452.
Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O'Neill J, Smyth C et al. Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23–q24, and suggests the presence of additional loci on 1p and 1q. Psychiatr Genet 2003; 13: 77–84.
Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signalling. Science 2005; 310: 1187–1191.
Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW . Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J Med Genet 2003; 40: 325–332.
Pickard BS, Malloy MP, Porteous DJ, Blackwood DH, Muir WJ . Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability. Am J Med Genet B Neuropsychiatr Genet 2005; 136: 26–32.
Gecz J, Barnett S, Liu J, Hollway G, Donnelly A, Eyre H et al. Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation. Genomics 1999; 62: 356–368.
Baysal BE, Willett-Brozick JE, Badner JA, Corona W, Ferrell RE, Nimgaonkar VL et al. A mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family. Neurogenetics 2002; 4: 43–53.
Doody GA, Johnstone EC, Sanderson TL, Owens DG, Muir WJ . ‘Pfropfschizophrenie’ revisited: schizophrenia in people with mild learning disability. Br J Psychiat 1998; 173: 145–153.
Sanderson TL, Best JJ, Doody GA, Owens DG, Johnstone EC . Neuroanatomy of comorbid schizophrenia and learning disability: a controlled study. Lancet 1999; 354: 1867–1871.
Wing JK, Ustun TB, Sartorius N (eds) Diagnosis and Clinical Measurement in Psychiatry: A Reference Manual for Scan/PSE-10. Cambridge University Press: Cambridge, 1998.
Endicott J, Spitzer RL . A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiat 1978; 35: 837–844.
Carvill S . Sensory impairments, intellectual disability and psychiatry. J Intellect Disabil Res 2001; 45: 467–483.
Breen M, Arveiler B, Murray I, Gosden JR, Porteous DJ . YAC mapping by FISH using Alu-PCR-generated probes. Genomics 1992; 13: 726–730.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Thomson PA, Wray NR, Millar JK, Evans KL, Le Hellard S, Condie A et al. Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Mol Psychiatry 2005; 10: 657–668.
Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.
Churchill GA, Doerge RW . Empirical threshold values for quantitative trait mapping. Genetics 1994; 138: 963–971.
Imoto I, Sonoda I, Yuki Y, Inazawa J . Identification and characterization of human PKNOX2, a novel homeobox-containing gene. Biochem Biophys Res Commun 2001; 287: 270–276.
Haller K, Rambaldi I, Kovacs EN, Daniels E, Featherstone M . Prep2: cloning and expression of a new prep family member. Dev Dyn 2002; 225: 358–364.
Fognani C, Kilstrup-Nielsen C, Berthelsen J, Ferretti E, Zappavigna V, Blasi F . Characterization of PREP2, a paralog of PREP1, which defines a novel sub-family of the MEINOX TALE homeodomain transcription factors. Nucleic Acids Res 2002; 30: 2043–2051.
Villaescusa JC, Verrotti AC, Ferretti E, Farookhi R, Blasi F . Expression of Hox cofactor genes during mouse ovarian follicular development and oocyte maturation. Gene 2004; 330: 1–7.
Tuson M, Marfany G, Gonzalez-Duarte R . Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa RP26. Am J Hum Genet 2004; 74: 128–138.
Fallin D, Cohen A, Essioux L, Chumakov I, Blumenfeld M, Cohen D et al. Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer's disease. Genome Res 2001; 11: 143–151.
Werner P, Voigt M, Keinanen K, Wisden W, Seeburg PH . Cloning of a putative high-affinity kainate receptor expressed predominantly in hippocampal CA3 cells. Nature 1991; 351: 742–744.
Kamboj RK, Schoepp DD, Nutt S, Shekter L, Korczak B, True RA et al. Molecular cloning, expression, and pharmacological characterization of humEAA1, a human kainate receptor subunit. J Neurochem 1994; 62: 1–9.
Velagaleti GV, Bien-Willner GA, Northup JK, Lockhart LH, Hawkins JC, Jalal SM et al. Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am J Hum Genet 2005; 76: 652–662.
Kleinjan DA, van Heyningen V . Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet 2005; 76: 8–32.
Gribble SM, Prigmore E, Burford DC, Porter KM, Ng BL, Douglas EJ et al. The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes. J Med Genet 2005; 42: 8–16.
Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 2001; 68: 661–673.
McQueen MB, Devlin B, Faraone SV, Nimgaonkar VL, Sklar P, Smoller JW et al. Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility Loci on chromosomes 6q and 8q. Am J Hum Genet 2005; 77: 582–595.
Shibata H, Aramaki T, Sakai M, Ninomiya H, Tashiro N, Iwata N et al. Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia. Psychiat Res 2006; 141: 39–51.
Kohn Y, Lerer B . Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm. Mol Psychiatry 2005; 10: 1062–1073.
Wang WY, Barratt BJ, Clayton DG, Todd JA . Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005; 6: 109–118.
Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Hafner R et al. CARD15 mutations in Blau syndrome. Nat Genet 2001; 29: 19–20.
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599–603.
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411: 603–606.
Meirhaeghe A, Amouyel P . Impact of genetic variation of PPARgamma in humans. Mol Genet Metab 2004; 83: 93–102.
Goff DC, Wine L . Glutamate in schizophrenia: clinical and research implications. Schizophr Res 1997; 27: 157–168.
Javitt DC . Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004; 9: 984–997.
Ibrahim HM, Hogg AJ, Healy Jr DJ, Haroutunian V, Davis KL, Meador-Woodruff JH . Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. Am J Psychiat 2000; 157: 1811–1823.
Meador-Woodruff JH, Davis KL, Haroutunian V . Abnormal kainate receptor expression in prefrontal cortex in schizophrenia. Neuropsychopharmacology 2001; 24: 545–552.
Sokolov BP . 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. J Neurochem 1998; 71: 2454–2464.
Mohn AR, Gainetdinov RR, Caron MG, Koller BH . Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999; 98: 427–436.
Chittajallu R, Braithwaite SP, Clarke VR, Henley JM . Kainate receptors: subunits, synaptic localization and function. Trends Pharmacol Sci 1999; 20: 26–35.
Lerma J, Paternain AV, Rodriguez-Moreno A, Lopez-Garcia JC . Molecular physiology of kainate receptors. Physiol Rev 2001; 81: 971–998.
Antonova E, Sharma T, Morris R, Kumari V . The relationship between brain structure and neurocognition in schizophrenia: a selective review. Schizophr Res 2004; 70: 117–145.
Miller S, Mayford M . Cellular and molecular mechanisms of memory: the LTP connection. Curr Opin Genet Dev 1999; 9: 333–337.
Martin SJ, Grimwood PD, Morris RG . Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 2000; 23: 649–711.
Abel T, Lattal KM . Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr Opin Neurobiol 2001; 11: 180–187.
Kuperberg G, Heckers S . Schizophrenia and cognitive function. Curr Opin Neurobiol 2000; 10: 205–210.
Elvevag B, Goldberg TE . Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol 2000; 14: 1–21.
Blackwood DH, Glabus MF, Dunan J, O'Carroll RE, Muir WJ, Ebmeier KP . Altered cerebral perfusion measured by SPECT in relatives of patients with schizophrenia. Correlations with memory and P300. Br J Psychiat 1999; 175: 357–366.
Contractor A, Swanson G, Heinemann SF . Kainate receptors are involved in short- and long-term plasticity at mossy fiber synapses in the hippocampus. Neuron 2001; 29: 209–216.
Lauri SE, Bortolotto ZA, Bleakman D, Ornstein PL, Lodge D, Isaac JT et al. A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP. Neuron 2001; 32: 697–709.
Acknowledgements
We thank Judy Fantes, Maura Walker, Margaret van Beck, Paul Perry, Veronica van Heyningen and Western General Hospital Cytogenetics service for expert assistance and advice. We also wish to acknowledge the HGMP Resource Centre for the provision of YAC, Cosmid and IMAGE clones and gridded DNA libraries. This work was supported by a collaborative research agreement with Merck, Sharp and Dohme (The Neuroscience Research Centre, Terlings Park, UK), SHERT Grant RG45/01, Wellcome Trust ‘Genes to Cognition’ grant and CSO Grant K/MRS/50/C2789. Part of the patient sample collection was supported by a grant from the State Hospital for Scotland at Carstairs.
The authors declare that there are no conflicts of interest.
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Pickard, B., Malloy, M., Christoforou, A. et al. Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. Mol Psychiatry 11, 847–857 (2006). https://doi.org/10.1038/sj.mp.4001867
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DOI: https://doi.org/10.1038/sj.mp.4001867
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