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.

The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy

Abstract

Brain-derived neurotrophic factor (BDNF) has a primary role in neuronal development, differentiation and plasticity in both the developing and adult brain. A single-nucleotide polymorphism in the proregion of BDNF, termed the Val66Met polymorphism, results in deficient subcellular translocation and activity-dependent secretion of BDNF, and has been associated with impaired neurocognitive function in healthy adults and in the incidence and clinical features of several psychiatric disorders. Research investigating the Val66Met polymorphism has increased markedly in the past decade, and a gap in integration exists between and within academic subfields interested in the effects of this variant. Here we comprehensively review the role and relevance of the Val66Met polymorphism in psychiatric disorders, with emphasis on suicidal behavior and anxiety, eating, mood and psychotic disorders. The cognitive and molecular neuroscience of the Val66Met polymorphism is also concisely reviewed to illustrate the effects of this genetic variant in healthy controls, and is complemented by a commentary on the behavioral neuroscience of BDNF and the Val66Met polymorphism where relevant to specific disorders. Lastly, a number of controversies and unresolved issues, including small effect sizes, sampling of allele inheritance but not genotype and putative ethnicity-specific effects of the Val66Met polymorphism, are also discussed to direct future research.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  1. Savitz J, Solms M, Ramesar R . The molecular genetics of cognition: dopamine, COMT and BDNF. Genes Brain Behav 2006; 5: 311–328.

    Article  CAS  PubMed  Google Scholar 

  2. Serretti A, Calati R, Mandelli L, De Ronchi D . Serotonin transporter gene variants and behavior: a comprehensive review. Curr Drug Targets 2006; 7: 1659–1669.

    Article  CAS  PubMed  Google Scholar 

  3. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    Article  CAS  PubMed  Google Scholar 

  4. Hong C-J, Liou Y-J, Tsai S-J . Effects of BDNF polymorphisms on brain function and behavior in health and disease. Brain Res Bull 2011; 86: 287–297.

    Article  CAS  PubMed  Google Scholar 

  5. Dincheva I, Glatt CE, Lee FS . Impact of the BDNF Val66Met polymorphism on cognition implications for behavioral genetics. Neuroscientist 2012; 18: 439–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T . Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 2007; 90: 397–406.

    Article  CAS  PubMed  Google Scholar 

  7. Chiaruttini C, Sonego M, Baj G, Simonato M, Tongiorgi E . BDNF mRNA splice variants display activity-dependent targeting to distinct hippocampal laminae. Mol Cell Neurosci 2008; 37: 11–19.

    Article  CAS  PubMed  Google Scholar 

  8. Pattabiraman PP, Tropea D, Chiaruttini C, Tongiorgi E, Cattaneo A, Domenici L . Neuronal activity regulates the developmental expression and subcellular localization of cortical BDNF mRNA isoforms in vivo. Mol Cell Neurosci 2005; 28: 556–570.

    Article  CAS  PubMed  Google Scholar 

  9. Baj G, Leone E, Chao MV, Tongiorgi E . Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments. Proc Natl Acad Sci USA 2011; 108: 16813–16818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tongiorgi E . Activity-dependent expression of brain-derived neurotrophic factor in dendrites: facts and open questions. Neurosci Res 2008; 61: 335–346.

    Article  CAS  PubMed  Google Scholar 

  11. Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 2001; 276: 12660–12666.

    Article  CAS  PubMed  Google Scholar 

  12. Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 2005; 25: 5455–5463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Seidah NG, Benjannet S, Pareek S, Chrétien M, Murphy RA . Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 1996; 379: 247–250.

    Article  CAS  PubMed  Google Scholar 

  14. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 2004; 306: 487–491.

    Article  CAS  PubMed  Google Scholar 

  15. Seidah NG, Mowla SJ, Hamelin J, Mamarbachi AM, Benjannet S, Touré BB, et al. Mammalian subtilisin/kexin isozyme SKI-1: a widely expressed proprotein convertase with a unique cleavage specificity and cellular localization. Proc Natl Acad Sci USA 1999; 96: 1321–1326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Soppet D, Escandon E, Maragos J, Middlemas DS, Raid SW, Blair J, et al. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trk B tyrosine kinase receptor. Cell 1991; 65: 895–903.

    Article  CAS  PubMed  Google Scholar 

  17. Chao MV . Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 2003; 4: 299–309.

    Article  CAS  PubMed  Google Scholar 

  18. Chen Z-Y, Ieraci A, Teng H, Dall H, Meng C-X, Herrera DG, et al. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J Neurosci 2005; 25: 6156–6166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chiaruttini C, Vicario A, Li Z, Baj G, Braiuca P, Wu Y, et al. Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation. Proc Natl Acad Sci USA 2009; 106: 16481–16486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen Z-Y, Jing D, Bath KG, Ieraci A, Khan T, Siao C-J, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 2006; 314: 140–143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Anastasia A, Deinhardt K, Chao MV, Will NE, Irmady K, Lee FS, et al. Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat Commun 2013; 4: 2490.

    Article  PubMed  CAS  Google Scholar 

  22. Rezgaoui M, Hermey G, Riedel IB, Hampe W, Schaller H, Hermans-Borgmeyer I . Identification of SorCS2, a novel member of the VPS10 domain containing receptor family, prominently expressed in the developing mouse brain. Mech Dev 2001; 100: 335–338.

    Article  CAS  PubMed  Google Scholar 

  23. Glerup S, Olsen D, Vaegter CB, Gustafsen C, Sjoegaard SS, Hermey G, et al. SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia. Neuron 2014; 82: 1074–1087.

    Article  CAS  PubMed  Google Scholar 

  24. Bath KG, Jing DQ, Dincheva I, Neeb CC, Pattwell SS, Chao MV, et al. BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. Neuropsychopharmacology 2012; 37: 1297–1304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ninan I, Bath KG, Dagar K, Perez-Castro R, Plummer MR, Lee FS, et al. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus. J Neurosci 2010; 30: 8866–8870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu R-J, Lee FS, Li X-Y, Bambico F, Duman RS, Aghajanian GK . Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 2012; 71: 996–1005.

    Article  CAS  PubMed  Google Scholar 

  27. Pattwell SS, Bath KG, Perez-Castro R, Lee FS, Chao MV, Ninan I . The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex. J Neurosci 2012; 32: 2410–2421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS . Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 2000; 3: 323–329.

    Article  CAS  PubMed  Google Scholar 

  29. Tyler WJ, Pozzo-Miller LD . BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci 2001; 21: 4249–4258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li Y-X, Zhang Y, Lester HA, Schuman EM, Davidson N . Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons. J Neurosci 1998; 18: 10231–10240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER . Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 1996; 16: 1137–1145.

    Article  CAS  PubMed  Google Scholar 

  32. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B . Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 1996; 381: 706–709.

    Article  CAS  PubMed  Google Scholar 

  33. Bramham CR, Messaoudi E . BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 2005; 76: 99–125.

    Article  CAS  PubMed  Google Scholar 

  34. Lu B . BDNF and activity-dependent synaptic modulation. Learn Mem 2003; 10: 86–98.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gottschalk WA, Jiang H, Tartaglia N, Feng L, Figurov A, Lu B . Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. Learn Mem 1999; 6: 243–256.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Alonso M, Medina JH, Pozzo-Miller L . ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 2004; 11: 172–178.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Tyler WJ, Pozzo‐Miller L . Miniature synaptic transmission and BDNF modulate dendritic spine growth and form in rat CA1 neurones. J Physiol 2003; 553: 497–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Horch HW, Katz LC . BDNF release from single cells elicits local dendritic growth in nearby neurons. Nat Neurosci 2002; 5: 1177–1184.

    Article  CAS  PubMed  Google Scholar 

  39. Spencer JL, Waters EM, Milner TA, Lee FS, McEwen BS . BDNF variant Val66Met interacts with estrous cycle in the control of hippocampal function. Proc Natl Acad Sci USA 2010; 107: 4395–4400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 2003; 23: 6690–6694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dempster E, Toulopoulou T, McDonald C, Bramon E, Walshe M, Filbey F, et al. Association between BDNF val66met genotype and episodic memory. Am J Med Genet B 2005; 134: 73–75.

    Article  Google Scholar 

  42. Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta J-K . BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry 2006; 59: 812–815.

    Article  CAS  PubMed  Google Scholar 

  43. Hashimoto R, Moriguchi Y, Yamashita F, Mori T, Nemoto K, Okada T, et al. Dose-dependent effect of the Val66Met polymorphism of the brain-derived neurotrophic factor gene on memory-related hippocampal activity. Neurosci Res 2008; 61: 360–367.

    Article  CAS  PubMed  Google Scholar 

  44. Hajek T, Kopecek M, Höschl C . Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: Meta-analysis. World J Biol Psychiatry 2012; 13: 178–187.

    Article  PubMed  Google Scholar 

  45. Molendijk ML, Bus BA, Spinhoven P, Kaimatzoglou A, Voshaar RCO, Penninx BW, et al. A systematic review and meta‐analysis on the association between BDNF val66met and hippocampal volume—a genuine effect or a winners curse? Am J Med Genet B 2012; 159: 731–740.

    Article  CAS  Google Scholar 

  46. Mandelman SD, Grigorenko EL . BDNF Val66Met and cognition: all, none, or some? A meta‐analysis of the genetic association. Genes Brain Behav 2012; 11: 127–136.

    Article  CAS  PubMed  Google Scholar 

  47. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 2004; 24: 10099–10102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim SN, Kang D-H, Yun J-Y, Lee TY, Jung WH, Jang JH et al. Impact of the BDNF Val66Met polymorphism on regional brain gray matter volumes: relevance to the stress response. Psychiatry Invest 2013; 10: 173–179.

    Article  CAS  Google Scholar 

  49. Nemoto K, Ohnishi T, Mori T, Moriguchi Y, Hashimoto R, Asada T, et al. The Val66Met polymorphism of the brain-derived neurotrophic factor gene affects age-related brain morphology. Neurosci Lett 2006; 397: 25–29.

    Article  CAS  PubMed  Google Scholar 

  50. Yang X, Liu P, Sun J, Wang G, Zeng F, Yuan K, et al. Impact of brain-derived neurotrophic factor Val66Met polymorphism on cortical thickness and voxel-based morphometry in healthy Chinese young adults. PLoS One 2012; 7: e37777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Phillips R, LeDoux J . Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 1992; 106: 274.

    Article  CAS  PubMed  Google Scholar 

  52. Adolphs R, Tranel D, Damasio H, Damasio A . Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 1994; 372: 669–672.

    Article  CAS  PubMed  Google Scholar 

  53. Montag C, Weber B, Fliessbach K, Elger C, Reuter M . The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: incremental support for a genetic risk factor for depression. Psychol Med 2009; 39: 1831.

    Article  CAS  PubMed  Google Scholar 

  54. Sublette ME, Baca-Garcia E, Parsey RV, Oquendo MA, Rodrigues SM, Galfalvy H, et al. Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1652–1655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. van Wingen G, Rijpkema M, Franke B, van Eijndhoven P, Tendolkar I, Jan Verkes R, et al. The brain-derived neurotrophic factor Val66Met polymorphism affects memory formation and retrieval of biologically salient stimuli. NeuroImage 2010; 50: 1212–1218.

    Article  CAS  PubMed  Google Scholar 

  56. Voineskos AN, Lerch JP, Felsky D, Shaikh S, Rajji TK, Miranda D, et al. The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. Arch Gen Psychiatry 2011; 68: 198–206.

    Article  PubMed  Google Scholar 

  57. Takahashi T, Suzuki M, Tsunoda M, Kawamura Y, Takahashi N, Tsuneki H, et al. Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons. Neurosci Lett 2008; 435: 34–39.

    Article  CAS  PubMed  Google Scholar 

  58. Kochunov P, Glahn DC, Lancaster JL, Winkler AM, Smith S, Thompson PM, et al. Genetics of microstructure of cerebral white matter using diffusion tensor imaging. NeuroImage 2010; 53: 1109–1116.

    Article  CAS  PubMed  Google Scholar 

  59. Kennedy KM, Rodrigue KM, Land SJ, Raz N . BDNF val66met polymorphism influences age differences in microstructure of the corpus callosum. Front Hum Neurosci 2009; 3: 19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science 2010; 327: 863–866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chiang M-C, Barysheva M, Toga AW, Medland SE, Hansell NK, James MR, et al. BDNF gene effects on brain circuitry replicated in 455 twins. NeuroImage 2011; 55: 448–454.

    Article  CAS  PubMed  Google Scholar 

  62. Tost H, Alam T, Geramita M, Rebsch C, Kolachana B, Dickinson D, et al. Effects of the BDNF Val66Met polymorphism on white matter microstructure in healthy adults. Neuropsychopharmacology 2013; 38: 525–532.

    Article  CAS  PubMed  Google Scholar 

  63. Taylor WD, Züchner S, McQuoid DR, Payne ME, MacFall JR, Steffens DC, et al. The brain-derived neurotrophic factor VAL66MET polymorphism and cerebral white matter hyperintensities in late-life depression. Am J Geriatr Psychiatry 2008; 16: 263–271.

    Article  PubMed  Google Scholar 

  64. Taylor WD, Payne ME, Krishnan K, Wagner HR, Provenzale JM, Steffens DC, et al. Evidence of white matter tract disruption in MRI hyperintensities. Biol Psychiatry 2001; 50: 179–183.

    Article  CAS  PubMed  Google Scholar 

  65. Iverson GL, Hakulinen U, Wäljas M, Dastidar P, Lange RT, Soimakallio S, et al. To exclude or not to exclude: white matter hyperintensities in diffusion tensor imaging research. Brain Inj 2011; 25: 1325–1332.

    Article  PubMed  Google Scholar 

  66. Jiang X, Xu K, Hoberman J, Tian F, Marko AJ, Waheed JF, et al. BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects. Neuropsychopharmacology 2005; 30: 1353–1361.

    Article  CAS  PubMed  Google Scholar 

  67. Montag C, Basten U, Stelzel C, Fiebach CJ, Reuter M . The BDNF Val66Met polymorphism and anxiety: Support for animal knock-in studies from a genetic association study in humans. Psychiatry Res 2010; 179: 86–90.

    Article  CAS  PubMed  Google Scholar 

  68. Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T, et al. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl) 2005; 180: 95–99.

    Article  CAS  Google Scholar 

  69. Hünnerkopf R, Strobel A, Gutknecht L, Brocke B, Lesch KP . Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits. Neuropsychopharmacology 2007; 32: 2552–2560.

    Article  PubMed  CAS  Google Scholar 

  70. Arias B, Aguilera M, Moya J, Sáiz P, Villa H, Ibáñez M, et al. The role of genetic variability in the SLC6A4, BDNF and GABRA6 genes in anxiety‐related traits. Acta Psychiat Scand 2012; 125: 194–202.

    Article  CAS  PubMed  Google Scholar 

  71. Frustaci A, Pozzi G, Gianfagna F, Manzoli L, Boccia S . Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits. Neuropsychobiology 2008; 58: 163–170.

    Article  CAS  PubMed  Google Scholar 

  72. Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M . Sequence variants of the brain-derived neurotrophic factor BDNF gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet 2003; 73: 370–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hemmings SM, Kinnear CJ, Van Der Merwe L, Lochner C, Corfield VA, Moolman-Smook JC, et al. Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD). World J Biol Psychiatry 2008; 9: 126–134.

    Article  PubMed  Google Scholar 

  74. Katerberg H, Lochner C, Cath DC, de Jonge P, Bochdanovits Z, Moolman‐Smook JC, et al. The role of the brain‐derived neurotrophic factor (BDNF) val66met variant in the phenotypic expression of obsessive‐compulsive disorder (OCD). Am J Med Genet B 2009; 150: 1050–1062.

    Article  CAS  Google Scholar 

  75. Rocha FFd, Malloy-Diniz L, Lage NV, Corrêa H . Positive association between MET allele (BDNF Val66Met polymorphism) and obsessive-compulsive disorder. Rev Bras Psiquiatr 2010; 32: 323–324.

    Article  PubMed  Google Scholar 

  76. Alonso P, Gratacòs M, Menchón JM, Saiz-Ruiz J, Segalàs C, Baca-García E et al. Extensive genotyping of the BDNF and NTRK2 genes define protective haplotypes against obsessive-compulsive disorder. Biol Psychiatry 2008; 63: 619–628.

    Article  CAS  PubMed  Google Scholar 

  77. Fullana M, Alonso P, Gratacos M, Jaurrieta N, Jimenez-Murcia S, Segalas C, et al. Variation in the BDNF Val66Met polymorphism and response to cognitive-behavior therapy in obsessive-compulsive disorder. Eur Psychiatry 2012; 27: 386–390.

    Article  CAS  PubMed  Google Scholar 

  78. Alonso P, López-Solà C, Gratacós M, Fullana MA, Segalàs C, Real E, et al. The interaction between COMT and BDNF variants influences obsessive–compulsive-related dysfunctional beliefs. J Anxiety Disord 2013; 27: 321–327.

    Article  PubMed  Google Scholar 

  79. Márquez L, Camarena B, Hernández S, Lóyzaga C, Vargas L, Nicolini H . Association study between BDNF gene variants and Mexican patients with obsessive–compulsive disorder. Eur Neuropsychopharmacol 2013; 23: 1600–1605.

    Article  PubMed  CAS  Google Scholar 

  80. Park JS, Lim S, Ha J, Lee MS, Oh KS . Lack of association between brain-derived neurotrophic factor gene Val66Met polymorphism and generalized social anxiety disorder in Korean population. Clin Psychopharmacol Neurosci 2011; 9: 129–133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lam P, Cheng C-Y, Hong C-J, Tsai S-J . Association study of a brain-derived neurotrophic factor (Val66Met) genetic polymorphism and panic disorder. Neuropsychobiology 2004; 49: 178–181.

    Article  CAS  PubMed  Google Scholar 

  82. Shimizu E, Hashimoto K, Koizumi H, Kobayashi K, Itoh K, Mitsumori M, et al. No association of the brain-derived neurotrophic factor (BDNF) gene polymorphisms with panic disorder. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 708–712.

    Article  CAS  PubMed  Google Scholar 

  83. Park JS, Lim S, Ha J, Lee MS, Oh KS . Lack of association between brain-derived neurotrophic factor gene Val66Met polymorphisms and panic disorder in Korean Population. Psychiatry Invest 2007; 4: 27–30.

    Google Scholar 

  84. Otowa T, Shimada T, Kawamura Y, Liu X, Inoue K, Sugaya N et al. No association between the brain-derived neurotrophic factor gene and panic disorder in Japanese population. J Hum Genet 2009; 54: 437–439.

    Article  CAS  PubMed  Google Scholar 

  85. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ . Induction of fear extinction with hippocampal-infralimbic BDNF. Science 2010; 328: 1288–1290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Liu IY, Lyons WE, Mamounas LA, Thompson RF . Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning. J Neurosci 2004; 24: 7958–7963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Karpova NN, Pickenhagen A, Lindholm J, Tiraboschi E, Kulesskaya N, Ágústsdóttir A, et al. Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science 2011; 334: 1731–1734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Psotta L, Lessmann V, Endres T . Impaired fear extinction learning in adult heterozygous BDNF knock-out mice. Neurobiol Learn Mem 2013; 103: 34–38.

    Article  CAS  PubMed  Google Scholar 

  89. Mühlberger A, Andreatta M, Ewald H, Glotzbach-Schoon E, Tröger C, Baumann C, et al. The BDNF Val66Met polymorphism modulates the generalization of cued fear responses to a novel context. Neuropsychopharmacology 2013; 39: 1187–1195.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Montag C, Reuter M, Newport B, Elger C, Weber B . The BDNF Val66Met polymorphism affects amygdala activity in response to emotional stimuli: evidence from a genetic imaging study. NeuroImage 2008; 42: 1554–1559.

    Article  PubMed  Google Scholar 

  91. Mukherjee P, Whalley HC, McKirdy JW, McIntosh AM, Johnstone EC, Lawrie SM, et al. Effects of the BDNF Val66Met polymorphism on neural responses to facial emotion. Psychiatry Res Neuroimag 2011; 191: 182–188.

    Article  CAS  Google Scholar 

  92. Lee HJ, Kang RH, Lim SW, Paik JW, Choi MJ, Lee MS . No association between the brain‐derived neurotrophic factor gene Val66Met polymorphism and post‐traumatic stress disorder. Stress Health 2006; 22: 115–119.

    Article  Google Scholar 

  93. Valente NLM, Vallada H, Cordeiro Q, Miguita K, Bressan RA, Andreoli SB, et al. Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF. J Mol Neurosci 2011; 44: 59–67.

    Article  CAS  PubMed  Google Scholar 

  94. Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS, et al. Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet B 2006; 141: 387–393.

    Article  CAS  Google Scholar 

  95. Pivac N, Kozaric-Kovacic D, Grubisic-Ilic M, Nedic G, Rakos I, Nikolac M, et al. The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder. World J Biol Psychiatry 2012; 13: 306–311.

    Article  PubMed  Google Scholar 

  96. Zhang L, Benedek D, Fullerton C, Forsten R, Naifeh J, Li X, et al. PTSD risk is associated with BDNF Val66Met and BDNF overexpression. Mol Psychiatry 2013; 19: 8–10.

    Article  PubMed  CAS  Google Scholar 

  97. Felmingham KL, Dobson-Stone C, Schofield PR, Quirk GJ, Bryant RA . The brain-derived neurotrophic factor Val66Met polymorphism predicts response to exposure therapy in posttraumatic stress disorder. Biol Psychiatry 2013; 73: 1059–1063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gonul AS, Akdeniz F, Taneli F, Donat O, Eker Ç, Vahip S . Effect of treatment on serum brain–derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 2005; 255: 381–386.

    Article  PubMed  Google Scholar 

  99. Castrén E, Rantamäki T . The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 2010; 70: 289–297.

    Article  PubMed  CAS  Google Scholar 

  100. Chen B, Dowlatshahi D, MacQueen GM, Wang J-F, Young LT . Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001; 50: 260–265.

    Article  CAS  PubMed  Google Scholar 

  101. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM . Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997; 56: 131–137.

    Article  CAS  PubMed  Google Scholar 

  102. Wray NR, James MR, Handoko HY, Dumenil T, Lind PA, Montgomery GW, et al. Association study of candidate variants from brain-derived neurotrophic factor and dystrobrevin-binding protein 1 with neuroticism, anxiety, and depression. Psychiatr Genet 2008; 18: 219–225.

    Article  PubMed  Google Scholar 

  103. Terracciano A, Tanaka T, Sutin AR, Deiana B, Balaci L, Sanna S, et al. BDNF Val66Met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism. Neuropsychopharmacology 2009; 35: 1083–1089.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB, et al. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry 2005; 58: 307–314.

    Article  CAS  PubMed  Google Scholar 

  105. Borroni B, Grassi M, Archetti S, Costanzi C, Bianchi M, Caimi L, et al. BDNF genetic variations increase the risk of Alzheimer's disease-related depression. J Alzheimers Dis 2009; 18: 867–875.

    Article  CAS  PubMed  Google Scholar 

  106. Autry AE, Monteggia LM . Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64: 238–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Duman RS, Monteggia LM . A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006; 59: 1116–1127.

    Article  CAS  PubMed  Google Scholar 

  108. Hwang J-P, Tsai S-J, Hong C-J, Yang C-H, Lirng J-F, Yang Y-M . The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging 2006; 27: 1834–1837.

    Article  CAS  PubMed  Google Scholar 

  109. Taylor WD, Züchner S, McQuoid DR, Steffens DC, Speer MC, Krishnan KRR . Allelic differences in the brain-derived neurotrophic factor Val66Met polymorphism in late-life depression. Am J Geriatr Psychiatry 2007; 15: 850–857.

    Article  PubMed  Google Scholar 

  110. Licinio J, Dong C, Wong M-L . Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry 2009; 66: 488–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chi MH, Chang HH, Lee S-Y, Lee IH, Gean PW, Yang YK, et al. Brain derived neurotrophic factor gene polymorphism (Val66Met) and short-term antidepressant response in major depressive disorder. J Affect Disord 2010; 126: 430–435.

    Article  CAS  PubMed  Google Scholar 

  112. Tsai SJ, Cheng CY, Yu YWY, Chen TJ, Hong CJ . Association study of a brain‐derived neurotrophic‐factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B 2003; 123: 19–22.

    Article  Google Scholar 

  113. Domschke K, Lawford B, Laje G, Berger K, Young R, Morris P, et al. Brain-derived neurotrophic factor (BDNF) gene: no major impact on antidepressant treatment response. Int J Neuropsychopharmacol 2010; 13: 93.

    Article  CAS  PubMed  Google Scholar 

  114. Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T, et al. No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study. Biol Psychiatry 2004; 56: 376–378.

    Article  CAS  PubMed  Google Scholar 

  115. Gratacòs M, González JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X . Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case–control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 2007; 61: 911–922.

    Article  PubMed  CAS  Google Scholar 

  116. Kanazawa T, Glatt SJ, Kia-Keating B, Yoneda H, Tsuang MT . Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder. Psychiatr Genet 2007; 17: 165–170.

    Article  PubMed  Google Scholar 

  117. Lohoff F, Sander T, Ferraro T, Dahl J, Gallinat J, Berrettini W . Confirmation of association between the Val66Met polymorphism in the brain‐derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am J Med Genet B 2005; 139: 51–53.

    Article  CAS  Google Scholar 

  118. Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook EH . Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2004; 161: 1698–1700.

    Article  PubMed  Google Scholar 

  119. Mueller DJ, De Luca V, Sicard T, King N, Strauss J, Kennedy JL . Brain-derived neurotrophic factor (BDNF) gene and rapid-cycling bipolar disorder Family-based association study. Br J Psychiatry 2006; 189: 317–323.

    Article  Google Scholar 

  120. Sklar P, Gabriel S, McInnis M, Bennett P, Lim Y, Tsan G, et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 2002; 7: 579–593.

    Article  CAS  PubMed  Google Scholar 

  121. Bus BA, Arias-Vasquez A, Franke B, Prickaerts J, de Graaf J, Voshaar RCO . Increase in serum brain-derived neurotrophic factor in Met allele carriers of the BDNF Val66Met polymorphism is specific to males. Neuropsychobiology 2012; 65: 183–187.

    Article  CAS  PubMed  Google Scholar 

  122. Elfving B, Buttenschøn HN, Foldager L, Poulsen PH, Andersen JH, Grynderup MB, et al. Depression, the Val66Met polymorphism, age, and gender influence the serum BDNF level. J Psychiatr Res 2012; 46: 1118–1125.

    Article  PubMed  Google Scholar 

  123. Verhagen M, Van Der Meij A, Van Deurzen P, Janzing J, Arias-Vasquez A, Buitelaar J, et al. Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatry 2010; 15: 260–271.

    Article  CAS  PubMed  Google Scholar 

  124. Lavebratt C, Åberg E, Sjöholm LK, Forsell Y . Variations in FKBP5 and BDNF genes are suggestively associated with depression in a Swedish population-based cohort. J Affect Disord 2010; 125: 249–255.

    Article  CAS  PubMed  Google Scholar 

  125. Alexander N, Osinsky R, Schmitz A, Mueller E, Kuepper Y, Hennig J . The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress. Psychoneuroendocrinology 2010; 35: 949–953.

    Article  CAS  PubMed  Google Scholar 

  126. Shalev I, Lerer E, Israel S, Uzefovsky F, Gritsenko I, Mankuta D, et al. BDNF Val66Met polymorphism is associated with HPA axis reactivity to psychological stress characterized by genotype and gender interactions. Psychoneuroendocrinology 2009; 34: 382–388.

    Article  CAS  PubMed  Google Scholar 

  127. Dougherty LR, Klein DN, Congdon E, Canli T, Hayden EP . Interaction between 5-HTTLPR and BDNF Val66Met polymorphisms on HPA axis reactivity in preschoolers. Biol Psychol 2010; 83: 93–100.

    Article  PubMed  Google Scholar 

  128. Yu H, Wang DD, Wang Y, Liu T, Lee FS, Chen ZY . Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J Neurosci 2012; 32: 4092–4101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Drachmann Bukh J, Bock C, Vinberg M, Werge T, Gether U, Vedel Kessing L . Interaction between genetic polymorphisms and stressful life events in first episode depression. J Affect Disord 2009; 119: 107–115.

    Article  CAS  Google Scholar 

  130. Aguilera M, Arias Sampériz B, Wichers M, Barrantes Vidal N, Moya Higueras J, Villa Martín E, et al. Early adversity and 5-HTT-BDNF genes: new evidences of gene–environment interactions on depressive symptoms in a general population. Psychol Med 2009; 39: 1425–1432.

    Article  CAS  PubMed  Google Scholar 

  131. Bath KG, Chuang J, Spencer-Segal JL, Amso D, Altemus M, McEwen BS, et al. Variant brain-derived neurotrophic factor (Valine66Methionine) polymorphism contributes to developmental and estrous stage-specific expression of anxiety-like behavior in female mice. Biol Psychiatry 2012; 72: 499–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 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 

  133. Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 2003; 23: 349–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zou Y-F, Ye D-Q, Feng X-L, Su H, Pan F-M, Liao F-F . Meta-analysis of BDNF Val66Met polymorphism association with treatment response in patients with major depressive disorder. Eur Neuropsychopharmacol 2010; 20: 535–544.

    Article  CAS  PubMed  Google Scholar 

  135. Dmitrzak-Weglarz M, Rybakowski JK, Suwalska A, Skibinska M, Leszczynska-Rodziewicz A, Szczepankiewicz A, et al. Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients. Pharmacogenomics 2008; 9: 1595–1603.

    Article  CAS  PubMed  Google Scholar 

  136. Rybakowski JK, Suwalska A, Skibinska M, Dmitrzak‐Weglarz M, Leszczynska‐Rodziewicz A, Hauser J . Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes. Am J Med Genet B 2007; 144: 820–823.

    Article  CAS  Google Scholar 

  137. Michelon L, Meira-Lima I, Cordeiro Q, Miguita K, Breen G, Collier D, et al. Association study of the INPP1, 5HTT, BDNF, AP-2β and GSK-3β GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder. Neurosci Lett 2006; 403: 288–293.

    Article  CAS  PubMed  Google Scholar 

  138. Anttila S, Huuhka K, Huuhka M, Rontu R, Hurme M, Leinonen E, et al. Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J Neural Transm 2007; 114: 1065–1068.

    Article  CAS  PubMed  Google Scholar 

  139. Antal A, Chaieb L, Moliadze V, Monte-Silva K, Poreisz C, Thirugnanasambandam N, et al. Brain-derived neurotrophic factor BDNF gene polymorphisms shape cortical plasticity in humans. Brain Stimul 2010; 3: 230–237.

    Article  PubMed  Google Scholar 

  140. Bocchio-Chiavetto L, Miniussi C, Zanardini R, Gazzoli A, Bignotti S, Specchia C, et al. 5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression. Neurosci Lett 2008; 437: 130–134.

    Article  CAS  PubMed  Google Scholar 

  141. Alexopoulos GS, Glatt CE, Hoptman MJ, Kanellopoulos D, Murphy CF, Kelly RE Jr, et al. BDNF Val66met polymorphism, white matter abnormalities and remission of geriatric depression. J Affect Disord 2010; 125: 262–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Taylor WD, McQuoid DR, Ashley-Koch A, MacFall JR, Bridgers J, Krishnan RR, et al. BDNF Val66Met genotype and 6-month remission rates in late-life depression. Pharmacogenomics J 2010; 11: 146–154.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Taylor WD, Züchner S, McQuoid DR, Steffens DC, Blazer DG, Krishnan KRR . Social support in older individuals: the role of the BDNF Val66Met polymorphism. Am J Med Genet B 2008; 147: 1205–1212.

    Article  Google Scholar 

  144. Fairburn CG, Harrison PJ . Eating disorders. Lancet 2003; 361: 407–416.

    Article  PubMed  Google Scholar 

  145. Bulik CM . Exploring the gene–environment nexus in eating disorders. J Psychiatry Neurosci 2005; 30: 335.

    PubMed  PubMed Central  Google Scholar 

  146. Monteleone P, Maj M . Genetic susceptibility to eating disorders: associated polymorphisms and pharmacogenetic suggestions. Pharmacogenomics 2008; 9: 1487–1520.

    Article  CAS  PubMed  Google Scholar 

  147. Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R, et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 2001; 15: 1748–1757.

    Article  CAS  PubMed  Google Scholar 

  148. Unger TJ, Calderon GA, Bradley LC, Sena-Esteves M, Rios M . Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J Neurosci 2007; 27: 14265–14274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 1999; 96: 15239–15244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Fox EA, Byerly MS . A mechanism underlying mature-onset obesity: evidence from the hyperphagic phenotype of brain-derived neurotrophic factor mutants. Am J Physiol Regul Integr Comp Physiol 2004; 286: 994–1004.

    Article  Google Scholar 

  151. Kernie SG, Liebl DJ, Parada LF . BDNF regulates eating behavior and locomotor activity in mice. EMBO J 2000; 19: 1290–1300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Duan W, Guo Z, Jiang H, Ware M, Mattson MP . Reversal of behavioral and metabolic abnormalities, and insulin resistance syndrome, by dietary restriction in mice deficient in brain-derived neurotrophic factor. Endocrinology 2003; 144: 2446–2453.

    Article  CAS  PubMed  Google Scholar 

  153. Wang C, Bomberg E, Levine A, Billington C, Kotz CM . Brain-derived neurotrophic factor in the ventromedial nucleus of the hypothalamus reduces energy intake. Am J Physiol Regul Integr Comp Physiol 2007; 293: 1037–1045.

    Article  CAS  Google Scholar 

  154. Pelleymounter MA, Cullen MJ, Wellman CL . Characteristics of BDNF-induced weight loss. Exp Neurol 1995; 131: 229–238.

    Article  CAS  PubMed  Google Scholar 

  155. Gray J, Yeo GS, Cox JJ, Morton J, Adlam A-LR, Keogh JM, et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 2006; 55: 3366–3371.

    Article  CAS  PubMed  Google Scholar 

  156. Han JC, Liu Q-R, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 2008; 359: 918–927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Shinawi M, Sahoo T, Maranda B, Skinner S, Skinner C, Chinault C, et al. 11p14. 1 Microdeletions associated with ADHD, autism, developmental delay, and obesity. Am J Med Gen A 2011; 155: 1272–1280.

    Article  CAS  Google Scholar 

  158. Koizumi H, Hashimoto K, Itoh K, Nakazato M, Shimizu E, Ohgake S, et al. Association between the brain‐derived neurotrophic factor 196G/A polymorphism and eating disorders. Am J Med Genet B 2004; 127: 125–127.

    Article  Google Scholar 

  159. Ribasés M, Gratacòs M, Fernández-Aranda F, Bellodi L, Boni C, Anderluh M, et al. Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. Eur J Hum Genet 2004; 13: 428–434.

    Article  CAS  Google Scholar 

  160. Hong KW, Lim JE, Go MJ, Shin YS, Ahn Y, Han BG, et al. Recapitulation of the association of the Val66Met polymorphism of BDNF gene with BMI in Koreans. Obesity 2012; 20: 1871–1875.

    Article  CAS  PubMed  Google Scholar 

  161. Dardennes RM, Zizzari P, Tolle V, Foulon C, Kipman A, Romo L, et al. Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset. Psychoneuroendocrinology 2007; 32: 106–113.

    Article  CAS  PubMed  Google Scholar 

  162. Rybakowski F, Dmitrzak-Weglarz M, Szczepankiewicz A, Skibinska M, Slopien A, Rajewski A, et al. Brain derived neurotrophic factor gene Val66Met and-270C/T polymorphisms and personality traits predisposing to anorexia nervosa. Neuroendocrinol Lett 2007; 28: 153–158.

    PubMed  Google Scholar 

  163. Hudson JI, Hiripi E, Pope HG Jr, Kessler RC . The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 2007; 61: 348–358.

    Article  PubMed  Google Scholar 

  164. Hill R, Wu Y, Kwek P, Buuse Mvd . Modulatory effects of sex steroid hormones on brain‐derived neurotrophic factor‐tyrosine kinase B expression during adolescent development in C57Bl/6 mice. J Neuroendocrinol 2012; 24: 774–788.

    Article  CAS  PubMed  Google Scholar 

  165. Monteleone P, Zanardini R, Tortorella A, Gennarelli M, Castaldo E, Canestrelli B, et al. The 196G/A (val66met) polymorphism of the BDNF gene is significantly associated with binge eating behavior in women with bulimia nervosa or binge eating disorder. Neurosci Lett 2006; 406: 133–137.

    Article  CAS  PubMed  Google Scholar 

  166. Akkermann K, Hiio K, Villa I, Harro J . Food restriction leads to binge eating dependent upon the effect of the brain-derived neurotrophic factor Val66Met polymorphism. Psychiatry Res 2011; 185: 39–43.

    Article  CAS  PubMed  Google Scholar 

  167. Zakharyan R, Boyajyan A, Arakelyan A, Gevorgyan A, Mrazek F, Petrek M . Functional variants of the genes involved in neurodevelopment and susceptibility to schizophrenia in an Armenian population. Hum Immunol 2011; 72: 746–748.

    Article  CAS  PubMed  Google Scholar 

  168. Gourion D, Goldberger C, Leroy S, Bourdel M-C, Olié J-P, Krebs M-O . Age at onset of schizophrenia: interaction between brain-derived neurotrophic factor and dopamine D3 receptor gene variants. NeuroReport 2005; 16: 1407–1410.

    Article  CAS  PubMed  Google Scholar 

  169. Zhou DH, Yan QZ, Yan XM, Li CB, Fang H, Zheng YL, et al. The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients. Progr Neuro-Psychopharmacol Biol Psychiatry 2010; 34: 930–933.

    Article  CAS  Google Scholar 

  170. Naoe Y, Shinkai T, Hori H, Fukunaka Y, Utsunomiya K, Sakata S, et al. 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 2007; 415: 108–112.

    Article  CAS  PubMed  Google Scholar 

  171. Skibinska M, Hauser J, Czerski P, Leszcynska-Rodziewicz A, Kosmowska M, Kapelski P, et al. Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymoprhism in schizophrenia and bipolar affective disorder. World J Biol Psychiatry 2004; 5: 215–220.

    Article  PubMed  Google Scholar 

  172. Tochigi M, Otowa T, Suga M, Rogers M, Minato T, Yamasue H, et al. No evidence for an association between the BDNF Val66Met polymorphism and schizophrenia or personality traits. Schizophr Res 2006; 87: 45–47.

    Article  PubMed  Google Scholar 

  173. Watanabe Y, Muratake T, Kaneko N, Nunokawa A, Someya T . No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population. Schizophr Res 2006; 84: 29–35.

    Article  PubMed  Google Scholar 

  174. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 2005; 10: 208–212.

    Article  CAS  PubMed  Google Scholar 

  175. Qian L, Zhao J, Shi Y, Zhao X, Feng G, Xu F, et al. Brain-derived neurotrophic factor and risk of schizophrenia: an association study and meta-analysis. Biochem Biophys Res Commun 2007; 353: 738–743.

    Article  CAS  PubMed  Google Scholar 

  176. Kawashima K, Ikeda M, Kishi T, Kitajima T, Yamanouchi Y, Kinoshita Y, et al. BDNF is not associated with schizophrenia: data from a Japanese population study and meta-analysis. Schizophr Res 2009; 112: 72–79.

    Article  PubMed  Google Scholar 

  177. Zintzaras E . Brain-derived neurotrophic factor gene polymorphisms and schizophrenia: a meta-analysis. Psychiatr Genet 2007; 17: 69–75.

    Article  PubMed  Google Scholar 

  178. Xu MQ St, Clair D, Ott J, Feng GY, He L . 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 2007; 91: 6–13.

    Article  PubMed  Google Scholar 

  179. Rosa A, Cuesta MJ, Fatjo-Vilas M, Peralta V, Zarzuela A, Fananas L . 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 2006; 141B: 135–138.

    Article  Google Scholar 

  180. Golimbet VE, Korovaitseva GI, Abramova LI, Kasparov SV, Uvarova LG . Association of the Val66Met polymorphism of the brain-derived neurotrophic factor gene with schizophrenia in Russians. Mol Biol 2008; 42: 531–535.

    Article  CAS  Google Scholar 

  181. Sullivan PF . The psychiatric GWAS consortium: big science comes to psychiatry. Neuron 2010; 68: 182–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lin Z, Su Y, Zhang C, Xing M, Ding W, Liao L, et al. The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia. PLoS One 2013; 8: e74264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Whalley HC, Baig BJ, Hall J, Job DE, McIntosh AM, Cunningham‐Owens DG, et al. Effects of the BDNF val66met polymorphism on prefrontal brain function in a population at high genetic risk of schizophrenia. Am J Med Genet B 2010; 153: 1474–1482.

    Article  Google Scholar 

  184. Skilleter AJ, Weickert CS, Moustafa AA, Gendy R, Chan M, Arifin N, et al. BDNF val66met genotype and schizotypal personality traits interact to influence probabilistic association learning. Behav Brain Res 2014; 274: 137–142.

    Article  CAS  PubMed  Google Scholar 

  185. Numata S, Ueno S, Iga J, Yamauchi K, Hongwei S, Ohta K, et al. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms. Neurosci Lett 2006; 401: 1–5.

    Article  CAS  PubMed  Google Scholar 

  186. Chao HM, Kao HT, Porton B . BDNF Val66Met variant and age of onset in schizophrenia. Am J Med Genet B 2008; 147B: 505–506.

    Article  Google Scholar 

  187. Decoster J, van Os J, Kenis G, Henquet C, Peuskens J, De Hert M, et al. Age at onset of psychotic disorder: cannabis, BDNF Val66Met, and sex-specific models of gene–environment interaction. Am J Med Genet B 2011; 156B: 363–369.

    Article  Google Scholar 

  188. Choi H, Lee J, Kim M, Jung S, Lee C, Park. S, Kim. Y . Association of BDNF Val66Met polymorphism with depressive and cognitive symptoms in patients with schizophrenia. Korean J Psychopharmacol 2007; 18: 143–151.

    Google Scholar 

  189. Sun M-M, Yang L-M, Wang Y, Feng X, Cui K-Y, Liu L-F, et al. BDNF Val66Met polymorphism and anxiety/depression symptoms in schizophrenia in a Chinese Han population. Psychiatr Genet 2013; 23: 124–129.

    Article  CAS  PubMed  Google Scholar 

  190. Zhai J, Yu Q, Chen M, Gao Y, Zhang Q, Li J, et al. Association of the brain-derived neurotrophic factor gene G196A rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. Int J Clin Exp Pathol 2013; 6: 1617–1623.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Alemany S, Arias B, Aguilera M, Villa H, Moya J, Ibanez MI, et al. Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences. Br J Psychiatry 2011; 199: 38–42.

    Article  PubMed  Google Scholar 

  192. Zai GC, Zai CC, Chowdhury NI, Tiwari AK, Souza RP, Lieberman JA, et al. The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 2012; 39: 96–101.

    Article  CAS  PubMed  Google Scholar 

  193. Hong C-J, Yu YWY, Lin C-H, Tsai S-J . 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 

  194. Xu M, Li S, Xing Q, Gao R, Feng G, Lin Z, et al. Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study. Eur J Hum Genet 2010; 18: 707–712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Lu W, Zhang C, Yi Z, Li Z, Wu Z, Fang Y . Association between BDNF Val66Met polymorphism and cognitive performance in antipsychotic-naive patients with schizophrenia. J Mol Neurosci 2012; 47: 505–510.

    Article  PubMed  CAS  Google Scholar 

  196. Rybakowski JK, Borkowska A, Skibinska M, Szczepankiewicz A, Kapelski P, Leszcynska-Rodziewicz A, et al. Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain‐derived neurotrophic factor gene. Psychiatry Clin Neurosci 2006; 60: 70–76.

    Article  CAS  PubMed  Google Scholar 

  197. Ho BC, Milev P, O'Leary DS, Librant A, Andreasen NC, Wassink TH . Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry 2006; 63: 731–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Tan YL, Zhou DF, Cao LY, Zou YZ, Wu GY, Zhang XY . Effect of the BDNF Val66Met genotype on episodic memory in schizophrenia. Schizophr Res 2005; 77: 355–356.

    Article  PubMed  Google Scholar 

  199. Eisenberg DP, Ianni AM, Wei S-M, Kohn PD, Kolachana B, Apud J, et al. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia. Mol Psychiatry 2013; 18: 713–720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Notaras M, Hill R, van den Buuse M . A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev 2015; 51C: 15–30.

    Article  CAS  Google Scholar 

  201. Tsai S-J, Hong C-J, Liou Y-J . Recent molecular genetic studies and methodological issues in suicide research. Progr Neuro-Psychopharmacol Biol Psychiatry 2011; 35: 809–817.

    Article  CAS  Google Scholar 

  202. Harris EC, Barraclough B . Suicide as an outcome for mental disorders. A meta-analysis. Brit J Psychiatry 1997; 170: 205–228.

    Article  CAS  Google Scholar 

  203. Qin P, Agerbo E, Mortensen PB . Suicide risk in relation to family history of completed suicide and psychiatric disorders: a nested case-control study based on longitudinal registers. The Lancet 2002; 360: 1126–1130.

    Article  Google Scholar 

  204. Voracek M, Loibl LM . Genetics of suicide: a systematic review of twin studies. Wien Klin Wochenschr 2007; 119: 463–475.

    Article  CAS  PubMed  Google Scholar 

  205. Brent DA, Mann JJ . Family genetic studies, suicide, and suicidal behavior. Am J Med Genet 2005; 133C: 13–24.

    Article  PubMed  Google Scholar 

  206. Kozicz T, Tilburg-Ouwens D, Faludi G, Palkovits M, Roubos E . Gender-related urocortin 1 and brain-derived neurotrophic factor expression in the adult human midbrain of suicide victims with major depression. Neuroscience 2008; 152: 1015–1023.

    Article  CAS  PubMed  Google Scholar 

  207. Pandey GN, Ren X, Rizavi HS, Conley RR, Roberts RC, Dwivedi Y . Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims. Int J Neuropsychopharmacol 2008; 11: 1047–1061.

    Article  CAS  PubMed  Google Scholar 

  208. Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R . Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Mol Brain Res 2005; 136: 29–37.

    Article  CAS  PubMed  Google Scholar 

  209. Kim Y-K, Lee H-P, Won S-D, Park E-Y, Lee H-Y, Lee B-H, et al. Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 78–85.

    Article  CAS  PubMed  Google Scholar 

  210. Lee B-H, Kim Y-K . BDNF mRNA expression of peripheral blood mononuclear cells was decreased in depressive patients who had or had not recently attempted suicide. J Affect Disord 2010; 125: 369–373.

    Article  CAS  PubMed  Google Scholar 

  211. Dwivedi Y . Brain-derived neurotrophic factor and suicide pathogenesis. Ann Med 2010; 42: 87–96.

    Article  PubMed  Google Scholar 

  212. Sarchiapone M, Carli V, Roy A, Iacoviello L, Cuomo C, Latella MC, et al. Association of polymorphism (Val66Met) of brain-derived neurotrophic factor with suicide attempts in depressed patients. Neuropsychobiology 2008; 57: 139–145.

    Article  CAS  PubMed  Google Scholar 

  213. Iga JI, Ueno SI, Yamauchi K, Numata S, Tayoshi‐Shibuya S, Kinouchi S, et al. The Val66Met polymorphism of the brain‐derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients. Am J Med Genet B 2007; 144: 1003–1006.

    Article  Google Scholar 

  214. Kim B, Kim CY, Hong JP, Kim SY, Lee C, Joo YH . Brain-derived neurotrophic factor Val/Met polymorphism and bipolar disorder. Neuropsychobiology 2008; 58: 97–103.

    Article  CAS  PubMed  Google Scholar 

  215. Huang T, Lee C . Associations between brain-derived neurotrophic factor G196A gene polymorphism and clinical phenotypes in schizophrenia patients. Chang Gung Med J 2007; 30: 408.

    PubMed  Google Scholar 

  216. Schenkel LC, Segal J, Becker JA, Manfro GG, Bianchin MM, Leistner-Segal S . The BDNF Val66Met polymorphism is an independent risk factor for high lethality in suicide attempts of depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 940–944.

    Article  CAS  PubMed  Google Scholar 

  217. Pregelj P, Nedic G, Paska AV, Zupanc T, Nikolac M, Balažic J, et al. The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide. J Affect Disord 2011; 128: 287–290.

    Article  CAS  PubMed  Google Scholar 

  218. Zai CC, Manchia M, De Luca V, Tiwari AK, Chowdhury NI, Zai GC, et al. The brain-derived neurotrophic factor gene in suicidal behaviour: a meta-analysis. Int J Neuropsychopharmacol 2012; 15: 1037.

    Article  CAS  PubMed  Google Scholar 

  219. Ratta-Apha W, Hishimoto A, Yoshida M, Ueno Y, Asano M, Shirakawa O, et al. Association study of BDNF with completed suicide in the Japanese population. Psychiatry Res 2013; 209: 734–736.

    Article  CAS  PubMed  Google Scholar 

  220. Vincze I, Perroud N, Buresi C, Baud P, Bellivier F, Etain B, et al. Association between brain‐derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene. Bipolar Disord 2008; 10: 580–587.

    Article  CAS  PubMed  Google Scholar 

  221. Perroud N, Aitchison KJ, Uher R, Smith R, Huezo-Diaz P, Marusic A, et al. Genetic predictors of increase in suicidal ideation during antidepressant treatment in the GENDEP project. Neuropsychopharmacology 2009; 34: 2517–2528.

    Article  CAS  PubMed  Google Scholar 

  222. Perroud N, Courtet P, Vincze I, Jaussent I, Jollant F, Bellivier F, et al. Interaction between BDNF Val66Met and childhood trauma on adult’s violent suicide attempt. Genes Brain Behav 2008; 7: 314–322.

    Article  CAS  PubMed  Google Scholar 

  223. Zarrilli F, Angiolillo A, Castaldo G, Chiariotti L, Keller S, Sacchetti S, et al. Brain derived neurotrophic factor (BDNF) genetic polymorphism (Val66Met) in suicide: a study of 512 cases. Am J Med Genet B 2009; 150: 599–600.

    Article  CAS  Google Scholar 

  224. Hiio K, Parik J, Merenäkk L, Harro J . Brain-derived neurotrophic factor gene val66met polymorphism, smoking and suicide-related thoughts in adolescents. Eur Neuropsychopharmacol 2009; 19: S165.

    Article  CAS  Google Scholar 

  225. Hong C-J, Huo S-J, Yen F-C, Tung C-L, Pan G-M, Tsai S-J . Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 2003; 48: 186–189.

    Article  CAS  PubMed  Google Scholar 

  226. Shimizu E, Hashimoto K, Iyo M . Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am J Med Genet B 2004; 126: 122–123.

    Article  Google Scholar 

  227. Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner S, et al. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry 2009; 15: 810–815.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  228. Bath KG, Lee FS . Variant BDNF (Val66Met) impact on brain structure and function. Cogn Affect Behav Neurosci 2006; 6: 79–85.

    Article  PubMed  Google Scholar 

  229. Brandys MK, Kas MJ, van Elburg AA, Ophoff R, Slof-Op't Landt MC, Middeldorp CM, et al. The Val66Met polymorphism of the BDNF gene in anorexia nervosa: new data and a meta-analysis. World J Biol Psychiatry 2011; 14: 441–451.

    Article  PubMed  Google Scholar 

  230. Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S . New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev 2008; 59: 201–220.

    Article  CAS  PubMed  Google Scholar 

  231. Li S-C, Chicherio C, Nyberg L, von Oertzen T, Nagel IE, Papenberg G, et al. Ebbinghaus revisited: influences of the BDNF Val66Met polymorphism on backward serial recall are modulated by human aging. J Cogn Neurosci 2010; 22: 2164–2173.

    Article  PubMed  Google Scholar 

  232. Ho B-C, Andreasen N, Dawson J, Wassink T . Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiatry 2007; 164: 1890–1899.

    Article  PubMed  PubMed Central  Google Scholar 

  233. Mirakhur A, Moorhead TWJ, Stanfield AC, McKirdy J, Sussmann JE, Hall J, et al. Changes in gyrification over 4 years in bipolar disorder and their association with the brain-derived neurotrophic factor valine 66 methionine variant. Biol Psychiatry 2009; 66: 293–297.

    Article  CAS  PubMed  Google Scholar 

  234. Anguelova M, Benkelfat C, Turecki G . A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 2003; 8: 574–591.

    Article  CAS  PubMed  Google Scholar 

  235. Martinowich K, Lu B . Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 2007; 33: 73–83.

    Article  PubMed  CAS  Google Scholar 

  236. Hyman C, Hofer M, Barde Y-A, Juhasz M, Yancopoulos GD, Squinto SP, et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991; 350: 230–232.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  238. Dluzen DE, Story GM, Xu K, Kucera J, Walro JM . Alterations in nigrostriatal dopaminergic function within BDNF mutant mice. Exp Neurol 1999; 160: 500–507.

    Article  CAS  PubMed  Google Scholar 

  239. Mössner R, Daniel S, Albert D, Heils A, Okladnova O, Schmitt A, et al. Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF). Neurochem Int 2000; 36: 197–202.

    Article  PubMed  Google Scholar 

  240. Choi M-J, Kang R-H, Lim S-W, Oh K-S, Lee M-S . Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res 2006; 1118: 176–182.

    Article  CAS  PubMed  Google Scholar 

  241. Gratacos M, Soria V, Urretavizcaya M, Gonzalez J, Crespo J, Bayes M, et al. A brain-derived neurotrophic factor (BDNF) haplotype is associated with antidepressant treatment outcome in mood disorders. Pharmacogenom J 2007; 8: 101–112.

    Article  CAS  Google Scholar 

  242. Rajewska-Rager A, Skibińska M, Szczepankiewicz A, Kapelski P, Dmitrzak-Weglarz M, Leszczyńska-Rodziewicz A, et al. Association between polymorphisms of Val66Met in the BDNF gene and the response to escitalopram and nortriptyline treatment in the light of the neurodevelopmental hypothesis of depression. Psychiatr Pol 2007; 42: 915–923.

    Google Scholar 

  243. Yoshida K, Higuchi H, Kamata M, Takahashi H, Inoue K, Suzuki T, et al. The G196A polymorphism of the brain-derived neurotrophic factor gene and the antidepressant effect of milnacipran and fluvoxamine. J Psychopharmacol 2007; 21: 650–656.

    Article  CAS  PubMed  Google Scholar 

  244. Kang R, Chang H, Wong M, Choi M, Park J, Lee H, et al. Brain-derived neurotrophic factor gene polymorphisms and mirtazapine responses in Koreans with major depression. J Psychopharmacol 2010; 24: 1755–1763.

    Article  CAS  PubMed  Google Scholar 

  245. Zou Y-F, Wang Y, Liu P, Feng X-L, Wang B-Y, Zang T-H, et al. Association of brain-derived neurotrophic factor genetic Val66Met polymorphism with severity of depression, efficacy of fluoxetine and its side effects in Chinese major depressive patients. Neuropsychobiology 2009; 61: 71–78.

    Article  PubMed  CAS  Google Scholar 

  246. Yoshimura R, Kishi T, Suzuki A, Umene-Nakano W, Ikenouchi-Sugita A, Hori H, et al. The brain-derived neurotrophic factor (BDNF) polymorphism Val66Met is associated with neither serum BDNF level nor response to selective serotonin reuptake inhibitors in depressed Japanese patients. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1022–1025.

    Article  CAS  PubMed  Google Scholar 

  247. Katsuki A, Yoshimura R, Kishi T, Hori H, Umene-Nakano W, Ikenouchi-Sugita A, et al. Serum levels of brain-derived neurotrophic factor (BDNF), BDNF gene Val66Met polymorphism, or plasma catecholamine metabolites, and response to mirtazapine in Japanese patients with major depressive disorder (MDD). CNS Spectr 2012; 17: 155–163.

    Article  PubMed  Google Scholar 

  248. Laje G, Lally N, Mathews D, Brutsche N, Chemerinski A, Akula N, et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry 2012; 72: 27.

    Article  CAS  Google Scholar 

  249. Xu G, Lin K, Rao D, Dang Y, Ouyang H, Mai G, et al. Brain-derived neurotrophic factor gene polymorphism (Val66Met) and the early response to antidepressant in Chinese Han population. Psychiatr Genet 2012; 22: 214–215.

    Article  CAS  PubMed  Google Scholar 

  250. Ribases M, Gratacos M, Armengol L, De Cid R, Badia A, Jimenez L, et al. Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol Psychiatry 2003; 8: 745–751.

    Article  CAS  PubMed  Google Scholar 

  251. de Krom M, Bakker SC, Hendriks J, van Elburg A, Hoogendoorn M, Verduijn W, et al. Polymorphisms in the brain-derived neurotrophic factor gene are not associated with either anorexia nervosa or schizophrenia in Dutch patients. Psychiatr Genet 2005; 15: 81.

    Article  PubMed  Google Scholar 

  252. Friedel S, Fontenla Horro F, Wermter A, Geller F, Dempfle A, Reichwald K, et al. Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention‐deficit/hyperactivity disorder. Am J Med Genet B 2005; 132: 96–99.

    Article  Google Scholar 

  253. Gunstad J, Schofield P, Paul RH, Spitznagel MB, Cohen RA, Williams LM, et al. BDNF Val66Met polymorphism is associated with body mass index in healthy adults. Neuropsychobiology 2006; 53: 153–156.

    Article  CAS  PubMed  Google Scholar 

  254. Shugart YY, Chen L, Day IN, Lewis SJ, Timpson NJ, Yuan W, et al. Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI. Eur J Hum Genet 2009; 17: 1050–1055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Arija V, Ferrer-Barcala M, Aranda N, Canals J . BDNF Val66Met polymorphism, energy intake and BMI: a follow-up study in schoolchildren at risk of eating disorders. BMC Public Health 2010; 10: 363.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  256. Ando T, Ishikawa T, Hotta M, Naruo T, Okabe K, Nakahara T, et al. No association of brain-derived neurotrophic factor Val66Met polymorphism with anorexia nervosa in Japanese. Am J Med Genet B 2012; 159B: 48–52.

    Article  CAS  Google Scholar 

  257. Perkovic MN, Mustapic M, Pavlovic M, Uzun S, Kozumplik O, Barisic I, et al. Lack of association between brain-derived neurotrophic factor Val66Met polymorphism and body mass index change over time in healthy adults. Neurosci Lett 2013; 545: 127–131.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

MN is a recipient of an Australian Postgraduate Award. RH is supported by a Career Development Fellowship from the National health and Medical Research Council of Australia (NHMRC). MvdB is supported by an NHMRC Senior Research Fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M van den Buuse.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Notaras, M., Hill, R. & van den Buuse, M. The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. Mol Psychiatry 20, 916–930 (2015). https://doi.org/10.1038/mp.2015.27

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.27

This article is cited by

Search

Quick links