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.

Parental brain‐derived neurotrophic factor genotype, child prosociality, and their interaction as predictors of parents’ warmth

“…In humans, the BDNF gene has a functional single‐nucleotide polymorphism, a Valine to Methionine substitution at codon 66 (Val66Met), which leads to impairments in intracellular trafficking and activity‐dependent secretion (Chen et al., 2004; Egan et al., 2003), and to various morphological changes in brain areas such as the hippocampus, prefrontal cortex, and the amygdala (reviewed in Notaras, Hill, & van den Buuse, 2015). The BDNF gene has been shown to interact with various environmental factors in affecting behavioral outcomes (Drury et al., 2012; Hayden et al., 2010; Willoughby, Mills‐Koonce, Propper, & Waschbusch, 2013).…”

No gene-by-environment interaction of BDNF Val66Met polymorphism and childhood maltreatment on anxiety sensitivity in a mixed race adolescent sample

“…Firstly, the grouping of Met66 allele carriers (i.e. Met66Met and Val66Met genotypes), as is frequently carried out in studies in which the rate of the Met66Met genotype is relatively low, such as in Caucasian samples (Gatt et al, 2009; Lehto, Maestu, Kiive, Veidebaum, & Harro, 2016; Nedic et al, 2013; Pivac et al, 2009), may introduce a bias in which a main effect of genotype is not detected due to the exclusion of the Met66Met genotype in analyses (Notaras et al, 2015). Secondly, the Val66Met and Met66Met genotypes, respectively, may have dissimilar effects (Hong et al, 2012).…”

“…Our findings highlight the importance of assessing gene-environment interactions in the assessment of genetic effects on anxiety-related phenotypes associated with anxiety disorders. Recommendations for future research include replication in larger samples of mixed race participants in which population stratification is corrected for and in which the Met66Met genotype is better represented (Notaras et al, 2015). Furthermore, variation across the BDNF gene would be useful to consider (Mandelman & Grigorenko, 2012).…”

“…Brain-derived neurotrophic factor (BDNF) is a secretory protein in the neurotrophin family known to influence the proliferation, survival, differentiation, repair and regulation of synaptic plasticity of neuronal cells in the developing and adult brain (Bath & Lee, 2006; Chen et al, 2006; Martinowich, Manji, & Lu, 2007; Notaras, Hill, & van den Buuse, 2015). BDNF is widely expressed in the hippocampus and cerebral cortex (Hofer, Pagliusi, Hohn, Leibrock, & Barde, 1990; Huang & Reichardt, 2001) and enhances hippocampal long-term potentiation (Figurov, Pozzo-Miller, Olafsson, Wang, & Lu, 1996) associated with both memory and learning efficiency (Hariri et al, 2003; Yamada, Mizuno, & Nabeshima, 2002).…”

“…Compared with the Val66 allele, the Met66 allele is associated with a decrease in activity-dependent secretion of BDNF (Egan et al, 2003). BDNF has received attention due to its evident role in anxiety and mood disorders (Angelucci et al, 2014; Hemmings et al, 2008; Li, Chang, & Xiao, 2016; Martinowich et al, 2007; Molendijk et al, 2014; Suliman, Hemmings, & Seedat, 2013), although findings have been inconsistent across studies (Frustaci, Pozzi, Gianfagna, Manzoli, & Boccia, 2008; Hong, Liou, & Tsai, 2012; Lam, Cheng, Hong, & Tsai, 2004; Minelli et al, 2011; Notaras et al, 2015; Surtees et al, 2007; Wang et al, 2015). …”