Abstract
The BDNF Val66Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val66Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val66Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Alexopoulos GS, Murphy CF, Gunning-Dixon FM, Glatt CE, Latoussakis V, Kelly RE et al (2009). Serotonin transporter polymorphisms, microstructural white matter abnormalities and remission of geriatric depression. J Affect Disord 119: 132–141.
Bath KG, Jing DQ, Dincheva I, Neeb CC, Pattwell SS, Chao MV et al (2012). BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. Neuropsychopharmacology 37: 1297–1304.
Cao L, Dhilla A, Mukai J, Blazeski R, Lodovichi C, Mason CA et al (2007). Genetic modulation of BDNF signaling affects the outcome of axonal competition in vivo. Curr Biol 17: 911–921.
Chiang MC, Barysheva M, Shattuck DW, Lee AD, Madsen SK, Avedissian C et al (2009). Genetics of brain fiber architecture and intellectual performance. J Neurosci 29: 2212–2224.
Chiang MC, Barysheva M, Toga AW, Medland SE, Hansell NK, James MR et al (2011). BDNF gene effects on brain circuitry replicated in 455 twins. NeuroImage 55: 448–454.
Cohen MX (2011). Hippocampal-prefrontal connectivity predicts midfrontal oscillations and long-term memory performance. Curr Biol 21: 1900–1905.
Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT et al (2011). Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478: 519–523.
Cui QL, Fragoso G, Miron VE, Darlington PJ, Mushynski WE, Antel J et al (2010). Response of human oligodendrocyte progenitors to growth factors and axon signals. J Neuropathol Exp Neurol 69: 930–944.
Dinacci D, Tessitore A, Russo A, De Bonis ML, Lavorgna L, Picconi O et al (2011). BDNF Val66Met polymorphism and brain volumes in multiple sclerosis. Neurol Sci 32: 117–123.
Du Y, Fischer TZ, Lee LN, Lercher LD, Dreyfus CF (2003). Regionally specific effects of BDNF on oligodendrocytes. Dev Neurosci 25: 116–126.
Egan MF, Goldberg TE, Gscheidle T, Weirich M, Rawlings R, Hyde TM et al (2001). Relative risk for cognitive impairments in siblings of patients with schizophrenia. Biol Psychiatry 50: 98–107.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112: 257–269.
Embleton KV, Haroon HA, Morris DM, Ralph MA, Parker GJ (2010). Distortion correction for diffusion-weighted MRI tractography and fMRI in the temporal lobes. Hum Brain Mapp 31: 1570–1587.
Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR et al (2009). Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 14: 681–695.
Gerritsen L, Tendolkar I, Franke B, Vasquez AA, Kooijman S, Buitelaar J et al (2011). BDNF Val66Met genotype modulates the effect of childhood adversity on subgenual anterior cingulate cortex volume in healthy subjects. Mol Psychiatry 17: 597–603.
Ho BC, Milev P, O'Leary DS, Librant A, Andreasen NC, Wassink TH (2006). 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 63: 731–740.
Kennedy KM, Rodrigue KM, Land SJ, Raz N (2009). BDNF Val66Met polymorphism influences age differences in microstructure of the Corpus Callosum. Front Hum Neurosci 3: 19.
King AV, Linke J, Gass A, Hennerici MG, Tost H, Poupon C et al (2012). Microstructure of a three-way anatomical network predicts individual differences in response inhibition: a tractography study. NeuroImage 59: 1949–1959.
Kochunov P, Glahn DC, Lancaster JL, Winkler AM, Smith S, Thompson PM et al (2010). Genetics of microstructure of cerebral white matter using diffusion tensor imaging. NeuroImage 53: 1109–1116.
Liguori M, Fera F, Gioia MC, Valentino P, Manna I, Condino F et al (2007). Investigating the role of brain-derived neurotrophic factor in relapsing-remitting multiple sclerosis. Genes Brain Behav 6: 177–183.
Lu B, Pang PT, Woo NH (2005). The yin and yang of neurotrophin action. Nature Rev 6: 603–614.
Martinowich K, Manji H, Lu B (2007). New insights into BDNF function in depression and anxiety. Nat Neurosci 10: 1089–1093.
McIntosh AM, Moorhead TW, Job D, Lymer GK, Munoz Maniega S, McKirdy J et al (2008). The effects of a neuregulin 1 variant on white matter density and integrity. Mol Psychiatry 13: 1054–1059.
Minichiello L (2009). TrkB signalling pathways in LTP and learning. Nature Rev 10: 850–860.
Montag C, Schoene-Bake JC, Faber J, Reuter M, Weber B (2010). Genetic variation on the BDNF gene is not associated with differences in white matter tracts in healthy humans measured by tract-based spatial statistics. Genes Brain Behav 9: 886–891.
Montag C, Weber B, Fliessbach K, Elger C, Reuter M (2009). The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: incremental support for a genetic risk factor for depression. Psychol Med 39: 1831–1839.
Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P et al (2005). BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 10: 208–212.
Pacheco J, Beevers CG, Benavides C, McGeary J, Stice E, Schnyer DM (2009). Frontal-limbic white matter pathway associations with the serotonin transporter gene promoter region (5-HTTLPR) polymorphism. J Neurosci 29: 6229–6233.
Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS et al (2008). Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry 13: 709–716.
Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE et al (2004). The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 24: 10099–10102.
Qin L, Kim E, Ratan R, Lee FS, Cho S (2011). Genetic variant of BDNF (Val66Met) polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator CD36 expression. J Neurosci 31: 775–783.
Rueckert D, Sonoda LI, Hayes C, Hill DL, Leach MO, Hawkes DJ (1999). Nonrigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 18: 712–721.
Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G et al (2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 7: 579–593.
Smith SM (2002). Fast robust automated brain extraction. Hum Brain Mapp 17: 143–155.
Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE et al (2006). Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage 31: 1487–1505.
Smith SM, Johansen-Berg H, Jenkinson M, Rueckert D, Nichols TE, Miller KL et al (2007). Acquisition and voxelwise analysis of multi-subject diffusion data with tract-based spatial statistics. Nat Protoc 2: 499–503.
Smith SM, Nichols TE (2009). Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. NeuroImage 44: 83–98.
Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS et al (2010). A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science (New York, NY) 327: 863–866.
Song SK, Sun SW, Ju WK, Lin SJ, Cross AH, Neufeld AH (2003). Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. NeuroImage 20: 1714–1722.
Song SK, Sun SW, Ramsbottom MJ, Chang C, Russell J, Cross AH (2002). Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. NeuroImage 17: 1429–1436.
Song SK, Yoshino J, Le TQ, Lin SJ, Sun SW, Cross AH et al (2005). Demyelination increases radial diffusivity in corpus callosum of mouse brain. NeuroImage 26: 132–140.
Sun SW, Liang HF, Trinkaus K, Cross AH, Armstrong RC, Song SK (2006). Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum. Magn Reson Med 55: 302–308.
Tan HY, Chen AG, Chen Q, Browne LB, Verchinski B, Kolachana B et al (2011). Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications. Mol Psychiatry 17: 1007–1016.
Tyszka JM, Readhead C, Bearer EL, Pautler RG, Jacobs RE (2006). Statistical diffusion tensor histology reveals regional dysmyelination effects in the shiverer mouse mutant. NeuroImage 29: 1058–1065.
Verhagen M, van der Meij A, van Deurzen PA, Janzing JG, Arias-Vasquez A, Buitelaar JK et al (2010). Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatry 15: 260–271.
Voineskos AN, Lerch JP, Felsky D, Shaikh S, Rajji TK, Miranda D et al (2011). The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. Arch Gen Psychiatry 68: 198–206.
Vondran MW, Clinton-Luke P, Honeywell JZ, Dreyfus CF (2010). BDNF+/− mice exhibit deficits in oligodendrocyte lineage cells of the basal forebrain. Glia 58: 848–856.
Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS et al (2006). 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 Neuropsychiatr Genet 141B: 387–393.
Zivadinov R, Weinstock-Guttman B, Benedict R, Tamano-Blanco M, Hussein S, Abdelrahman N et al (2007). Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor. Hum Mol Genet 16: 2659–2668.
Zuliani R, Moorhead TW, Bastin ME, Johnstone EC, Lawrie SM, Brambilla P et al (2011). Genetic variants in the ErbB4 gene are associated with white matter integrity. Psychiatry Res 191: 133–137.
Acknowledgements
This research was supported by the Intramural Research Program of the National Institute of Mental Health, NIH, funding of the Weinberger Lab and a DFG-NIH (To539/1) grant to HT. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
Supplementary information
Rights and permissions
About this article
Cite this article
Tost, H., Alam, T., Geramita, M. et al. Effects of the BDNF Val66Met Polymorphism on White Matter Microstructure in Healthy Adults. Neuropsychopharmacol 38, 525–532 (2013). https://doi.org/10.1038/npp.2012.214
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2012.214
Keywords
This article is cited by
-
Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits
Molecular Psychiatry (2022)
-
Structural and functional thalamocortical connectivity study in female fibromyalgia
Scientific Reports (2021)
-
Electrophysiological correlates of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism
Scientific Reports (2020)
-
Effect of the interaction between BDNF Val66Met polymorphism and daily physical activity on mean diffusivity
Brain Imaging and Behavior (2020)
-
Effects of BDNF Val66Met genotype and schizophrenia familial risk on a neural functional network for cognitive control in humans
Neuropsychopharmacology (2019)