Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Psychiatry
Published in: BMC Psychiatry 1/2014

Open Access 01-12-2014 | Research article

Association between brain-derived neurotrophic factor genetic polymorphism Val66Met and susceptibility to bipolar disorder: a meta-analysis

Published in: BMC Psychiatry | Issue 1/2014

Login to get access

Abstract

Background

In view of previous conflicting findings, this meta-analysis was performed to comprehensively determine the overall strength of associations between brain-derived neurotrophic factor (BDNF) genetic polymorphism Val66Met and susceptibility to bipolar disorders (BPD).

Methods

Literatures published and cited in Pubmed and Wanfang Data was searched with terms of ‘Val66Met’, ‘G196A’, ‘rs6265’, ‘BDNF’, ‘association’, and ‘bipolar disorder’ up to March 2014. All original case–control association studies were meta-analyzed with a pooled OR to estimate the risk and 95% confidence interval (CI) to reflect the magnitude of variance.

Results

Twenty-one case–control association studies met our criteria for the meta-analysis. Overall, there was no significant difference in allelic distribution of Val66Met polymorphism between patients and controls with a pooled OR = 1.03 (95% CI 0.98, 1.08) although there was a trend towards association between Val66Met polymorphism and BPD in Caucasians with an OR of 1.08 (95% CI 1.00, 1.16). However, subgroup analyses showed that there was a significant association of Val allele with decreased disease susceptibility for bipolar disorder type II with a pooled OR of 0.88 (95% CI 0.78, 0.99).

Conclusions

There is no compelling evidence to supportVal66Met polymorphism in BDNF gene playing an important role in the susceptibility to BPD across different ethnicities.
Appendix
Available only for authorised users
Literature
1.
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, Kessler RC: Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007, 64: 543-552. 10.1001/archpsyc.64.5.543.CrossRefPubMedPubMedCentral
2.
Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, Viana MC, Andrade LH, Hu C, Karam EG, Ladea M, Medina-Mora ME, Ono Y, Posada-Villa J, Sagar R, Wells JE, Zarkov Z: Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011, 68: 241-251. 10.1001/archgenpsychiatry.2011.12.CrossRefPubMedPubMedCentral
3.
Phillips MR, Zhang J, Shi Q, Song Z, Ding Z, Pang S, Li X, Zhang Y, Wang Z: Prevalence, treatment, and associated disability of mental disorders in four provinces in China during 2001–05: an epidemiological survey. Lancet. 2009, 373: 2041-2053. 10.1016/S0140-6736(09)60660-7.CrossRefPubMed
4.
Geddes JR, Miklowitz DJ: Treatment of bipolar disorder. Lancet. 2013, 381: 1672-1682. 10.1016/S0140-6736(13)60857-0.CrossRefPubMed
5.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O’Donovan C, Macqueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI, Lafer B, Birmaher B, Ha K, Nolen WA, Berk M: Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013, 15: 1-44. 10.1111/bdi.12025.CrossRefPubMed
6.
Muzina DJ, Kemp DE, McIntyre RS: Differentiating bipolar disorders from major depressive disorders: treatment implications. Ann Clin Psychiatry. 2007, 19: 305-312. 10.1080/10401230701653591.CrossRefPubMed
7.
Gao K, Kemp DE, Conroy C, Ganocy SJ, Findling RL, Calabrese JR: Comorbid anxiety and substance use disorders associated with a lower use of mood stabilizers in patients with rapid cycling bipolar disorder: a descriptive analysis of the cross-sectional data of 566 patients. Int J Clin Prac. 2010, 64: 336-344. 10.1111/j.1742-1241.2009.02284.x.CrossRef
8.
Hu C, Xiang YT, Ungvari GS, Dickerson FB, Kilbourne AM, Si TM, Fang YR, Lu Z, Yang HC, Chiu HF, Lai KY, Hu J, Chen ZY, Huang Y, Sun J, Wang XP, Li HC, Zhang JB, Wang G: Undiagnosed bipolar disorder in patients treated for major depression in China. J Affect Disord. 2012, 140: 181-186. 10.1016/j.jad.2012.02.014.CrossRefPubMed
9.
Xiang YT, Zhang L, Wang G, Hu C, Ungvari GS, Dickerson FB, Kilbourne AM, Si TM, Fang YR, Lu Z, Yang HC, Lai KY, Lee EH, Hu J, Chen ZY, Huang Y, Sun J, Wang XP, Li HC, Zhang JB, Chiu HF: Sociodemographic and clinical features of bipolar disorder patients misdiagnosed with major depressive disorder in China. Bipolar Disord. 2013, 15: 199-205. 10.1111/bdi.12052.CrossRefPubMed
10.
Wu R, Fan J, Zhao J, Calabrese JR, Gao K: The relationship between neurotrophins and bipolar disorder. Expert Rev Neurother. 2014, 14: 51-65. 10.1586/14737175.2014.863709.CrossRefPubMed
11.
12.
McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A: The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry. 2003, 60: 497-502. 10.1001/archpsyc.60.5.497.CrossRefPubMed
13.
Smoller JW, Finn CT: Family, twin, and adoption studies of bipolar disorder. Am J Med Genet C Semin Med Genet. 2003, 123C: 48-58. 10.1002/ajmg.c.20013.CrossRefPubMed
14.
Hayden EP, Nurnberger JI: Molecular genetics of bipolar disorder. Genes Brain Behav. 2006, 5: 85-95. 10.1111/j.1601-183X.2005.00138.x.CrossRefPubMed
15.
Fan J, Sklar P: Genetics of bipolar disorder: focus on BDNF Val66Met polymorphism. Novartis Found Symp. 2008, 289: 60-72. 10.1002/9780470751251.ch5.CrossRefPubMed
16.
Duman RS, Malberg J, Nakagawa S, D’Sa C: Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000, 48: 732-739. 10.1016/S0006-3223(00)00935-5.CrossRefPubMed
17.
Manji HK, Moore GJ, Rajkowska G, Chen G: Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry. 2000, 5: 578-593. 10.1038/sj.mp.4000811.CrossRefPubMed
18.
Craddock N, Lendon C: Chromosome workshop: chromosomes 11, 14, and 15. Am J Med Genet. 1999, 88: 244-254. 10.1002/(SICI)1096-8628(19990618)88:3<244::AID-AJMG7>3.0.CO;2-1.CrossRefPubMed
19.
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES: Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet. 1999, 22: 231-238. 10.1038/10290.CrossRefPubMed
20.
Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL: The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet. 2002, 71: 651-655. 10.1086/342288.CrossRefPubMedPubMedCentral
21.
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim Y, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES: 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. 10.1038/sj.mp.4001058.CrossRefPubMed
22.
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. 10.1097/YPG.0b013e32801da2e2.CrossRefPubMed
23.
Dersimonian R: Combining evidence from clinical-trials. Anesth Analg. 1990, 70: 475-476. 10.1213/00000539-199005000-00001.CrossRefPubMed
24.
Woolf B: On estimating the relation between blood group and disease. Ann Hum Genet. 1955, 19: 251-253. 10.1111/j.1469-1809.1955.tb01348.x.CrossRefPubMed
25.
The Cochrane Collaboration: Review Manager (RevMan) [Computer program] Version 5.2. 2012, The Nordic Cochrane Centre, Copenhagen
26.
Huang CC, Chang YH, Lee SY, Chen SL, Chen SH, Chu CH, Huang SY, Tzeng NS, Lee IH, Yeh TL, Yang YK, Lu RB: The interaction between BDNF and DRD2 in bipolar II disorder but not in bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet. 2012, 159B: 501-507. 10.1002/ajmg.b.32055.CrossRefPubMed
27.
Lee SY, Chen SL, Chen SH, Chu CH, Chang YH, Lin SH, Huang SY, Tzeng NS, Kuo PH, Lee IH, Yeh TL, Yang YK, Lu RB: Interaction of the DRD3 and BDNF gene variants in subtyped bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012, 39: 382-387. 10.1016/j.pnpbp.2012.07.015.CrossRefPubMed
28.
Lee SY, Chen SL, Wang YS, Chang YH, Huang SY, Tzeng NS, Lee IH, Yeh TL, Yang YK, Lu RB: COMT and BDNF interacted in bipolar II disorder not comorbid with anxiety disorder. Behav Brain Res. 2013, 237: 243-248. 10.1016/j.bbr.2012.09.039.CrossRefPubMed
29.
Chen SL, Lee SY, Chang YH, Chen SH, Chu CH, Wang TY, Chen PS, Lee IH, Yang YK, Hong JS, Lu RB: The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese patients with bipolar disorder and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2014, 51C: 99-104. 10.1016/j.pnpbp.2014.01.012.CrossRef
30.
Chang YH, Lee SY, Chen SL, Tzeng NS, Wang TY, Lee IH, Chen PS, Huang SY, Yang YK, Ko HC, Lu RB: Genetic variants of the BDNF and DRD3 genes in bipolar disorder comorbid with anxiety disorder. J Affect Disord. 2013, 151: 967-972. 10.1016/j.jad.2013.08.017.CrossRefPubMed
31.
Chepenik LG, Fredericks C, Papademetris X, Spencer L, Lacadie C, Wang F, Pittman B, Duncan JS, Staib LH, Duman RS, Gelernter J, Blumberg HP: Effects of the brain-derived neurotrophic growth factor val66met variation on hippocampus morphology in bipolar disorder. Neuropsychopharmacology. 2009, 34: 944-951. 10.1038/npp.2008.107.CrossRefPubMed
32.
Matsuo K, Walss-Bass C, Nery FG, Nicoletti MA, Hatch JP, Frey BN, Monkul ES, Zunta-Soares GB, Bowden CL, Escamilla MA, Soares JC: Neuronal correlates of brain-derived neurotrophic factor Val66Met polymorphism and morphometric abnormalities in bipolar disorder. Neuropsychopharmacology. 2009, 34: 1904-1913. 10.1038/npp.2009.23.CrossRefPubMed
33.
Carrard A, Salzmann A, Perrou N, Gafner J, Malafoss A, Karege F: Genetic association of the Phosphoinositide-3 kinase in schizophrenia and bipolar disorder and interaction with a BDNF gene polymorphism. Brain Behav. 2011, 1: 119-124. 10.1002/brb3.23.CrossRefPubMedPubMedCentral
34.
Gruber O, Hasan A, Scherk H, Wobrock T, Schneider-Axmann T, Ekawardhani S, Schmitt A, Backens M, Reith W, Meyer J, Falkai P: Association of the brain-derived neurotrophic factor val66met polymorphism with magnetic resonance spectroscopic markers in the human hippocampus: in vivo evidence for effects on the glutamate system. Eur Arch Psychiatry Clin Neurosci. 2012, 262: 23-31. 10.1007/s00406-011-0214-6.CrossRefPubMed
35.
Teh CA, Lee TS, Kuchibhatla M, Ashley-Koch A, Macfall J, Krishnan R, Beyer J: Bipolar disorder, brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and brain morphology. PLoS One. 2012, 7: e38469-10.1371/journal.pone.0038469.CrossRefPubMedPubMedCentral
36.
Kenna HA, Reynolds-May M, Stepanenko A, Ketter TA, Hallmayer J, Rasgon NL: Blood levels of brain derived neurotrophic factor in women with bipolar disorder and healthy control women. J Affect Disord. 2014, 156: 214-218. 10.1016/j.jad.2013.01.054.CrossRefPubMed
37.
Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007, 447: 661-678. 10.1038/nature05911.CrossRef
38.
Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ: Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology. 2003, 48: 186-189. 10.1159/000074636.CrossRefPubMed
39.
Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T, Katsu T, Tanaka Y, Hamamura T, Kuroda S: Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci Lett. 2003, 337: 17-20. 10.1016/S0304-3940(02)01292-2.CrossRefPubMed
40.
Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T, Sakamoto K, Fukunaga T, Inada T, Suzuki T, Iwata N, Ozaki N, Yamada K, Yoshikawa T: No association between the Val66Met polymorphism of the brain-derived neurotrophic factorgene and bipolar disorder in a Japanese population: a multicenter study. Biol Psychiatry. 2004, 56: 376-378. 10.1016/j.biopsych.2004.06.017.CrossRefPubMed
41.
Oswald P, Del-Favero J, Massat I, Souery D, Claes S, Van Broeckhoven C, Mendlewicz J: Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: a Belgian patient-control study. Am J Med Genet B Neuropsychiatr Genet. 2004, 129B: 34-35. 10.1002/ajmg.b.30056.CrossRefPubMed
42.
Skibinska M, Hauser J, Czerski PM, Leszczynska-Rodziewicz A, Kosmowska M, Kapelski P, Slopien A, Zakrzewska M, Rybakowski JK: Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. World J Biol Psychiatry. 2004, 5: 215-220. 10.1080/15622970410029936.CrossRefPubMed
43.
Lohoff FW, Sander T, Ferraro TN, Dahl JP, Gallinat J, Berrettini WH: Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet. 2005, 139B: 51-53. 10.1002/ajmg.b.30215.CrossRefPubMed
44.
Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, Sinclair M, Crombie C, Walker N, St Clair DM: BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry. 2005, 10: 208-212. 10.1038/sj.mp.4001575.CrossRefPubMed
45.
Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB, Schulze TG, Deschner M, Schmäl C, Höfels S, Zobel A, Illig T, Propping P, Holsboer F, Rietschel M, Nöthen MM, Cichon S: Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry. 2005, 58: 307-314. 10.1016/j.biopsych.2005.04.006.CrossRefPubMed
46.
Green EK, Raybould R, Macgregor S, Hyde S, Young AH, O’Donovan MC, Owen MJ, Kirov G, Jones L, Jones I, Craddock N: Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case–control study of over 3000 individuals from the UK. Br J Psychiatry. 2006, 188: 21-25. 10.1192/bjp.bp.105.009969.CrossRefPubMed
47.
Liu M, Ling SH, Li WB, Wang CY, Chen DF, Wang G: An association study between GRIN1, BDNF genes and bipolar disorder. Yi Chuan. 2007, 29: 41-46. 10.1360/yc-007-0041.CrossRefPubMed
48.
Tramontina J, Frey BN, Andreazza AC, Zandona M, Santin A, Kapczinski F: Val66met polymorphism and serum brain-derived neurotrophic factor levels in bipolar disorder. Mol Psychiatry. 2007, 12: 230-231. 10.1038/sj.mp.4001941.CrossRefPubMed
49.
Kim B, Kim CY, Hong JP, Kim SY, Lee C, Joo YH: Brain-derived neurotrophic factor Val/Met polymorphism and bipolar disorder. association of the Met allele with suicidal behavior of bipolar patients. Neuropsychobiology. 2008, 58: 97-103. 10.1159/000162356.CrossRefPubMed
50.
Tang J, Xiao L, Shu C, Wang G, Liu Z, Wang X, Wang H, Bai X: Association of the brain-derived neurotrophic factor gene and bipolar disorder with early age of onset in mainland China. Neurosci Lett. 2008, 433: 98-102. 10.1016/j.neulet.2008.01.001.CrossRefPubMed
51.
Vincze I, Perroud N, Buresi C, Baud P, Bellivier F, Etain B, Fournier C, Karege F, Matthey ML, Preisig M, Leboyer M, Malafosse A: 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. 10.1111/j.1399-5618.2008.00603.x.CrossRefPubMed
52.
Ye CY, Xu YQ, Hu H, Yu SY, Wang DX, Shi SX, Wang LW: An association study of brain-derived neurotrophic factor gene polymorphism in bipolar disorders. Zhonghua Yi Xue Za Zhi. 2009, 89: 1897-1901.PubMed
53.
Hosang GM, Uher R, Keers R, Cohen-Woods S, Craig I, Korszun A, Perry J, Tozzi F, Muglia P, McGuffin P, Farmer AE: Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder. J Affect Disord. 2010, 125: 345-349. 10.1016/j.jad.2010.01.071.CrossRefPubMed
54.
Xu J, Liu Y, Wang P, Li S, Wang Y, Li J, Zhou D, Chen Z, Zhao T, Wang T, Xu H, Yang Y, Feng G, He L, Yu L: Positive association between the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder in the Han Chinese population. Am J Med Genet B Neuropsychiatr Genet. 2010, 153B: 275-279. 10.1002/ajmg.b.31096.CrossRefPubMed
55.
Min HJ, Cho HS, Kim SJ, Seok JH, Lee E, Jon DI: Association of the brain-derived neurotrophic factor gene and clinical features of bipolar disorder in Korea. Clin Psychopharmacol Neurosci. 2012, 10: 163-167. 10.9758/cpn.2012.10.3.163.CrossRefPubMedPubMedCentral
56.
Wang Z, Li Z, Chen J, Huang J, Yuan C, Hong W, Yu S, Fang Y: Association of BDNF gene polymorphism with bipolar disorders in Han Chinese population. Genes Brain Behav. 2012, 11: 524-528. 10.1111/j.1601-183X.2012.00797.x.CrossRefPubMed
57.
Pae CU, Chiesa A, Porcelli S, Han C, Patkar AA, Lee SJ, Park MH, Serretti A, De Ronchi D: Influence of BDNF variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia. Neuropsychobiology. 2012, 65: 1-11. 10.1159/000327605.CrossRefPubMed
58.
Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner SF, Waggoner SG, Tahl AR, Sklar P: Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry. 2010, 15: 810-815. 10.1038/mp.2009.24.CrossRefPubMed
59.
Müller 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. 10.1192/bjp.bp.105.010587.CrossRefPubMed
60.
Liu L, Foroud T, Xuei X, Berrettini W, Byerley W, Coryell W, El-Mallakh R, Gershon ES, Kelsoe JR, Lawson WB, MacKinnon DF, McInnis M, McMahon FJ, Murphy DL, Rice J, Scheftner W, Zandi PP, Lohoff FW, Niculescu AB, Meyer ET, Edenberg HJ, Nurnberger JI: Evidence of association between brain-derived neurotrophic factor gene and bipolar disorder. Psychiatr Genet. 2008, 18: 267-274. 10.1097/YPG.0b013e3283060f59.CrossRefPubMedPubMedCentral
Metadata
Title
Association between brain-derived neurotrophic factor genetic polymorphism Val66Met and susceptibility to bipolar disorder: a meta-analysis
Publication date
01-12-2014
Published in
BMC Psychiatry / Issue 1/2014
Electronic ISSN: 1471-244X
DOI
https://doi.org/10.1186/s12888-014-0366-9

Other articles of this Issue 1/2014

BMC Psychiatry 1/2014 Go to the issue

Research article

The association between internet addiction and psychiatric co-morbidity: a meta-analysis

Research article

Sleep architecture and cognitive changes in olanzapine-treated patients with depression: A double blind randomized placebo controlled trial

Study protocol

Improving the retention rate for residential treatment of substance abuse by sequential intervention for social anxiety

Research article

Delayed circadian phase is linked to glutamatergic functions in young people with affective disorders: a proton magnetic resonance spectroscopy study

Research article

Exercise therapy in adults with serious mental illness: a systematic review and meta-analysis

Research article

Measurement invariance of the depressive symptoms scale during adolescence