A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review

Notaras, Michael; Hill, Rachel Anne; Buuse, Maarten van den

doi:10.1016/j.neubiorev.2014.12.016

Cited by 121 publications

(88 citation statements)

References 201 publications

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“…15 Fig. 3), so that BDNF rs6265 methylation is associated with 2-back WM performance both in ValVal and ValMet subjects with a qualitatively different direction; consistent with previous studies, 8,38 this analysis also confirmed lower WM performance in ValMet compared with ValVal (t D ¡2.51, P D 0.01 Ã ). Post-hoc analyses of the interaction indicated that greater methylation is associated with lower accuracy in ValVal homozygous (t D ¡2.46, P D 0.01 Ã ), while the opposite is found in ValMet (t D 2.55, P D 0.01 Ã ; Fig.…”

Section: Resultssupporting

confidence: 87%

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

et al. 2016

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Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val 66 Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

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Section: Resultssupporting

confidence: 87%

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

et al. 2016

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“…These results have important implications for the clinical schizophrenia literature focused on BDNF, which has implicated that the BDNF 66Met allele may alter clinical features such as the positive symptoms of schizophrenia. 14 …”

Section: Bdnf Val66met and Prepulse Inhibition Discussionmentioning

confidence: 99%

“…13 However, the role of the BDNF Val66Met polymorphism within this disorder remains controversial. 14 Sensorimotor gating refers to the latent ability to inhibit a motor response given a preceding sensory stimulus. Sensorimotor gating deficits are observed amongst schizophrenia patients 15,16 and are typically quantified using the Prepulse Inhibition (PPI) paradigm; where a blunted startle response to an auditory pulse stimulus is observed when preceded by the presentation of a weaker auditory prepulse.…”

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confidence: 99%

BDNF Val66Met Genotype Interacts With a History of Simulated Stress Exposure to Regulate Sensorimotor Gating and Startle Reactivity

Notaras

Hill

Gogos

et al. 2016

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Reduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNF Val66Met (hBDNF Val66Met) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the longterm effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30 ms and 100 ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100 ms ISI identified that, irrespective of CORT treatment, the hBDNF

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“…BDNF is critically important for neural development, differentiation and plasticity in both the developing and adult brain 34,35 . The relevance of BDNF to ADHD is underscored by several observations.…”

Section: Discussionmentioning

confidence: 99%

“…Third, animal studies demonstrate that psychostimulants such as methylphenidate that are used in the treatment of ADHD, modulate BDNF expression 41,42 . A common exonic Val66Met substitution within the pro-region of BDNF has been widely implicated as contributing to a diverse range of cognitive functions and psychiatric disorders, including ADHD 35,43 . The Val66Met polymorphism is widely believed to disrupt activity-dependent release of BDNF with consequences for physiological processes Our novel application of next generation sequencing to ADHD raises several methodological issues that warrant comment.…”

Section: Discussionmentioning

confidence: 99%