Abstract
Brain-derived neurotrophic factor (BDNF) plays an important role in promoting and modifying growth, development, and survival of neuronal populations, and, in the mature nervous system, is involved in activity-dependent neuronal plasticity. Based on several lines of evidence, BDNF has been hypothesized to play an important role in the pathogenesis of mood disorder and the therapeutic action of at least some effective treatments. The gene encoding BDNF lies on the short arm of chromosome 11 in a region where some linkage studies of bipolar disorder have reported evidence for a susceptibility gene. BDNF can, thus, be considered as an attractive candidate gene for involvement in the pathogenesis of bipolar disorder, and two recent family-based association studies have provided evidence that one or more sequence variants within or near the BDNF gene show an association with disease susceptibility. These findings are of great interest and may open up a new chapter in the understanding of the causation and treatment of bipolar disorder. However, it is still early in the genetic investigation of BDNF in bipolar disorder, and it is important that these findings are replicated in large independent samples and that functional studies can confirm and characterize the pathogenic relevance of this genetic variation.
Similar content being viewed by others
References and Recommended Reading
Sklar P, Gabriel SB, McInnis MG, 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. This is a well-conducted genetic association study using multiple samples that provides evidence that BDNF is a susceptibility gene for bipolar disorder.
Neves-Pereira M, Mundo E, Muglia P, et al.: 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. This is a second well-conducted genetic association study that provides evidence that BDNF is a susceptibility gene for bipolar disorder.
Craddock N, Jones I: Genetics of bipolar disorder. J Med Genet 1999, 36:585–594.
Craddock N, Khodel V, Van Eerdewegh P, Reich T: Mathematical limits of multilocus models: the genetic transmission of bipolar disorder. Am J Med Genet 1995, 57:690–702.
Craddock N, Dave S, Greening J: Association studies of bipolar disorder. Bipolar Disord. 2001, 3:284–298. This review discusses in detail the strengths and weaknesses of association studies in bipolar disorder and review findings with the “traditional” candidates.
Harrison PJ, Owen MJ: Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003, 361:417–419. This is an interesting, succinct summary of some current findings in candidate gene studies of schizophrenia.
Baron M: Manic-depression genes and the new millennium: poised for discovery. Mol Psychiatry 2002, 7:342–358.
Badner JA, Gershon ES: Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002, 7:405–411.
Segurado R, Detera-Wadleigh SD, Levinson DF, et al.: Genome scan meta-analysis of schizophrenia and bipolar disorder, III: bipolar disorder. Am J Hum Genet 2003, 73:49–62. A meta-analysis of systematic linkage studies in bipolar disorder.
Preisig M, Bellivier F, Fenton BT, et al.: Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study. Am J Psychiatry 2000, 157:948–955.
Jones I, Craddock N: Candidate gene studies of bipolar disorder. Ann Med 2001, 33:248–256.
Anguelova M, Benkelfat C, Turecki G: A systematic review for association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 2003, 8:574–591.
Chumakov I, Blumenfeld M, Guerassimenko O, 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 U S A 2002, 99:13675–13680.
Hattori E, Liu C, Badner JA, et al.: Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. Am J Hum Genet 2003, 72:1131–1140.
Thoenen H: Neurotrophins and neuronal plasticity. Science 1995, 270:593–598.
Maisonpierre PC, Le Beau MM, Espinosa R, et al.: Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 1991, 10:558–568.
Duman RS: The neurochemistry of mood disorders: preclinical studies. In The Neurobiology of Mental Illness Edited by Charney DS, Nestler EJ, Bunney BS. New York: Oxford University Press; 1999:333–347.
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.
Seidah NG, Benjannet S, Pareek S, et al.: Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 1996, 379:247–50.
Bibel M, Barde YA: Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 2000, 14:2919–2937.
Dechant G: Molecular interactions between neurotrophin receptors. Cell Tissue Res 2001, 305:229–238.
Smith MA, Makino S, Kvetnansky R, Post RM: Stress and glucocorticoids affect the expression of brain-derived neutrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995, 15:1768–1777.
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.
Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP: Physical activity-antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behav Brain Res 2001, 120:87–95.
Russo-Neustadt AA, Beard RC, et al.: Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 2000, 101:305–312.
Nibuya M, Nestler EJ, Duman RS: Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996, 16:2365–2372.
Shieh PB, Hu SC, Bobb K, et al.: Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 1998, 20:727–740.
Tao X, Finkbeiner S, Arnold DB, et al.: Ca2+ influx regulates BDNF transcription by a CREB family transcription factordependent mechanism. Neuron 1998, 20:709–726.
Chen B, Dowlatshahi D, MacQueen GM, et al.: Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001, 50:260–265.
Dowlatshahi D, MacQueen GM, Wang JF, Young LT: Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet 1998, 352:1754–1755.
Conti AC, Cryan JF, Dalvi A, et al.: cAMP response elementbinding protein is essential for the upregulation of brainderived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs. J Neurosci 2002, 22:3262–3268.
Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM: Antidepressantlike effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997, 56:131–137.
Shirayama Y, Chen AC, Nakagawa S, et al.: Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002, 22:3251–3261.
Lyons WE, Mamounas LA, Ricaurte GA, et al.: Brain-derived neuroptrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A 1999, 96:15239–15244.
Zuccato C, Ciammola A, Rigamonti D, et al.: Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 2001, 293:493–498.
Hyman SE, Nestler EJ: Initiation and adaptation: a paradigm for understanding psychotropic drug action. Am J Psychiatry 1996, 153:151–162.
Popoli M, Gennarelli M, Racagni G: Modulation of synaptic plasticity by stress and antidepressants. Bipolar Disord 2002, 4:166–182.
Duman RS, Malberg J, Thome J: Neuronal plasticity to stress and antidepressant treatment. Biol Psychiatry 1999, 46:1181–1191.
Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry 1997, 54:507–606.
D’Sa C, Duman RS: Antidepressants and neuroplasticity. Bipolar Disord 2002, 4:183–194.
Craddock N, Lendon C, Cichon S, et al.: Chromosome workshop: chromosomes 11, 14, and 15. Am J Med Genet 1999, 88:244–254.
Zandi PP, Willour VL, Huo Y, et al.: Genome scan of a second wave of NIMH genetics initiative bipolar pedigrees: chromosomes 2, 11, 13, 14, and X. Am J Med Genet 2003, 119B:69–76.
Dick DM, Foroud T, Flury L, et al.: Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. Am J Hum Genet 2003, 73:107–114.
Nakata K, Ujike H, Sakai A, et al.: Association study of brainderived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci Lett 2003, 337:17–20.
Hall D, Dhilla A, Charalambous A, et al.: 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.
Ribases M, Gratacos M, Armengol L, et al.: Met66 in the brainderived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol Psychiatry 2003, 8:745–751.
Muglia P, Vicente AM, Verga M, et al.: Association between the BDNF gene and schizophrenia. Mol Psychiatry 2003, 8:146–147.
Egan MF, Kojima M, Callicott JH, et al.: The BDNF Val66Met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003, 112:257–269. Study of the possible cognitive and biologic effects of the common Val66Met polymorphism in BDNF.
Schulze TG, Hardy J, McMahon FJ: Inconsistent designs of association studies: a missed opportunity. Mol Psychiatry 2003, 770–772.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Green, E., Craddock, N. Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: Evidence, limitations, and implications. Curr Psychiatry Rep 5, 469–476 (2003). https://doi.org/10.1007/s11920-003-0086-1
Issue Date:
DOI: https://doi.org/10.1007/s11920-003-0086-1