Human Genetics

, Volume 131, Issue 7, pp 1187–1195 | Cite as

Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls

  • Xiang Yang ZhangEmail author
  • Da Chun Chen
  • Mei Hong Xiu
  • Colin N. Haile
  • Xingguang Luo
  • Ke Xu
  • Hui Ping Zhang
  • Lingjun Zuo
  • Zhijun Zhang
  • Xiangrong Zhang
  • Therese A. Kosten
  • Thomas R. KostenEmail author
Original Investigation


Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may mediate hippocampal-dependent cognitive functions. A few studies have reported its role in cognitive deficits in schizophrenia including its association with peripheral BDNF levels as a mediator of these cognitive deficits. We assessed 657 schizophrenic inpatients and 445 healthy controls on the repeatable battery for the assessment of neuropsychological status (RBANS), the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that visuospatial/constructional abilities significantly differed by genotype but not genotype × diagnosis, and the Val allele was associated with better visuospatial/constructional performance in both schizophrenic patients and healthy controls. Attention performance showed a significant genotype by diagnosis effect. Met allele-associated attention impairment was specific to schizophrenic patients and not shown in healthy controls. In the patient group, partial correlation analysis showed a significant positive correlation between serum BDNF and the RBANS total score. Furthermore, the RBANS total score showed a statistically significant BDNF level × genotype interaction. We demonstrated an association between the BDNF Met variant and poor visuospatial/constructional performance. Furthermore, the BDNF Met variant may be specific to attentional decrements in schizophrenic patients. The association between decreased BDNF serum levels and cognitive impairment in schizophrenia is dependent on the BDNF Val66Met polymorphism.


Schizophrenia Schizophrenic Patient BDNF Level Val66Met Polymorphism Serum BDNF 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was funded by the Stanley Medical Research Institute (03T-459 and 05T-726), and the Department of Veterans Affairs, VISN 16, Mental Illness Research, Education and Clinical Center (MIRECC), United States National Institute of Health K05-DA0454, P50-DA18827 and U01-MH79639.

Conflict of interest

No conflict of interest was disclosed for each author.


  1. Altar CA, Cai N, Bliven T, Juhasz M, Conner JM, Acheson AL, Lindsay RM, Wiegand SJ (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389(6653):856–860PubMedCrossRefGoogle Scholar
  2. Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK (2006) BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 59(9):812–815PubMedCrossRefGoogle Scholar
  3. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24(18):4401–4411PubMedCrossRefGoogle Scholar
  4. Ciammola A, Sassone J, Cannella M, Calza S, Poletti B, Frati L, Squitieri F, Silani V (2007) Low brain-derived neurotrophic factor (BDNF) levels in serum of Huntington’s disease patients. Am J Med Genet B Neuropsychiatr Genet 144B(4):574–577PubMedCrossRefGoogle Scholar
  5. Cubells JF, Kobayashi K, Nagatsu T, Kidd KK, Kidd JR, Calafell F, Kranzler HR, Ichinose H, Gelernter J (1997) Population genetics of a functional variant of the dopamine beta-hydroxylase gene (DBH). Am J Med Genet 74(4):374–379PubMedCrossRefGoogle Scholar
  6. Deary IJ, Penke L, Johnson W (2010) The neuroscience of human intelligence differences. Nat Rev Neurosci 11(3):201–211PubMedGoogle Scholar
  7. Dempster E, Toulopoulou T, McDonald C, Bramon E, Walshe M, Filbey F, Wickham H, Sham PC, Murray RM, Collier DA (2005) Association between BDNF val66 met genotype and episodic memory. Am J Med Genet B Neuropsychiatr Genet 134B(1):73–75PubMedCrossRefGoogle Scholar
  8. Dickerson F, Boronow JJ, Stallings C, Origoni AE, Cole SK, Yolken RH (2004) Cognitive functioning in schizophrenia and bipolar disorder: comparison of performance on the repeatable battery for the assessment of neuropsychological status. Psychiatry Res 129(1):45–53PubMedCrossRefGoogle Scholar
  9. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269PubMedCrossRefGoogle Scholar
  10. Granholm E, McQuaid JR, Link PC, Fish S, Patterson T, Jeste DV (2008) Neuropsychological predictors of functional outcome in cognitive behavioral social skills training for older people with schizophrenia. Schizophr Res 100(1–3):133–143PubMedCrossRefGoogle Scholar
  11. Gunstad J, Benitez A, Smith J, Glickman E, Spitznagel MB, Alexander T, Juvancic-Heltzel J, Murray L (2008) Serum brain-derived neurotrophic factor is associated with cognitive function in healthy older adults. J Geriatr Psychiatry Neurol 21(3):166–170PubMedCrossRefGoogle Scholar
  12. Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes C (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 20(11):3993–4001PubMedGoogle Scholar
  13. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23(17):6690–6694PubMedGoogle Scholar
  14. Harvey PD (2009) Pharmacological cognitive enhancement in schizophrenia. Neuropsychol Rev 19:324–335PubMedCrossRefGoogle Scholar
  15. Harvey PD, Geyer MA, Robbins TW, Krystal JH (2003) Cognition in schizophrenia: from basic science to clinical treatment. Psychopharmacology 169:213–214PubMedCrossRefGoogle Scholar
  16. Ho BC, Andreasen NC, Dawson JD, Wassink TH (2007) Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatry 164(12):1890–1899PubMedCrossRefGoogle Scholar
  17. Hughes C, Kumari V, Soni W, Das M, Binneman B, Drozd S, O’Neil S, Mathew V, Sharma T (2003) Longitudinal study of symptoms and cognitive function in chronic schizophrenia. Schizophr Res 59(2–3):137–146PubMedCrossRefGoogle Scholar
  18. Kaneda Y, Jayathilak K, Meltzer HY (2009) Determinants of work outcome in schizophrenia and schizoaffective disorder: role of cognitive function. Psychiatry Res 169(2):178–179PubMedCrossRefGoogle Scholar
  19. Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM, Aznar S (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol 14(3):347–353PubMedCrossRefGoogle Scholar
  20. Komulainen P, Pedersen M, Hänninen T, Bruunsgaard H, Lakka TA, Kivipelto M, Hassinen M, Rauramaa TH, Pedersen BK, Rauramaa R (2008) BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA Study. Neurobiol Learn Mem 90(4):596–603PubMedCrossRefGoogle Scholar
  21. Kraus MS, Keefe RS (2007) Cognition as an outcome measure in schizophrenia. Br J Psychiatry 50:46–51CrossRefGoogle Scholar
  22. Lang UE, Hellweg R, Sander T, Gallinat J (2009) The Met allele of the BDNF Val66Met polymorphism is associated with increased BDNF serum concentrations. Mol Psychiatry 14(2):120–122PubMedCrossRefGoogle Scholar
  23. Lencz T, Lipsky RH, DeRosse P, Burdick KE, Kane JM, Malhotra AK (2009) Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes. Br J Psychiatry 194(4):313–318PubMedCrossRefGoogle Scholar
  24. Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K, Gilmore J (2001) The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 50(11):884–897PubMedCrossRefGoogle Scholar
  25. Lu B, Gottschalk W (2000) Modulation of hippocampal synaptic transmission and plasticity by neurotrophins. Prog Brain Res 128:231–241PubMedCrossRefGoogle Scholar
  26. Lu Y, Christian K, Lu B (2008) BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 89(3):312–323PubMedCrossRefGoogle Scholar
  27. Naoe Y, Shinkai T, Hori H, Fukunaka Y, Utsunomiya K, Sakata S, Matsumoto C, Shimizu K, Hwang R, Ohmori O, Nakamura J (2007) No association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and schizophrenia in Asian populations: evidence from a case-control study and meta-analysis. Neurosci Lett 415(2):108–112PubMedCrossRefGoogle Scholar
  28. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, Sinclair M, Crombie C, Walker N, St Clair DM (2005) BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 10(2):208–212PubMedCrossRefGoogle Scholar
  29. Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner SF, Waggoner SG, Tahl AR, Sklar P (2010) Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry 15(8):810–815PubMedCrossRefGoogle Scholar
  30. Pillai A, Kale A, Joshi S, Naphade N, Raju MS, Nasrallah H, Mahadik SP (2010) Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. Int J Neuropsychopharmacol 13(4):535–553PubMedCrossRefGoogle Scholar
  31. Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2(1):24–32PubMedCrossRefGoogle Scholar
  32. Radka SF, Holst PA, Fritsche M, Altar CA (1996) Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay. Brain Res 709(1):122–301PubMedCrossRefGoogle Scholar
  33. Randolph C, Tierney MC, Mohr E, Chase TN (1998) The repeatable battery for the assessment of neuropsychological status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol 20:310–319PubMedCrossRefGoogle Scholar
  34. Rizos EN, Rontos I, Laskos E, Arsenis G, Michalopoulou PG, Vasilopoulos D, Gournellis R, Lykouras L (2008) Investigation of serum BDNF levels in drug-naive patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32:1308–1311PubMedCrossRefGoogle Scholar
  35. Rosa A, Cuesta MJ, Fatjó-Vilas M, Peralta V, Zarzuela A, Fañanás L (2006) The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with risk for psychosis: evidence from a family-based association study. Am J Med Genet B Neuropsychiatr Genet 141B(2):135–138PubMedCrossRefGoogle Scholar
  36. Sharma T, Antonova L (2003) Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment. J Psychopharmacol 17(1):89–95PubMedCrossRefGoogle Scholar
  37. Shimizu E, Hashimoto K, Watanabe H, Komatsu N, Okamura N, Koike K, Shinoda N, Nakazato M, Kumakiri C, Okada S, Iyo M (2003) Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia are indistinguishable from controls. Neurosci Lett 351:111–114PubMedCrossRefGoogle Scholar
  38. Szeszko PR, Lipsky R, Mentschel C, Robinson D, Gunduz-Bruce H, Sevy S, Ashtari M, Napolitano B, Bilder RM, Kane JM, Goldman D, Malhotra AK (2005) Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry 10(7):631–636PubMedCrossRefGoogle Scholar
  39. Terracciano A, Piras MG, Lobina M, Mulas A, Meirelles O, Sutin AR, Chan W, Sanna S, Uda M, Crisponi L, Schlessinger D (2011) Genetics of serum BDNF: meta-analysis of the Val66Met and genome-wide association study. World J Biol Psychiatry [Epub ahead of print]Google Scholar
  40. Trajkovska V, Marcussen AB, Vinberg M, Hartvig P, Aznar S, Knudsen GM (2007) Measurements of brain-derived neurotrophic factor: methodological aspects and demographical data. Brain Res Bull 73(1–3):143–149PubMedCrossRefGoogle Scholar
  41. Tramontina J, Frey BN, Andreazza AC, Zandona M, Santin A, Kapczinski F (2007) Val66met polymorphism and serum brain-derived neurotrophic factor levels in bipolar disorder. Mol Psychiatry 12(3):230–231PubMedCrossRefGoogle Scholar
  42. Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9(5):224–237PubMedCrossRefGoogle Scholar
  43. Varnäs K, Lawyer G, Jönsson EG, Kulle B, Nesvåg R, Hall H, Terenius L, Agartz I (2008) Brain-derived neurotrophic factor polymorphisms and frontal cortex morphology in schizophrenia. Psychiatr Genet 18(4):177–183PubMedCrossRefGoogle Scholar
  44. Vinogradov S, Fisher M, Holland C, Shelly W, Wolkowitz O, Mellon SH (2009) Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? Biol Psychiatry 66(6):549–553PubMedCrossRefGoogle Scholar
  45. Xiu MH, Hui L, Dang YF, Hou TD, Zhang CX, Zheng YL, da Chen C, Kosten TR, Zhang XY (2009) Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 33(8):1508–1512PubMedCrossRefGoogle Scholar
  46. Xu MQ, St Clair D, Ott J, Feng GY, He L (2007) Brain-derived neurotrophic factor gene C-270T and Val66Met functional polymorphisms and risk of schizophrenia: a moderate-scale population-based study and meta-analysis. Schizophr Res 91(1–3):6–13PubMedCrossRefGoogle Scholar
  47. Yi Z, Zhang C, Wu Z, Hong W, Li Z, Fang Y, Yu S (2011) Lack of effect of brain derived neurotrophic factor (BDNF) Val66Met polymorphism on early onset schizophrenia in Chinese Han population. Brain Res 1417:146–150PubMedCrossRefGoogle Scholar
  48. Yu H, Zhang Z, Shi Y, Bai F, Xie C, Qian Y, Yuan Y, Deng L (2008) Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han. J Clin Psychiatry 69(7):1104–1111PubMedCrossRefGoogle Scholar
  49. Zhang XY, Zhou DF, Wu GY, Cao LY, Tan YL, Haile CN, Li J, Lu L, Kosten TA, Kosten TR (2008) BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology 33(9):2200–2205PubMedCrossRefGoogle Scholar
  50. Zhang BH, Tan YL, Zhang WF, Wang ZR, Yang GG, Shi C, Zhang XY, Zhou DF (2009) Repeatable battery for the assessment of neuropsychological status (RBANS) as a screening test in Chinese: reliability and validity. Chin Ment Health J 28:865–869Google Scholar
  51. Zhou DH, Yan QZ, Yan XM, Li CB, Fang H, Zheng YL, Zhang CX, Yao HJ, Chen da C, Xiu MH, Kosten TR, Zhang XY (2010) The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 34(6):930–933PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Xiang Yang Zhang
    • 1
    • 5
    Email author
  • Da Chun Chen
    • 2
  • Mei Hong Xiu
    • 2
  • Colin N. Haile
    • 1
  • Xingguang Luo
    • 3
  • Ke Xu
    • 3
  • Hui Ping Zhang
    • 3
  • Lingjun Zuo
    • 3
  • Zhijun Zhang
    • 4
  • Xiangrong Zhang
    • 4
  • Therese A. Kosten
    • 1
  • Thomas R. Kosten
    • 1
    • 6
    Email author
  1. 1.Menninger Department of Psychiatry and Behavioral SciencesBaylor College of MedicineHoustonUSA
  2. 2.Center for Psychiatric ResearchBeijing HuiLongGuan HospitalBeijingPeople’s Republic of China
  3. 3.Department of PsychiatryYale University School of MedicineNew HavenUSA
  4. 4.Department of NeurologyAffiliated ZhongDa Hospital of Southeast UniversityNanjingPeople’s Republic of China
  5. 5.VA Medical CenterHoustonUSA
  6. 6.VA Medical CenterHoustonUSA

Personalised recommendations