Skip to main content
SpringerLink
Log in

Polymorphism of the glutamate receptor genes and risk of paranoid schizophrenia in Russians and Tatars from the Republic of Bashkortostan

  • Genomics. Transcriptomics
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

Schizophrenia is a severe mental disorder that affects approximately 1% of the global population, leading to disability and social deadaptation. One of the main neurobiological mechanisms hypothesized for the disease suggests a defect in glutamatergic neurotransmission. Changes in affinity of glutamate receptors, transcription of their genes, and expression of their subunits in the prefrontal cortex, hippocampus, and thalamus have been revealed in schizophrenics in post mortem studies. Association studies of the genes for kainate and AMPA ionotropic glutamate receptors have yielded discrepant results. In this study, GRIA2 and GRIK2 polymorphisms were tested for association with paranoid schizophrenia (PSZ) and response to haloperidol treatment in Russians and Tatars (257 patients and 349 healthy subjects) from Bashkortostan. Higher PSZ risk was associated with GRIK2*ATG (OR = 3.5) and GRIK2*TGG (OR = 3.12) in Tatars and GRIA2*CCC (OR = 9.60) in Russians. The markers of lower PSZ risk were genotype GRIA2*T/T (rs43025506) (OR = 0.34) in Tatars and GRIA2*CCT (OR = 0.481) in Russians. Genotypes GRIK2*T/T (rs2227281) and GRIA2*C/C in Russians and GRIK2*A/A (rs995640) in Tatars were identified as markers of a low efficacy of haloperidol treatment in improving both negative (NEGAT; flat affect, alogia, and anhedonia) and positive (POSIT; delusions, hallucinations, and disorganized thinking) symptoms. Genotype GRIA2*C/Cy was associated with low efficacy of haloperidol treatment in improving positive symptoms in Russians; such markers were not identified in Tatars. The findings support the hypothesis that glutamate receptor genes are involved in the etiology and pathogenesis of schizophrenia. Interethnic differences in genetic risk factors were observed.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

RB:

Republic of Bashkortostan

PSZ:

paranoid schizophrenia

PANSS:

positive and negative syndrome scale

POSIT:

positive symptom subscale (delusions, hallucinations, and disorganized thinking)

NEGAT:

negative symptom subscale (flat affect, alogia, and anhedonia)

PSYCH:

general psychopathology subscale (somatic concerns, anxiety, guilt feeling, and tension)

OCSs:

obsessive compulsive symptoms

References

  1. Cardno A.G., Gottesman I.I. 2000. Twin studies of schizophrenia: From bow-and-arrow concordances to star wars Mx and functional genomics. Am. J. Med. Genet. 97, 12–17.

    Article  PubMed  CAS  Google Scholar 

  2. Sullivan P.F., Kendler K.S., Neale M.C. 2003. Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry. 60, 1187–1192.

    Article  PubMed  Google Scholar 

  3. Stone J.M., Morrison P.D., Pilowsky L.S. 2007. Glutamate and dopamine dysregulation in schizophrenia: A synthesis and selective review. J. Psychopharmacol. 21, 440–452.

    Article  PubMed  CAS  Google Scholar 

  4. Clinton S.M., Meador-Woodruff J.H. 2004. Thalamic dysfunction in schizophrenia: Neurochemical, neuropathological, and in vivo imaging abnormalities. Schizophr. Res. 69, 237–253.

    Article  PubMed  Google Scholar 

  5. Watis L., Chen S.H., Chua H.C., Chong S.A., Sim K. 2008. Glutamatergic abnormalities of the thalamus in schizophrenia: A systematic review. J. Neural Transmission. 115, 493–511.

    Article  CAS  Google Scholar 

  6. Giegling I., Drago A., Dolžan V., Plesničar B.K., Schäfer M., Hartmann A.M., Sander T., Toliat M.R., Möller H.J., Stassen H.H., Rujescu D., Serretti A. 2011. Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. Pharmacogenet. Genomics. 21, 206–216.

    PubMed  CAS  Google Scholar 

  7. Du J., Creson T.K., Wu L.J., Ren M., Gray N.A., Falke C., Wei Y., Wang Y., Blumenthal R., Machado-Vieira R., Yuan P., Chen G., Zhuo M., Manji H.K. 2008. The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior. J. Neurosci. 28, 68–79.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. O’Connor J.A., Muly E.C., Arnold S.E., Hemby S.E. 2007. AMPA receptor subunit and splice variant expression in the DLPFC of schizophrenic subjects and rhesus monkeys chronically administered antipsychotic drugs. Schizophr. Res. 90, 28–40.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sampaio A.S., Fagerness J., Crane J., Leboyer M., Delorme R., Pauls D.L., Stewart S.E. 2011. Association between polymorphisms in GRIK2 gene and obsessive-compulsive disorder: A family-based study. CNS Neurosci. Ther. 17, 141–147.

    Article  PubMed  CAS  Google Scholar 

  10. Shibata H., Shibata A., Ninomiya H., Tashiro N., Fukumaki Y. 2002. Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2) with schizophrenia. Psychiatry Res. 113, 59–67.

    Article  PubMed  CAS  Google Scholar 

  11. Bah J., Quach R., Ebstein P., Segman R.H., Melke J., Jamain S., Rietschel M., Modai I., Kanas K., Karni O., Lerer B., Gourion D., Krebs M.O., Etain B., Schürhoff F., Szöke A., Leboyer M., Bourgeron T. 2004. Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia. Neuroreport. 15, 1987–1991.

    Article  PubMed  CAS  Google Scholar 

  12. Ekholm J.M., Kieseppa T., Hiekkalinna T. 2003. Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder. Hum. Mol. Genet. 12, 1907–1915.

    Article  PubMed  CAS  Google Scholar 

  13. Trifonova E.A., Eremina E.R., Urnov F.D., Stepanov V.A. 2012. The genetic diversity and structure of linkage disequilibrium of the MTHFR gene in populations of Northern Eurasia. Acta Naturae. 4, 53–69.

    PubMed  CAS  PubMed Central  Google Scholar 

  14. Bochkov N.P. 2002. Klinicheskaya genetika (Clinical Genetics). Moscow: GEOTAR-MED.

    Google Scholar 

  15. Mathew C.C. 1984. The isolation of high molecular weight eucariotic DNA. In: Methods in Molecular Biology, vol. 2. Ed. Walker J.M. NY: Humana Press, pp. 31–34.

    Google Scholar 

  16. Shuang M., Liu J., Jia M.X., Yang J.Z., Wu S.P., Gong X.H., Ling Y.S., Ruan Y., Yang X.L., Zhang D. 2004. Family based association study between autism and glutamate receptor 6 gene in Chinese Han trios. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 131, 48–50.

    Article  Google Scholar 

  17. Tiganov A.S., Snezhnevsky A.V., Orlov D.D. 1999. Rukovodstvo po psikhiatrii (A Manual of Psychiatry). Moscow: Meditsina, pp. 407–437.

    Google Scholar 

  18. StatSoft, Inc. 2001. STATISTICA (Data Analysis Soft-ware System), Version 6. www.statsoft.com

    Google Scholar 

  19. Barrett J.C., Fry B., Maller J., Daly M.J. 2005. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics. 21, 263–265.

    Article  PubMed  CAS  Google Scholar 

  20. Magri C., Gardella R., Valsecchi P., Barlati S.D., Guizzetti L., Imperadori L., Bonvicini C., Tura G.B., Gennarelli M., Sacchetti E., Barlati S. 2008. Study on GRIA2, GRIA3, and GRIA4 genes highlights a positive association between schizophrenia and GRIA3 in female patients. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 147, 745–753.

    Article  Google Scholar 

  21. Crisafulli C., Chiesa A., De Ronchi D., Han C., Lee S.J., Park M.H., Patkar A.A., Pae C.U., Serretti A. 2012. Influence of GRIA1, GRIA2, and GRIA4 polymorphisms on diagnosis and response to antipsychotic treatment in patients with schizophrenia. Neurosci. Lett. 506, 170–174.

    Article  PubMed  CAS  Google Scholar 

  22. Kang W.S., Park J.K., Kim S.K., Park H.J., Lee S.M., Song J.Y., Chung J.H., Kim J.W. 2012. Genetic variants of GRIA1 are associated with susceptibility to schizophrenia in Korean population. Mol. Biol. Rep. 39, 10697–10703.

    Article  PubMed  CAS  Google Scholar 

  23. Magri C., Gardella R., Barlati S.D., Podavini D., Iatropoulos P., Bonomi S., Valsecchi P., Sacchetti E., Barlati S. 2006. Glutamate AMPA receptor subunit 1 gene (GRIA1) and DSM-IV-TR schizophrenia: A pilot casecontrol association study in an Italian sample. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 141, 287–293.

    Article  Google Scholar 

  24. Fijal B.A., Stouffer V.L., Kinon B.J., Conley R.R., Hoffmann V.P., Witte M.M., Zhao F., Houston J.P. 2012. Analysis of gene variants previously associated with iloperidone response in patients with schizophrenia who are treated with risperidone. J. Clin. Psychiatry. 73, 367–371.

    Article  PubMed  CAS  Google Scholar 

  25. Drago A., Giegling I., Schafer M., Hartmann A.M., Friedl M., Konte B., Möller H.J., De Ronchi D., Stassen H.H., Serretti A., Rujescu D. 2013. AKAP13, CACNA1, GRIK4, and GRIA1 genetic variations may be associated with haloperidol efficacy during acute treatment. Eur. Neuropsychopharmacol. 23, 887–894.

    Article  PubMed  CAS  Google Scholar 

  26. Chiesa A.C., Crisafulli S., Porcelli C., Han C., Patkar A.A., Lee S.J., Park M.H., Jun T.Y., Serretti A., Pae C.U. 2012. Influence of GRIA1, GRIA2, and GRIA4 polymorphisms on diagnosis and response to treatment in patients with major depressive disorder. Eur. Arch. Psychiatry Clin. Neurosci. 262, 305–311.

    Article  PubMed  Google Scholar 

  27. Chiesa A., Lia L., Lia C., Lee S.J., Han C., Patkar A.A., Pae C.U., Serretti A. 2013. Investigation of possible epistatic interactions between GRIA2 and GRIA4 variants on clinical outcomes in patients with major depressive disorder. J. Int. Med. Res. 41, 809–815.

    Article  PubMed  CAS  Google Scholar 

  28. Dutta S., Das S., Guhathakurta S. 2007. Glutamate receptor 6 gene (GluR6 or GRIK2) polymorphisms in the Indian population: A genetic association study on autism spectrumdisorder. Cell Mol. Neurobiol. 27, 1035–1047.

    Article  PubMed  CAS  Google Scholar 

  29. Diguet E., Fernagut P.O., Normand E.L., Centelles L., Mulle C., Tison F. 2004. Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington’s disease natural history. Neurobiol. Dis. 15, 667–675.

    Article  PubMed  CAS  Google Scholar 

  30. Motazacker M.M., Rost B.R., Hucho T., Garshasbi M., Kahrizi K., Ullmann R., Abedini S.S., Nieh S.E., Amini S.H., Goswami C., Tzschach A., Jensen L.R., Schmitz D., Ropers H.H., Najmabadi H., Kuss A.W. 2007. A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am. J. Hum. Genet. 81, 792–798.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Smith A.K., Fang H., Whistler T., Unger E.R., Rajeevan M.S. 2011. Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. Neuropsychobiology. 64, 183–194.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Myung W., Song J., Lim S.W., Won H.H., Kim S., Lee Y., Kang H.S., Lee H., Kim J.W., Carroll B..J, Kim D.K. 2012. Genetic association study of individual symptoms in depression. Psychiatry Res. 198, 400–406.

    Article  PubMed  Google Scholar 

  33. Delorme R., Krebs M.O., Chabane N., Roy I., Millet B., Mouren-Simeoni M.C., Maier W., Bourgeron T., Leboyer M. 2004. Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder. Neuroreport. 15, 699–702.

    Article  PubMed  CAS  Google Scholar 

  34. Begni S., Popoli S., Moraschi S., Bignotti S., Tura G.B., Gennarelli M. 2002. Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia. Mol. Psychiatry. 7, 416–418.

    Article  PubMed  CAS  Google Scholar 

  35. Shibata H., Aramaki T., Sakai M., Ninomiya H., Tashiro N., Iwata N., Ozaki N., Fukumaki Y. 2006. Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia. Psychiatry Res. 141, 39–51.

    Article  PubMed  CAS  Google Scholar 

  36. Ibrahim H., Hogg A.J., Healy D.J., Haroutunian V., Davis K.L., Meador-Woodruff J.H. 2000. Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. Am. J. Psychiatry. 157, 1811–1823.

    Article  PubMed  CAS  Google Scholar 

  37. Evins A.E., Amico E.T., Shih V., Goff D.C. 1997. Clozapine treatment increases serum glutamate and aspartate compared to conventional neuroleptics. J. Neural Transm. 104, 761–766.

    Article  PubMed  CAS  Google Scholar 

  38. Cai J., Zhang W., Yi Z., Lu W., Wu Z., Chen J., Yu S., Fang Y., Zhang C. 2013. Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive-compulsive symptoms. Psychopharmacology. 230, 49–55.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Biochemistry and Genetics, Ufa Research Center, Russian Academy of Sciences, Ufa, 450054, Russia

    A. E. Gareeva & E. K. Khusnutdinova

Authors
  1. A. E. Gareeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. K. Khusnutdinova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. E. Gareeva.

Additional information

Original Russian Text © A.E. Gareeva, E.K. Khusnutdinova, 2014, published in Molekulyarnaya Biologiya, 2014, Vol. 48, No. 5, pp. 771–781.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gareeva, A.E., Khusnutdinova, E.K. Polymorphism of the glutamate receptor genes and risk of paranoid schizophrenia in Russians and Tatars from the Republic of Bashkortostan. Mol Biol 48, 671–680 (2014). https://doi.org/10.1134/S0026893314050033

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893314050033

Keywords

Search

Navigation