Skip to main content

Advertisement

Log in

An Association Study Between Genetic Polymorphisms in Functional Regions of Five Genes and the Risk of Schizophrenia

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Schizophrenia is a severe mental disorder that is likely to be strongly determined by genetic factors. To identify markers of disks, large homolog 2 (DLG2), FAT atypical cadherin 3 (FAT3), kinectin1 (KTN1), deleted in colorectal carcinoma (DCC), and glycogen synthase kinase-3β (GSK3β) that contribute to the genetic susceptibility to schizophrenia, we systematically screened for polymorphisms in the functional regions of these genes. A total of 22 functional single-nucleotide polymorphisms (SNPs) in 940 Chinese subjects were genotyped using SNaPshot. The results first suggested that the allelic and genotypic frequencies of the DCC polymorphism rs2229080 were nominally associated with schizophrenia. The patients were significantly less likely to be CC homozygous (P = 0.005, odds ratio [OR] = 0.635, 95 % confidence interval [95 % CI] = 0.462–0.873), and the schizophrenia subjects exhibited lower frequency of the C allele (P = 0.024, OR = 0.811, 95 % CI = 0.676–0.972). Regarding GSK3β, there was a significant difference in genotype distribution of rs3755557 between schizophrenia and healthy control subjects (P = 0.009). The patients exhibited a significantly lower frequency of the T allele of rs3755557 (P = 0.002, OR = 0.654, 95 % CI = 0.498–0.860). Our results point to the polymorphisms of DCC and GSK3β as contributors to the genetic basis of individual differences in the susceptibility to schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig 1

Similar content being viewed by others

References

  • Alemany S, Ribases M, Vilor-Tejedor N, et al. (2015) New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. doi:10.1002/ajmg.b.32341

    PubMed  Google Scholar 

  • Cha PC, Zembutsu H, Takahashi A, Kubo M, Kamatani N, Nakamura Y (2012) A genome-wide association study identifies SNP in DCC is associated with gallbladder cancer in the Japanese population. J Hum Genet 57:235–237

    Article  CAS  PubMed  Google Scholar 

  • De Peri L, Crescini A, Deste G, Fusar-Poli P, Sacchetti E, Vita A (2012) Brain structural abnormalities at the onset of schizophrenia and bipolar disorder: a meta-analysis of controlled magnetic resonance imaging studies. Curr Pharm Design 18:486–494

    Article  Google Scholar 

  • Deans MR, Krol A, Abraira VE, Copley CO, Tucker AF, Goodrich LV (2011) Control of neuronal morphology by the atypical cadherin Fat3. Neuron 71:820–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Djansugurova L, Zhunussova G, Khussainova E, et al. (2015) Association of DCC, MLH1, GSTT1, GSTM1, and TP53 gene polymorphisms with colorectal cancer in Kazakhstan. Tumor Biol 36:279–289

    Article  CAS  Google Scholar 

  • Dobson-Stone C, Polly P, Korgaonkar MS, et al. (2013) GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals. PLoS One 8:e71750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Egger G, Roetzer KM, Noor A, et al. (2014) Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families. Neurogenetics 15:117–127

    Article  CAS  PubMed  Google Scholar 

  • Fiorentini M, Bach A, Stromgaard K, Kastrup JS, Gajhede M (2013) Interaction partners of PSD-93 studied by X-ray crystallography and fluorescence polarization spectroscopy. Acta crystallographica Section D, Biological crystallography 69:587–594

    Article  CAS  PubMed  Google Scholar 

  • Flores C, Manitt C, Rodaros D, et al. (2005) Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine. Mol Psychiatry 10:606–612

    Article  CAS  PubMed  Google Scholar 

  • Global Burden of Disease Study C (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386:743–800

    Article  Google Scholar 

  • Grant A, Fathalli F, Rouleau G, Joober R, Flores C (2012) Association between schizophrenia and genetic variation in DCC: a case-control study. Schizophr Res 137:26–31

    Article  PubMed  Google Scholar 

  • Grant A, Speed Z, Labelle-Dumais C, Flores C (2009) Post-pubertal emergence of a dopamine phenotype in netrin-1 receptor-deficient mice. Eur J Neurosci 30:1318–1328

    Article  PubMed  Google Scholar 

  • Hamasaki T, Goto S, Nishikawa S, Ushio Y (2001) A role of netrin-1 in the formation of the subcortical structure striatum: repulsive action on the migration of late-born striatal neurons. J Neurosci Off J Soc Neurosci 21:4272–4280

    CAS  Google Scholar 

  • Hibar DP, Stein JL, Renteria ME, et al. (2015) Common genetic variants influence human subcortical brain structures. Nature 520:224–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holt DJ, Lebron-Milad K, Milad MR, et al. (2009) Extinction memory is impaired in schizophrenia. Biol Psychiatry 65:455–463

    Article  PubMed  Google Scholar 

  • Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–562

    Article  PubMed  PubMed Central  Google Scholar 

  • Ingason A, Giegling I, Hartmann AM, et al. (2015) Expression analysis in a rat psychosis model identifies novel candidate genes validated in a large case-control sample of schizophrenia. Transl Psychiatry 5:e656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwahashi K, Nishizawa D, Narita S, et al. (2014) Haplotype analysis of GSK-3 beta gene polymorphisms in bipolar disorder lithium responders and nonresponders. Clin Neuropharmacol 37:108–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang HJ, Kawasawa YI, Cheng F, et al. (2011) Spatio-temporal transcriptome of the human brain. Nature 478:483–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kantrowitz J, Javitt DC (2012) Glutamatergic transmission in schizophrenia: from basic research to clinical practice. Curr Opin Psychiatry 25:96–102

    PubMed  Google Scholar 

  • Kirov G, Pocklington AJ, Holmans P, et al. (2012) De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 17:142–153

    Article  CAS  PubMed  Google Scholar 

  • Kozlovsky N, Belmaker RH, Agam G (2000) Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry 157:831–833

    Article  CAS  PubMed  Google Scholar 

  • Kozlovsky N, Belmaker RH, Agam G (2001) Low GSK-3 activity in frontal cortex of schizophrenic patients. Schizophr Res 52:101–105

    Article  CAS  PubMed  Google Scholar 

  • Kozlovsky N, Belmaker RH, Agam G (2002) GSK-3 and the neurodevelopmental hypothesis of schizophrenia. Eur Neuropsychopharm 12:13–25

    Article  CAS  Google Scholar 

  • Kumar J, Yu H, Sheetz MP (1995) Kinectin, an essential anchor for kinesin-driven vesicle motility. Science 267:1834–1837

    Article  CAS  PubMed  Google Scholar 

  • Kwok JB, Loy CT, Hamilton G, et al. (2008) Glycogen synthase kinase-3beta and tau genes interact in Alzheimer’s disease. Ann Neurol 64:446–454

    Article  CAS  PubMed  Google Scholar 

  • Lachman HM, Pedrosa E, Petruolo OA, et al. (2007) Increase in GSK3beta gene copy number variation in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 144B:259–265

    Article  CAS  PubMed  Google Scholar 

  • Lee KY, Ahn YM, Joo EJ, et al. (2006) No association of two common SNPs at position −1727 A/T, −50 C/T of GSK-3 beta polymorphisms with schizophrenia and bipolar disorder of Korean population. Neurosci Lett 395:175–178

    Article  CAS  PubMed  Google Scholar 

  • Li M, Mo Y, Luo XJ, et al. (2011) Genetic association and identification of a functional SNP at GSK3beta for schizophrenia susceptibility. Schizophr Res 133:165–171

    Article  PubMed  Google Scholar 

  • Lichtenstein P, Yip BH, Bjork C, et al. (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373:234–239

    Article  CAS  PubMed  Google Scholar 

  • Lin YF, Huang MC, Liu HC (2013) Glycogen synthase kinase 3 beta gene polymorphisms may be associated with bipolar I disorder and the therapeutic response to lithium. J Affect Disorders 147:401–406

    Article  CAS  PubMed  Google Scholar 

  • Malik MA, Gupta A, Zargar SA, Mittal B (2013) Role of genetic variants of deleted in colorectal carcinoma (DCC) polymorphisms and esophageal and gastric cancers risk in Kashmir Valley and meta-analysis. Tumor Biol 34:3049–3057

    Article  CAS  Google Scholar 

  • Manitt C, Eng C, Pokinko M, et al. (2013) DCC orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients. Translational psychiatry 3:e338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manitt C, Mimee A, Eng C, et al. (2011) The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. J Neurosci Off J Soc Neurosci 31:8381–8394

    Article  CAS  Google Scholar 

  • Mao YW, Ge XC, Frank CL, et al. (2009) Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3 beta/beta-catenin signaling. Cell 136:1017–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noor A, Lionel AC, Cohen-Woods S, et al. (2014) Copy number variant study of bipolar disorder in Canadian and UK populations implicates synaptic genes. Am J Med Genet B Neuropsychiatr Genet 165B:303–313

    Article  PubMed  Google Scholar 

  • Olabi B, Ellison-Wright I, McIntosh AM, Wood SJ, Bullmore ET, Lawrie SM (2011) Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiat 70:88–96

    Article  PubMed  Google Scholar 

  • van Os J, Kapur S (2009) Schizophrenia. Lancet 374:635–645

    Article  PubMed  Google Scholar 

  • Owen MJ, Williams HJ, O’Donovan MC (2009) Schizophrenia genetics: advancing on two fronts. Current Opin Genet Dev 19:266–270

    Article  CAS  Google Scholar 

  • Pandey GN, Rizavi HS, Tripathi M, Ren XG (2015) Region-specific dysregulation of glycogen synthase kinase-3 beta and beta-catenin in the postmortem brains of subjects with bipolar disorder and schizophrenia. Bipolar Disord 17:160–171

    Article  CAS  PubMed  Google Scholar 

  • Park SW, Lee JG, Kong BG, et al. (2009) Genetic association of BDNF val66met and GSK-3beta-50 T/C polymorphisms with tardive dyskinesia. Psychiatry Clin Neurosci 63:433–439

    Article  CAS  PubMed  Google Scholar 

  • Peng YM, Xu YF, Cui DH (2014) Wnt signaling pathway in schizophrenia. Cns Neurol Disord-Dr 13:755–764

    Article  CAS  Google Scholar 

  • Rai R, Sharma KL, Tiwari S, Misra S, Kumar A, Mittal B (2013) DCC (deleted in colorectal carcinoma) gene variants confer increased susceptibility to gallbladder cancer (Ref. no.: Gene-D-12-01446). Gene 518:303–309

    Article  CAS  PubMed  Google Scholar 

  • Ramos-Miguel A, Barr AM, Honer WG (2015) Spines, synapses, and schizophrenia. Biol Psychiatry 78:741–743

    Article  PubMed  Google Scholar 

  • Schmitt CA, Thaler KR, Wittig BM, Kaulen H, KH M z B, WG D (1998) Detection of the DCC gene product in normal and malignant colorectal tissues and its relation to a codon 201 mutation. Br J Cancer 77:588–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shim SH, Hwangbo Y, Kwon YJ, et al. (2012) Association between glycogen synthase kinase-3beta gene polymorphisms and attention deficit hyperactivity disorder in Korean children: a preliminary study. Prog Neuro-Psychopharmacol Biol Psychiatry 39:57–61

    Article  CAS  Google Scholar 

  • Souza RP, Romano-Silva MA, Lieberman JA, Meltzer HY, Wong AH, Kennedy JL (2008) Association study of GSK3 gene polymorphisms with schizophrenia and clozapine response. Psychopharmacology 200:177–186

    Article  CAS  PubMed  Google Scholar 

  • Sullivan PF, Kendler KS, Neale MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60:1187–1192

    Article  PubMed  Google Scholar 

  • Szczepankiewicz A, Skibinska M, Hauser J, et al. (2006) Association analysis of the GSK-3beta T-50C gene polymorphism with schizophrenia and bipolar disorder. Neuropsychobiology 53:51–56

    Article  CAS  PubMed  Google Scholar 

  • Tang H, Shen N, Jin H, Liu D, Miao X, Zhu LQ (2013) GSK-3beta polymorphism discriminates bipolar disorder and schizophrenia: a systematic meta-analysis. Mol Neurobiol 48:404–411

    Article  CAS  PubMed  Google Scholar 

  • Tepass U, Truong K, Godt D, Ikura M, Peifer M (2000) Cadherins in embryonic and neural morphogenesis. Nat Rev Mol Cell Biol 1:91–100

    Article  CAS  PubMed  Google Scholar 

  • Thomas DC, Witte JS (2002) Point: population stratification: a problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomarkers Prev 11:505–512

    PubMed  Google Scholar 

  • Toyoshima I, Sheetz MP (1996) Kinectin distribution in chicken nervous system. Neurosci Lett 211:171–174

    Article  CAS  PubMed  Google Scholar 

  • Winterer G, Weinberger DR (2004) Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 27:683–690

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Arbman G, Sun XF (2003) Codon 201 polymorphism of DCC gene is a prognostic factor in patients with colorectal cancer. Cancer Detect Prev 27:216–221

    Article  CAS  PubMed  Google Scholar 

  • Zheng WH, Wang HT, Zeng ZW, et al. (2012) The possible role of the Akt signaling pathway in schizophrenia. Brain Res 1470:145–158

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Science Foundation of China (NSFC 81571856 and NSFC 81373247; http://www.nsfc.gov.cn).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jianghua Lai.

Ethics declarations

Written informed consent was obtained from all participants. The study was approved by the Medical Ethics Committee of Xi’an Jiaotong University.

Conflict of Interest

The authors have declared that no conflict of interest exists.

Electronic Supplementary Material

ESM 1

(PDF 171 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, P., Qiao, X., Wu, H. et al. An Association Study Between Genetic Polymorphisms in Functional Regions of Five Genes and the Risk of Schizophrenia. J Mol Neurosci 59, 366–375 (2016). https://doi.org/10.1007/s12031-016-0751-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-016-0751-6

Keywords

Navigation