Female gender specific association of the Reelin (RELN) gene rs7341475 variant with schizophrenia

  • Mavi Deniz Sozuguzel
  • Ali SazciEmail author
  • Mustafa Yildiz
Original Article


RELN gene encodes a large extracellular matrix protein which is critical for neuronal migration, cell positioning and cell–cell interactions. It also controls the synaptic plasticity of neurons for initiation and maintenance of long term potentiation. The aim of this study is to investigate the association of RELN rs7341475 variant with schizophrenia. Genomic DNA isolation was performed from 105 schizophrenic patients and 137 healthy controls to determine RELN rs7341475 genotypes. Genotype and allele frequencies were determined by a polymerase chain reaction-restriction fragment length polymorphism method developed in our laboratory. Statistical analysis was performed using χ2 test. The frequencies for G allele were 79.5% in cases and 81.0% in controls, for A allele 20.5% in cases and 19.0% in controls in the overall population. The genotype frequencies of the RELN gene rs7341475 variant were GG; 63.8%, GA; 31.4% and AA; 4.8% in cases, GG; 63.5%, GA; 35.0% and AA; 1.5% in controls in the overall population. There was no statistically significant association between the rs7341475 variant of RELN gene and schizophrenia in the overall population (χ2 = 2.473, p = 0.290). In the gender specific analysis, female gender specific association was only found. The RELN rs7341475 variant GG genotype was significantly associated with schizophrenia (p = 0.034, OR 2.760, 95% CI 1.058–7.197) and A allele was protective against schizophrenia (p = 0.034, OR 0.362, 95% CI 0.139–0.945). All cases and controls were in Hardy–Weinberg equilibrium (p > 0.05). Population size can be increased to improve the statistical power. Moreover, other RELN gene variants which are especially involved in neuronal migration and epigenetic regulation may be analyzed for revealing the complex genetic architecture of schizophrenia. In conclusion, there was only association between the RELN rs7341475 variant and schizophrenia in the female gender in a Turkish population.


RELN gene Schizophrenia Polymorphism rs7341475 Female gender Specific association Turkish population 



This study was supported by Kocaeli University, Project No: 2011/68 to AS.

Compliance with ethical standards

Conflict of interest

No conflict of interest exists.


  1. 1.
    Farrell MS, Werge T, Sklar P, Owen MJ, Ophoff RA, O’Donovan MC, Corvin A, Cichon S, Sullivan PF (2015) Evaluating historical candidate genes for schizophrenia. Mol Psychiatry 20(5):555–562CrossRefGoogle Scholar
  2. 2.
    Sazci A, Ergül E, Güzelhan Y, Kaya G, Kara I (2003) Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Mol Brain Res 117(1):104–107CrossRefGoogle Scholar
  3. 3.
    Sazci A, Ergul E, Kucukali I, Kara I, Kaya G (2005) Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: association is significant in men but not in women. Prog Neuropsychopharmacol Biol Psychiatry 29(7):1113–1123CrossRefGoogle Scholar
  4. 4.
    Owen MJ, Williams HJ, O’Donovan MC (2009) Schizophrenia genetics: advancing on two fronts. Curr Opin Genet Dev 19(3):266–270CrossRefGoogle Scholar
  5. 5.
    Shifman S, Johannesson M, Bronstein M, Chen SX, Collier DA, Craddock NJ, Kendler KS, Li T, O’Donovan M, O’Neill FA, Owen MJ, Walsh D, Weinberger DR, Sun C, Flint J, Darvasi A (2008) Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet 4(2):e28CrossRefGoogle Scholar
  6. 6.
    Eastwood SL, Harrison PJ (2003) Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis. Mol Psychiatry 8:769–821CrossRefGoogle Scholar
  7. 7.
    Absil P, Pinxten R, Balthazart J, Eens M (2003) Effects of testosterone on Reelin expression in the brain of male European starlings. Cell Tissue Res 312:81–93Google Scholar
  8. 8.
    D’Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T (1995) A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374(6524):719–723CrossRefGoogle Scholar
  9. 9.
    Folsom TD, Fatemi SH (2013) The involvement of Reelin in neurodevelopmental disorders. Neuropharmacology 68:122–135CrossRefGoogle Scholar
  10. 10.
    Nogi T, Yasui N, Hattori M, Iwasaki K, Takagi J (1999) Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron 24(2):481–489CrossRefGoogle Scholar
  11. 11.
    Nogi T, Yasui N, Hattori M, Iwasaki K, Takagi J (2006) Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography. EMBO J 25(15):3675–3683CrossRefGoogle Scholar
  12. 12.
    Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, Uzunov DP, Smalheiser NR, Davis JM, Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E (1998) A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci USA 95(26):15718–15723CrossRefGoogle Scholar
  13. 13.
    Guidotti A, Auta J, Davis JM, Dong E, Gavin DP, Grayson DR, Sharma RP, Smith RC, Tueting P, Zhubi A (2000) Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 57(11):1061–1069CrossRefGoogle Scholar
  14. 14.
    Ruscio AM, Hallion LS, Lim CCW, Aguilar-Gaxiola S, Al-Hamzawi A, Alonso J, Andrade LH, Borges G, Bromet EJ, Bunting B, Caldas de Almeida JM, Demyttenaere K, Florescu S, de Girolamo G, Gureje O, Haro JM, He Y, Hinkov H, Hu C, de Jonge P, Karam EG, Lee S, Lepine JP, Levinson D, Mneimneh Z, Navarro-Mateu F, Posada-Villa J, Slade T, Stein DJ, Torres Y, Uda H, Wojtyniak B, Kessler RC, Chatterji S, Scott KM (2017) Cross-sectional comparison of the epidemiology of DSM-5 generalized anxiety disorder across the globe. JAMA Psychiatry 74:465–475CrossRefGoogle Scholar
  15. 15.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215CrossRefGoogle Scholar
  16. 16.
    Réthelyi JM, Benkovits J, Bitter I (2013) Genes and environments in schizophrenia: the different pieces of a manifold puzzle. Neurosci Biobehav Rev 37:2424–2437CrossRefGoogle Scholar
  17. 17.
    Kim YI, Zerwas S, Trace SE, Sullivan PF (2011) Schizophrenia genetics: where next? Schizophr Bull 37(3):456–463CrossRefGoogle Scholar
  18. 18.
    Ovadia G, Shifman S (2011) The genetic variation of RELN expression in schizophrenia and bipolar disorder. PLoS ONE 6(5):e19955CrossRefGoogle Scholar
  19. 19.
    Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA (2000) Authosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26(1):93–96CrossRefGoogle Scholar
  20. 20.
    Dazzo E, Fanciulli M, Serioli E, Minervini G, Pulitano P, Binelli S, Di Bonaventura C, Luisi C, Pasini E, Striano S, Striano P, Coppola G, Chiavegato A, Radovic S, Spadotto A, Uzzau S, La Neve A, Giallonardo AT, Mecarelli O, Tosatto SC, Ottman R, Michelucci R, Nobile C (2015) Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy. Am J Hum Genet 96(6):992–1000CrossRefGoogle Scholar
  21. 21.
    Fehér Á, Juhász A, Pákáski M, Kálmán J, Janka Z (2015) Genetic analysis of the RELN gene: gender specific association with Alzheimer’s disease. Psychiatry Res 230(2):716–718CrossRefGoogle Scholar
  22. 22.
    Lammert DB, Howell BW (2016) RELN mutations in autism spectrum disorder. Front Cell Neurosci 31(10):84Google Scholar
  23. 23.
    Suzuki K, Nakamura K, Iwata Y, Sekine Y, Kawai M, Sugihara G, Tsuchiya KJ, Suda S, Matsuzaki H, Takei N, Hashimoto K, Mori N (2008) Decreased expression of reelin receptor VLDLR in peripheral lymphocytes of drug-naive schizophrenic patients. Schizophr Res 98(1–3):148–156CrossRefGoogle Scholar
  24. 24.
    Wedenoja J, Loukola A, Tuulio-Henriksson A, Paunio T, Ekelund J, Silander K, Varilo T, Heikkilä K, Suvisaari J, Partonen T, Lönnqvist J, Peltonen L (2008) Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families. Mol Psychiatry 13(7):673–684CrossRefGoogle Scholar
  25. 25.
    Grayson DR, Jia X, Chen Y, Sharma RP, Mitchell CP, Guidotti A, Costa E (2005) Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci USA 102(26): 9341–9346CrossRefGoogle Scholar
  26. 26.
    Nabil Fikri RM, Norlelawati AT, Nour El-Huda AR, Hanisah MN, Kartini A, Norsidah K, Nor Zamzila A (2017) Reelin (RELN) DNA methylation in the peripheral blood of schizophrenia. J Psychiatr Res 88:28–37CrossRefGoogle Scholar
  27. 27. (Last accession date: 25.07.2017)
  28. 28.
    Yang XB, Kang C, Liu H, Yang J (2013) Association study of the reelin (RELN) gene with Chinese Va schizophrenia. Psychiatr Genet 23(3):138CrossRefGoogle Scholar
  29. 29.
    Chen N, Bao Y, Xue Y, Sun Y, Hu D, Meng S, Lu L, Shi J (2017) Meta-analyses of TELN variants in neuropsychiatric disorders. Behav Brain Res 332:110–119CrossRefGoogle Scholar
  30. 30.
    Li W, Guo X, Xiao S (2015) Evaluating the relationship between reelin gene variants (rs7341475 and rs262355) and schizophrenia: a meta-analysis. Neurosci Lett 609:42–47CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Medical Biology, International School of MedicineIstanbul Medipol UniversityIstanbulTurkey
  2. 2.Department of Medical Biology and Genetics, Faculty of MedicineUniversity of KocaeliKocaeliTurkey
  3. 3.Department of Psychiatry, Faculty of MedicineUniversity of KocaeliKocaeliTurkey

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