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Analysis of HapMap tag-SNPs in dysbindin (DTNBP1) reveals evidence of consistent association with schizophrenia

Published online by Cambridge University Press:  16 April 2020

J. Voisey ,
C.D. Swagell ,
I.P. Hughes ,
B.R. Lawford ,
R.M. Young  and
C.P. Morris
J. Voisey
Affiliation:
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
C.D. Swagell
Affiliation:
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
I.P. Hughes
Affiliation:
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
B.R. Lawford
Affiliation:
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia Division of Mental Health, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
R.M. Young
Affiliation:
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
C.P. Morris*
Affiliation:
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
*
*Corresponding author. Tel.: +61 7 31386196; fax: +61 7 31386030. E-mail address: p.morris@qut.edu.au (C.P. Morris).
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Abstract

Dystrobrevin binding protein 1 (DTNBP1), or dysbindin, is thought to be critical in regulating the glutamatergic system. While the dopamine pathway is known to be important in the aetiology of schizophrenia, it seems likely that glutamatergic dysfunction can lead to the development of schizophrenia. DTNBP1 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and a DTNBP1 polymorphism has been associated with reduced brain expression. Despite numerous genetic studies no DTNBP1 polymorphism has been strongly implicated in schizophrenia aetiology. Using a haplotype block-based gene-tagging approach we genotyped 13 SNPs in DTNBP1 to investigate possible associations with DTNBP1 and schizophrenia. Four polymorphisms were found to be significantly associated with schizophrenia. The strongest association was found with an A/C SNP in intron 7 (rs9370822). Homozygotes for the C allele of rs9370822 were more than two and a half times as likely to have schizophrenia compared to controls. The other polymorphisms showed much weaker association and are less likely to be biologically significant. These results suggest that DTNBP1 is a good candidate for schizophrenia risk and rs9370822 is either functionally important or in disequilibrium with a functional SNP, although our observations should be viewed with caution until they are independently replicated.

Keywords

Schizophrenia and psychosisGeneticsMolecular biologyPolymorphismGenetic associationGlutamatergic pathwayDystrobrevin binding protein 1
Type
Psychiatric Genetics
Information
European Psychiatry , Volume 25 , Issue 6 , October 2010 , pp. 314 - 319
Copyright
Copyright © Elsevier Masson SAS 2010

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References

Abramson, JHWINPEPI (PEPI-for-Windows): computer programs for epidemiologists. Epidemiol Perspect Innov 2004;1:6.CrossRefGoogle ScholarPubMed
Benjamini, Y, Hochberg, YControlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc 1995;57:289–300. Series BGoogle Scholar
Benson, MA, Newey, SE, Martin-Rendon, E, Hawkes, R, Blake, DJ, Dysbindin, a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain. J Biol Chem 2001;276:24232–24241.CrossRefGoogle ScholarPubMed
Betcheva, ET, Mushiroda, T, Takahashi, A, Kubo, M, Karachanak, SK, Zaharieva, ITet al.Case-control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population. J Hum Genet 2009;54:98–107.CrossRefGoogle ScholarPubMed
Bhardwaj, SK, Baharnoori, M, Sharif-Askari, B, Kamath, A, Williams, S, Srivastava, LKBehavioral characterization of dysbindin-1 deficient sandy mice. Behav Brain Res 2009;197:435–441.CrossRefGoogle ScholarPubMed
Bray, NJ, Preece, A, Williams, NM, Moskvina, V, Buckland, PR, Owen, MJet al.Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 2005;14:1947–1954.CrossRefGoogle ScholarPubMed
Cardno, AG, Marshall, EJ, Coid, B, Macdonald, AM, Ribchester, TR, Davies, NJet al.Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999;56:162–168.CrossRefGoogle ScholarPubMed
Cox, MM, Tucker, AM, Tang, J, Talbot, K, Richer, DC, Yeh, Let al.Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background. Genes Brain Behav 2009;8:390–397.CrossRefGoogle ScholarPubMed
Datta, SR, McQuillin, A, Puri, V, Choudhury, K, Thirumalai, S, Lawrence, Jet al.Failure to confirm allelic and haplotypic association between markers at the chromosome 6p22.3 dystrobrevin-binding protein 1 (DTNBP1) locus and schizophrenia. Behav Brain Funct 2007;3:50.CrossRefGoogle Scholar
Duan, J, Martinez, M, Sanders, AR, Hou, C, Burrell, GJ, Krasner, AJet al.DTNBP1 (Dystrobrevin binding protein 1) and schizophrenia: association evidence in the 3’ end of the gene. Hum Hered 2007;64:97–106.CrossRefGoogle ScholarPubMed
Fallin, MD, Lasseter, VK, Avramopoulos, D, Nicodemus, KK, Wolyniec, PS, McGrath, JAet al.Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet 2005;77:918–936.CrossRefGoogle ScholarPubMed
Feng, YQ, Zhou, ZY, He, X, Wang, H, Guo, XL, Hao, CJet al.Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia. Schizophr Res 2008;106:218–228.CrossRefGoogle Scholar
Frazer, KA, Ballinger, DG, Cox, DR, Hinds, DA, Stuve, LL, Gibbs, RAet al.A second generation human haplotype map of over 3.1 million SNPs. Nature 2007;449:851–861.Google ScholarPubMed
Funke, B, Finn, CT, Plocik, AM, Lake, S, DeRosse, P, Kane, JMet al.Association of the DTNBP1 locus with schizophrenia in a U.S. population. Am J Hum Genet 2004;75:891–898.CrossRefGoogle Scholar
Hattori, S, Murotani, T, Matsuzaki, S, Ishizuka, T, Kumamoto, N, Takeda, Met al.Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Biochem Biophys Res Commun 2008;373:298–302.CrossRefGoogle Scholar
Holliday, EG, Handoko, HY, James, MR, McGrath, JJ, Nertney, DA, Tirupati, Set al.Association study of the dystrobrevin-binding gene with schizophrenia in Australian and Indian samples. Twin Res Hum Genet 2006;9:531–539.CrossRefGoogle ScholarPubMed
Iizuka, Y, Sei, Y, Weinberger, DR, Straub, REEvidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. J Neurosci 2007;27:12390–12395.CrossRefGoogle Scholar
Kirov, G, Ivanov, D, Williams, NM, Preece, A, Nikolov, I, Milev, Ret al.Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria. Biol Psychiatry 2004;55:971–975.CrossRefGoogle ScholarPubMed
Lang, UE, Puls, I, Muller, DJ, Strutz-Seebohm, N, Gallinat, JMolecular mechanisms of schizophrenia. Cell Physiol Biochem 2007;20:687–702.CrossRefGoogle ScholarPubMed
Li, D, He, LAssociation study between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia: a meta-analysis. Schizophr Res 2007;96:112–118.CrossRefGoogle ScholarPubMed
Li, T, Zhang, F, Liu, X, Sun, X, Sham, PC, Crombie, Cet al.Identifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations. Mol Psychiatry 2005;10:1037–1044.CrossRefGoogle Scholar
Lichtenstein, P, Yip, BH, Bjork, C, Pawitan, Y, Cannon, TD, Sullivan, PFet al.Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009;373:234–239.CrossRefGoogle ScholarPubMed
Moises, HW, Yang, L, Kristbjarnarson, H, Wiese, C, Byerley, W, Macciardi, Fet al.An international two-stage genome-wide search for schizophrenia susceptibility genes. Nat Genet 1995;11:321–324.CrossRefGoogle ScholarPubMed
Morris, DW, McGhee, KA, Schwaiger, S, Scully, P, Quinn, J, Meagher, Det al.No evidence for association of the dysbindin gene [DTNBP1] with schizophrenia in an Irish population-based study. Schizophr Res 2003;60:167–172.CrossRefGoogle Scholar
Mutsuddi, M, Morris, DW, Waggoner, SG, Daly, MJ, Scolnick, EM, Sklar, PAnalysis of high-resolution HapMap of DTNBP1 (Dysbindin) suggests no consistency between reported common variant associations and schizophrenia. Am J Hum Genet 2006;79:903–909.CrossRefGoogle Scholar
Numakawa, T, Yagasaki, Y, Ishimoto, T, Okada, T, Suzuki, T, Iwata, Net al.Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 2004;13:2699–2708.CrossRefGoogle Scholar
Ott, JUtility programs for analysis of genetic linkage. Program. HWE version 1.10. New York: Columbia University; 1988.Google Scholar
Owen, MJ, Williams, NM, O’Donovan, MCDysbindin-1 and schizophrenia: from genetics to neuropathology. J Clin Invest 2004;113:1255–1257.CrossRefGoogle ScholarPubMed
Pae, CU, Mandelli, L, De Ronchi, D, Kim, JJ, Jun, TY, Patkar, AAet al.Dysbindin gene (DTNBP1) and schizophrenia in Korean population. Eur Arch Psychiatry Clin Neurosci 2009;259:137–142.CrossRefGoogle ScholarPubMed
Patil, ST, Zhang, L, Martenyi, F, Lowe, SL, Jackson, KA, Andreev, BV, et al.Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 2007;13(10):1264.CrossRefGoogle ScholarPubMed
Peralta, V, Cuesta, MJPsychometric properties of the positive and negative syndrome scale (PANSS) in schizophrenia. Psychiatry Res 1994;53:31–40.CrossRefGoogle Scholar
Peters, K, Wiltshire, S, Henders, AK, Dragovic, M, Badcock, JC, Chandler, Det al.Comprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes. Am J Med Genet B Neuropsychiatr Genet 147B 2008 1159–1166.CrossRefGoogle ScholarPubMed
Peters, K, Wiltshire, S, Henders, AK, Dragovic, M, Badcock, JC, Chandler, Det al.Comprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes. Am J Med Genet 147B 2008 1159–1166. Part BCrossRefGoogle ScholarPubMed
Riley, B, Kendler, KSMolecular genetic studies of schizophrenia. Eur J Hum Genet 2006;14:669–680.CrossRefGoogle ScholarPubMed
Sanders, AR, Duan, J, Levinson, DF, Shi, J, He, D, Hou, Cet al.No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry 2008;165:497–506.CrossRefGoogle Scholar
Schwab, SG, Knapp, M, Mondabon, S, Hallmayer, J, Borrmann-Hassenbach, M, Albus, Met al.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 2003;72:185–190.CrossRefGoogle Scholar
Straub, RE, Jiang, Y, MacLean, CJ, Ma, Y, Webb, BT, Myakishev, MVet al.Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002;71:337–348.CrossRefGoogle ScholarPubMed
Sullivan, PF, Kendler, KS, Neale, MCSchizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003;60:1187–1192.CrossRefGoogle ScholarPubMed
Takao, K, Toyama, K, Nakanishi, K, Hattori, S, Takamura, H, Takeda, Met al.Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Mol Brain 2008;1:11.CrossRefGoogle Scholar
Talbot, K, Eidem, WL, Tinsley, CL, Benson, MA, Thompson, EW, Smith, RJet al.Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 2004;113:1353–1363.CrossRefGoogle Scholar
Tang, JX, Zhou, J, Fan, JB, Li, XW, Shi, YY, Gu, NFet al.Family-based association study of DTNBP1 in 6p22.3 and schizophrenia. Mol Psychiatry 2003;8:717–718.CrossRefGoogle Scholar
Tochigi, M, Zhang, X, Ohashi, J, Hibino, H, Otowa, T, Rogers, Met al.Association study of the dysbindin (DTNBP1) gene in schizophrenia from the Japanese population. Neurosci Res 2006;56:154–158.CrossRefGoogle ScholarPubMed
Tosato, S, Ruggeri, M, Bonetto, C, Bertani, M, Marrella, G, Lasalvia, Aet al.Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients. Am J Med Genet B Neuropsychiatr Genet 2007;144B:647–659.CrossRefGoogle Scholar
Van Den Bogaert, A, Schumacher, J, Schulze, TG, Otte, AC, Ohlraun, S, Kovalenko, Set al.The DTNBP1 (dysbindin) gene contributes to schizophrenia, depending on family history of the disease. Am J Hum Genet 2003;73:1438–1443.CrossRefGoogle ScholarPubMed
van den Oord, EJ, Sullivan, PF, Jiang, Y, Walsh, D, O’Neill, FA, Kendler, KSet al.Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families. Mol Psychiatry 2003;8:499–510.CrossRefGoogle ScholarPubMed
Vilella, E, Costas, J, Sanjuan, J, Guitart, M, De Diego, Y, Carracedo, Aet al.Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. J Psychiatr Res 2008;42:278–288.CrossRefGoogle Scholar
Wang, S, Sun, CE, Walczak, CA, Ziegle, JS, Kipps, BR, Goldin, LRet al.Evidence for a susceptibility locus for schizophrenia on chromosome 6pter-p22. Nat Genet 1995;10:41–46.CrossRefGoogle ScholarPubMed
Weickert, CS, Straub, RE, McClintock, BW, Matsumoto, M, Hashimoto, R, Hyde, TMet al.Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 2004;61:544–555.CrossRefGoogle ScholarPubMed
Weickert, CS, Rothmond, DA, Hyde, TM, Kleinman, JE, Straub, REReduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res 2008;98:105–110.CrossRefGoogle ScholarPubMed
Williams, NM, Preece, A, Morris, DW, Spurlock, G, Bray, NJ, Stephens, Met al.Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1). Arch Gen Psychiatry 2004;61:336–344.CrossRefGoogle Scholar
Wood, LS, Pickering, EH, Dechairo, BMSignificant support for DAO as a schizophrenia susceptibility locus: examination of five genes putatively associated with schizophrenia. Biol Psychiatry 2007;61:1195–1199.CrossRefGoogle ScholarPubMed
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