Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

BDNF gene is a risk factor for schizophrenia in a Scottish population

Abstract

Schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P=0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (P<1 × 10−8) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Owen MJ, O’Donovan M, Gottesman II . Psychiatric Genetics and Genomics. Oxford University Press: Oxford, 2003 pp 247–266.

    Google Scholar 

  2. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, Part II: schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Levinson DF, Levinson MD, Segurado R, Lewis CM . Genome scan meta-analysis of schizophrenia and bipolar disorder, Part I: methods and power analysis. Am J Med Genet 2003; 73: 17–33.

    CAS  Google Scholar 

  4. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    Article  CAS  PubMed  Google Scholar 

  5. Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P . BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 2001; 411: 86–89.

    Article  CAS  PubMed  Google Scholar 

  6. Levine ES, Kolb JE . Brain-derived neurotrophic factor increases activity of NR2B-containing N-methyl-D-aspartate receptors in excised patches from hippocampal neurons. J Neurosci Res 2000; 62: 357–362.

    Article  CAS  PubMed  Google Scholar 

  7. Molteni R, Lipska BK, Weinberger DR, Racagni G, Riva MA . Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia. Mol Psychiatry 2001; 3: 285–292.

    Article  Google Scholar 

  8. Smith MA, Makino S, Kvetnansky R, Post RM . Stress alters the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995; 15: 1768–1777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nibuya M, Morinobu S, Duman RS . Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995; 15: 7539–7547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chlan-Fourney J, Ashe P, Nylen K, Juorio AV, Li XM . Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 2002; 954: 11–20.

    Article  CAS  PubMed  Google Scholar 

  11. Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K et al. Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000; 5: 293–300.

    Article  CAS  PubMed  Google Scholar 

  12. Hanson IM, Seawright A, van Heyningen V . The human BDNF gene maps between FSHB and HVBS1 at the boundary of 11p13-p14. Genomics 1992; 13: 1331–1333.

    Article  CAS  PubMed  Google Scholar 

  13. Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci USA 1999; 96: 5604–5609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S et al. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci USA 1996; 93: 13060–13065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Proschel M, Saunders A, Roses AD, Muller CR . Dinucleotide repeat polymorphism at the human gene for the brain-derived neurotrophic factor (BDNF). Hum Mol Genet 1992; 1: 353.

    Article  CAS  PubMed  Google Scholar 

  16. Sasaki T, Dai XY, Kuwata S, Fukuda R, Kunugi H, Hattori M . Brain-derived neurotrophic factor gene and schizophrenia in Japanese subjects. Am J Med Genet 1997; 74: 443–444.

    Article  CAS  PubMed  Google Scholar 

  17. Hawi Z, Straub RE, O’Neill A, Kendler KS, Walsh D, Gill M . No linkage or linkage disequilibrium between brain-derived neurotrophic factor (BDNF) dinucleotide repeat polymorphism and schizophrenia in Irish families. Psychiatry Res 1998; 81: 111–116.

    Article  CAS  PubMed  Google Scholar 

  18. Wassink TH, Nelson JJ, Crowe RR, Andreasen NC . Heritability of BDNF alleles and their effect on brain morphology in schizophrenia. Am J Med Genet 1999; 88: 724–728.

    Article  CAS  PubMed  Google Scholar 

  19. Krebs MO, Guillin O, Bourdell MC, Schwartz JC, Olie JP, Poirier MF et al. Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol Psychiatry 2000; 5: 558–562.

    Article  CAS  PubMed  Google Scholar 

  20. Virgos C, Martorell L, Valero J, Figuera L, Civeira F, Joven J et al. Association study of schizophrenia with polymorphisms at six candidate genes. Schizophr Res 2001; 49: 65–71.

    Article  CAS  PubMed  Google Scholar 

  21. Muglia P, Vicente AM, Verga M, King N, Macciardi F, Kennedy JL . Association between the BDNF gene and schizophrenia. Mol Psychiatry 2003; 8: 146–147.

    Article  CAS  PubMed  Google Scholar 

  22. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL . The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 2002; 71: 651–655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Egan MF, Weinberger DR, Lu B . Schizophrenia, III: brain-derived neurotropic factor and genetic risk. Am J Psychiatry 2003; 160: 1242.

    Article  PubMed  Google Scholar 

  24. Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol Psychiatry 2002; 7: 579–593.

    Article  CAS  PubMed  Google Scholar 

  25. Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T et al. Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci Lett 2003; 337: 17–20.

    Article  CAS  PubMed  Google Scholar 

  26. Hong CJ, Yu YW, Lin CH, Tsai SJ . An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett. 2003; 349: 206–208.

    Article  CAS  PubMed  Google Scholar 

  27. Nanko S, Kunugi H, Hirasawa H, Kato N, Nabika T, Kobayashi S . Brain-derived neurotrophic gene and schizophrenia: polymorphism screening and asociation analysis. Schizophr Res. 2003; 62: 281–283.

    Article  PubMed  Google Scholar 

  28. McGinnis RE, Fox H, Yates P, Cameron LA, Barnes MR, Gray IC et al. Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland. Nat Genet 2001; 28: 128–129.

    Article  CAS  PubMed  Google Scholar 

  29. Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 2003; 72: 83–87.

    Article  CAS  PubMed  Google Scholar 

  30. Jobs M, Howell WM, Stromqvist L, Mayr T, Brookes AJ . DASH-2: flexible, low-cost, and high-throughput SNP genotyping by dynamic allele-specific hybridization on membrane arrays. Genome Res 2003; 13: 916–924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Woolf B . On estimating the relation between blood group and disease. Ann Hum Genet. 1955; 19: 251–253.

    Article  CAS  PubMed  Google Scholar 

  32. Stephens M, Smith NJ, Donnely P . Anew statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sham PC, Curtis D . Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995; 59: 97–105.

    Article  CAS  PubMed  Google Scholar 

  34. Klitz W, Stephen JC, Grote M, Carrington M . Discordant patterns of linkage disequilibrium of the peptide transporter loci within the HLA class II region. Am J Hum Genet 1995; 57: 1436–1444.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Weisstein EW . Bonferroni Test, From Mathworld--A Wolfram Web Resource. http://mathworld.wolfram.com/BonferroniTest.html.

  36. McGinnis R . General equations for Pt, Ps, and the power of the TDT and the affected-sib-pair test. Am J Hum Genet 2000; 67: 1340–1347.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Harrison PJ, Owen MJ . Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361: 417–419.

    Article  CAS  PubMed  Google Scholar 

  38. Stefansson H, Sigurdsson E, Steinhorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV et 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schwab SG, Knapp M, Mondabon S, Hallmayer J, Borrmann-Hassenbach, Albus M et al. Support for an 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.

    Article  CAS  PubMed  Google Scholar 

  41. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002; 99: 13675–13680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML et al. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002; 99: 3717–3722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M et al. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC encoding the calcineurin gamma subunit. Proc Natl Acad Sci USA 2003; 100: 8993–8998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Gillian Fraser, Lynne Priestley, and Joanna Haggath. This work has been funded by GlaxoSmithKline, Genset (Paris), Royal College of Physicians Edinburgh, and Scottish Hospitals Endowments Research Trust (SHERT).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D M St Clair.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neves-Pereira, M., Cheung, J., Pasdar, A. et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 10, 208–212 (2005). https://doi.org/10.1038/sj.mp.4001575

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001575

Keywords

This article is cited by

Search

Quick links