The BDNF gene Val66Met polymorphism as a

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Mar 31, 2015 - number of articles returned over the designated search period identifies the Val66Met polymorphism as a trending topic within the literature.
Molecular Psychiatry (2015), 1–15 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp

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The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy M Notaras1, R Hill1 and M van den Buuse1,2 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. Molecular Psychiatry advance online publication, 31 March 2015; doi:10.1038/mp.2015.27

INTRODUCTION It is now widely accepted that psychiatric disorders arise from complex gene–gene and gene–environment interactions, and that their clinical heterogeneity may be the result of the differential involvement of discrete etiological and genetic factors. In recent years, a number of genetic variants have been identified as modulators of cognitive function.1 This includes genetic variants within the dopaminergic system, such as the DRD3 Ser9Gly and COMT Val158Met polymorphisms,1 as well as those within the serotonergic system, such as the 5HTTLPR (serotonin transporter gene-linked polymorphic region) variant.2 These variants have revealed how disruptions in optimal cellular or system function can modify cognition and risk of development of psychiatric disorders and their resulting clinical phenotype. Brain-derived neurotrophic factor (BDNF) is a protein that transects several hypotheses of psychiatric disorder development by being a prominent promoter of neuronal development, maturation and plasticity in both the developing and adult brain. Several gene variants have been identified within the BDNF gene, and many of these variants appear to be in strong linkage disequilibrium (LD) with one another. However, one BDNF variant has garnered more attention than others. The exonic Val66Met polymorphism, in which an amino-acid residue substitution from valine (Val) to methionine (Met) occurs at codon 66 within the proregion of BDNF, has been shown to be a functional single-nucleotide polymorphism (SNP) that results in deficient BDNF translocation and secretion.3 Genetic association studies have shown that the Val66Met polymorphism may be a risk factor for the development of neuropsychiatric disorders,4 and that there is evidence that the polymorphism modulates aspects of neurocognitive function in

otherwise healthy adults.5 Since 2003, the year in which the Val66Met polymorphism was first described as a functional variant,3 the number of studies evaluating the effects of this evolutionarily recent genetic aberration has progressively increased (Figure 1). The pace of publication on BDNF and the Val66Met polymorphism has produced a gap in knowledge integration both between and within fields interested in the functional effects of this variant and the trophic effects of BDNF in its wild-type form. Here we review the role and relevance of the Val66Met polymorphism in modulating neurocognitive function as well as susceptibility to, and the phenotype of, psychiatric disorders. MOLECULAR NEUROSCIENCE OF BDNF AND THE VAL66MET POLYMORPHISM The BDNF gene is comprised of one main coding exon (exon IX) and nine alternatively spliced promoters to direct site-specific transcription6 and subcellular localization.7–10 The assembly of a 32 kDa proBDNF peptide precedes the formation of mature BDNF,11 and this precursor protein can bind with high affinity to the p75 neurotrophin and sortilin receptor complex to induce apoptosis.12 The proBDNF peptide is cleaved intracellularly and within vesicles by furin and proprotein convertases13 and extracellularly by matrix metalloproteinases 7 and plasmin.14 Cleavage of proBDNF yields a 28 kDa truncated proBDNF or the 14 kDa mature BDNF peptide.11 The truncated proBDNF molecule is a product of subtilisin-kexin-isozyme-1-dependent cleavage and is a proteolytic end product whose functions remain elusive.15 The mature BDNF peptide elicits its trophic effects by binding to the

1 Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia and 2School of Psychological Science, La Trobe University, Melbourne, VIC, Australia. Correspondence: Professor M van den Buuse, School of Psychological Science, La Trobe University, LIMS2, Room 218, Bundoora, Melbourne, VIC 3086, Australia. E-mail: [email protected] Received 16 September 2014; revised 22 December 2014; accepted 9 February 2015

BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

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Figure 1. The number of articles returned by Google Scholar and PubMed that have ostensibly investigated the BDNF Val66Met polymorphism and were published between 2003 and 2013. The Boolean search term ‘title: BDNF AND Val66Met OR rs6265 OR G196A’ was used on Google Scholar, whereas the query ‘((((BDNF) AND VAL66MET) OR rs6265) OR G196A)’ was used to search PubMed. The increasing number of articles returned over the designated search period identifies the Val66Met polymorphism as a trending topic within the literature. BDNF, brain-derived neurotrophic factor.

Figure 2. The molecular phenotype of the BDNF gene Val66Met polymorphism at the level of the synapse. The valine-to-methionine substitution at codon 66 of BDNF has been reported to disrupt dendritic BDNF mRNA trafficking, binding to the intracellular transport molecules, sortilin and translin, and activity-dependent secretion of BDNF. Altered NMDA receptor-mediated plasticity within the hippocampus and transmission in the infralimbic medial prefrontal cortex has also been reported, while the 66Met prodomain of BDNF may bind differentially to receptor targets such as SorCS2. BDNF, brain-derived neurotrophic factor; NMDA, N-methyl-D-aspartate.

TrkB (tropomyosin-related kinase B) receptor,16 with phosphorylation of TrkB initiating a number of trophic signaling cascades including the phosphatidylinosotol-3-kinase, mitogen-activated protein kinase and calmodulin-dependent protein kinase II pathways.17 Despite being located within the proregion of BDNF that is cleaved from the mature BDNF molecule, several in vitro experiments have shed light on how the Val66Met polymorphism modifies the molecular biology of BDNF function (Figure 2). These studies have taken two approaches, namely (1) determining how the 66Met substitution within the BDNF prodomain alters functionality and (2) what effect this substitution confers on neuronal morphology and physiology. A major function of the BDNF prodomain is to mediate the intracellular trafficking of Molecular Psychiatry (2015), 1 – 15

BDNF. The 66Met substitution critically occurs at a residue within the BDNF prodomain that has a role in the effective interaction with molecules controlling the trafficking of BDNF protein and mRNA. Specifically, the 66Met substitution appears to occur within a segment of the prodomain that is involved in the interaction with sortilin, a VPS10 domain protein that controls the trafficking of BDNF to the regulated secretory pathway.18 Likewise, the guanine-to-adenine shift at nucleotide 196 interferes with the interaction of BDNF mRNA with translin, resulting in disrupted dendritic sorting of BDNF mRNA.19 These two mechanisms are therefore believed to potentially underlie the diminished activitydependent release of BDNF, which is reduced by ~ 18 and 29% in hippocampal–cortical neurons transfected with one and two 66Met alleles, respectively.20 However, it should be noted that the © 2015 Macmillan Publishers Limited

BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

effects of the Val66Met polymorphism may not strictly arise from deficient BDNF secretion during activity-dependent processing. Specifically, a complementary mechanism is now emerging where the BDNF 66Met prodomain may act as a ligand to receptor targets such as SorCS2,21 a member of the VPS10 domain containing receptor family,22 which is a recently established proneurotrophin receptor involved in dopaminergic wiring.23 An effect of the Val66Met polymorphism at the cellular level is also evident, with neuronal morphology and physiology being altered both within the hippocampus and the medial–prefrontal cortex of 66Met allele-carrying genetically modified mice. Within the hippocampus, the 66Met allele is associated with reductions in BDNF protein expression and neurogenesis,24 as well as decreased hippocampal volume, dendritic complexity and fractal dimensionality.20 In addition, the 66Met allele disrupts N-methylD-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission and plasticity at CA3-CA1 synapses within hippocampal slices.25 Within the medial–prefrontal cortex, the 66Met allele has a gene–dosage effect on spine head diameter and dendritic length of layer V pyramidal neurons, deficits that are accompanied by significant reductions in 5-HT (5-hydroxytryptamine)- and hypocretin-induced excitatory postsynaptic currents.26 Within the infralimbic–medial–prefrontal cortex, NMDA receptor neurotransmission is also impaired in layer II/III and V neurons, as is in spike-timing-dependent plasticity; the latter of which can be rescued by pretreatment with BDNF.27 When taken as a whole, the conventional view is that the Val66Met polymorphism disrupts the activity-dependent release of BDNF (Figure 2), potentially having consequences for physiological functions modulated by BDNF such as neurotransmitter release28–30 and long-term potentiation.31,32 Other mechanisms may also be involved in the production of these phenotypes, such as altered actions at the p75 neurotrophin–sortilin receptor complex or altered binding of the 66Met prodomain to SorCS2, but require further study. HUMAN NEUROSCIENCE OF THE VAL66MET POLYMORPHISM Hippocampal structure and function BDNF is an established regulator of synaptic plasticity,33–35 dendritic spine density36–38 and other molecular correlates believed to underpin cognitive performance. Therefore, it is of little surprise that the BDNF gene and the Val66Met polymorphism are among the most commonly studied gene and gene variants within the field of cognitive neuroscience. Since being established as a functional variant, the Val66Met polymorphism has been implicated as a modifier of neurocognitive function.5 Memory performance was the first cognitive domain to be extensively screened for the effects of the Val66Met polymorphism, and while several types of memory impairments have been associated with the mutant 66Met allele in both humans5 and mice,20,39 episodic memory3,40,41 has been shown to be particularly affected by restricted activity-dependent secretion of BDNF. Translating cognitive performance to brain structure and function, the effects of the Val66Met on hippocampal function and morphology has been the topic of much investigation. Volumetric reductions of the hippocampal formation have been reported in healthy adult carriers of a 66Met allele relative to Val/Val genotype controls.42 One study reported that an interaction between Val66Met genotype and hippocampal activity during encoding of an episodic memory task accounted for 25% of the variation in task performance,40 whereas another reported a negative correlation between number of 66Met alleles carried and activity of the hippocampi and right parahippocampal gyrus.43 Consistent with these individual reports, two meta-analyses (n = 399 and 3620, respectively) have confirmed that 66Met allele carriers have smaller bilateral hippocampi relative to 66Val homozygote © 2015 Macmillan Publishers Limited

controls.44,45 However, these meta-analyses noted that the effect size of the 66Met allele on reduced hippocampal volume is relatively small44 and that most studies suffer from underpowered samples.45 This small effect size, when coupled with heterogeneous sampling and nuisance variability between studies, may explain why some studies have failed to report an effect of the Val66Met polymorphism on hippocampal structure and function. Nevertheless, this small effect size has led to the suggestion that the study of hippocampal volume, and possibly the study of memory too,46 among 66Met allele carriers, may represent a ‘winner’s curse’.45 The mechanisms underlying these changes in hippocampal structure and function remain unconfirmed, although basic research using transgenic mice is likely to lead to a better understanding of these phenotypes. As both 66Met knock-in mice and 66Met allele-carrying humans have reductions in hippocampal volumes, it is possible that other cellular phenotypes observed in these mice, such as disrupted neurogenesis24 and reductions in how well dendrites fill their field,20 could underlie the reductions in hippocampal volume observed in human 66Met carriers. Likewise, changes in receptor physiology may also underlie memory deficits.25 Importantly, these Val66Met mice studies highlight that alterations in the size of soma of hippocampal neurons20 is unlikely to account for reductions in hippocampal volumes among 66Met allele carriers. However, the distinct lack of research that has used genotype-acquired human brain tissue limits the findings of these mouse studies as extrapolations with predictive merit. Other brain morphology A growing number of studies suggest that the Val66Met polymorphism also modulates the morphology and connectivity of regions outside of the hippocampus. Lower gray matter volumes have been reported within the dorsolateral prefrontal cortex47,48 among 66 Met allele carriers, a finding that may be modulated by age and sex.49 Reductions in gray matter volumes and cortical thickness, particularly within frontal, temporal, cingulate and insular cortices,50 have also been observed among 66Met homozygotes relative to those carrying the wild-type Val/Val genotype. Volumetric reductions of the amygdala, a region of functional importance for the processing of fear 51 and emotion,52 have been associated with carrying the 66Met allele53 in an age-dependent manner.54 As a functional corollary to these studies, greater recruitment of the amygdala has been reported among male, but not female, 66Met allele carriers during encoding of a recognition memory task, while regions of the prefrontal and cingulate cortex were over-recruited during retrieval.55 Cortical thickness of the entorhinal cortex, inferior temporal gyrus, middle and superior temporal gyri and parietooccipital sulcus are also regulated by both the Val66Met polymorphism and age, with a significant interaction between the two factors resulting in greater cortical thickness among 66Val homozygotes earlier in life, but reduced thickness later in life relative to 66Met allele carriers.56 Other regions reported to be smaller in 66Met allele carriers include the thalamus and fusiform gyrus,53 as well as the parahippocampal and left superior frontal gyri.57 Tract integrity Given evidence that measures of cerebral connectivity have high heritability estimates,58 it has been suggested that the Val66Met polymorphism may also modify white matter microstructure. Although the 66Met allele has been associated with age-related reductions of fractional anisotropy within the splenium of the corpus callosum59 and bilateral uncincate fasciculus among a cohort with extinction learning deficits,60 these studies comprised relatively small samples. To the contrary, larger studies have gone on to show the opposite. For instance, in a study of 455 twins and Molecular Psychiatry (2015), 1 – 15

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BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

4 their siblings, the 66Val allele was associated with fractional anisotropy reductions of up to 15% within major tracts including the splenium of the CC, left optic radiation, inferior fronto-occipital fasciculus and superior corona radiata.61 Similarly, in a study of 85 healthy Caucasians, it was reported that 66Val homozygotes had significantly lower fractional anisotropy within prefrontal and occipital regions than 66Met allele carriers.62 Providing a potential explanantion for discrepant results, it was recently reported that, similar to cortical thickness (see section 'Other brain morphology'), Val66Met polymorphism status interacts with age to predict tract integrity of the left cingulum bundle, inferior longitudinal fasciculus and arcuate fasciculus.56 In this respect, aging may determine Val66Met phenotypes related to brain structure. Further, a recent report, which found that 66Met allele was associated with increased white matter hyperintensity volumes among a sample of aged (⩾60 years) individuals,63 draws attention to the need to ensure that white matter hyperintensity frequency or volume is controlled for, or is analyzed as a covariate, so as not to potentially confound data analysis.64,65 THE BDNF VAL66MET SNP AND PSYCHIATRIC DISORDER SUSCEPTIBILITY Anxiety-related behavior, traits and disorders Anxiety disorders, as a class, are characterized by overarching feelings of intense worry, anxiety and fear (the latter of which is discussed in further detail within section 'Memory of fear and posttraumatic stress disorder', along with posttraumatic stress disorder (PTSD)). Genetic association studies have previously found that different loci of genetic variation within the BDNF gene may be associated with both anxiogenic- and anxiolytic-like effects,66 drawing attention to the role of BDNF in both the maintenance and potential treatment of anxiety-related phenotypes. In 2006, Chen et al.20 generated a Val66Met knock-in mouse model to use as a preclinical tool for investigating a genetic role for BDNF in anxiety and affective disorders. In their study, Met/Met homozygote mice were shown to have an anxiety-like phenotype as compared with Val/Val controls.20 Complementing the results from these ‘bottom-up’ animal experiments, human studies have also provided evidence that the Val66Met polymorphism is related to anxiety-related traits,67 albeit inconsistently.68 This may be further regulated by interactions with the dopamine transporter gene variable number tandem repeat variant69 and 5HTTLPR variant.70 Although preclinical studies have shown a role for the BDNF Val66Met polymorphism in the manifestation of anxietyrelated behavior and traits, there is only limited evidence for a role of the Val66Met polymorphism in the prevalence of anxiety disorders.71 Aspects of obsessive-compulsive disorder, an anxiety disorder involving intrusive thoughts of anxiety and the need to complete physical or mental compulsions, have been associated with the Val66Met polymorphism; however, some inconsistent results have also been reported.72–79 Many anxiety disorders, to date, have failed to associate with the Val66Met polymorphism. For instance, no association of the Val66Met polymorphism has been observed for treatment response to venlafaxine XR in generalized anxiety disorder patients nor prevalence of generalized social anxiety disorder (total n = 225).80 However, few studies have investigated a relationship between BDNF and these particular types of anxiety disorders, urging caution in their extrapolation, especially given the small sample sizes. Further, given several association studies (n = 103–1241), there is also insufficient evidence to suggest that panic disorder, an anxiety disorder characterized by disabling and recurrent panic attacks, is associated with the Val66Met polymorphism.81–84 Meta-analyses have also generally failed to report significant associations between Val66Met genotype or allelotype and anxiety disorders.71 Ultimately, it may be the case that the Val66Met polymorphism only provides Molecular Psychiatry (2015), 1 – 15

susceptibility to trait anxiety that is independent of a psychiatric diagnosis, with the aforementioned anxiety disorders presumably maintaining otherwise distinct etiologies. Memory of fear and PTSD PTSD is an anxiety disorder characterized by intrusive flashbacks of a preceding traumatic event. Preclinical animal models often use memory, extinction, renewal and spontaneous recovery of conditioned fear as endophenotypes for exploring the molecular mechanisms of PTSD. BDNF has been implicated in the fear memory circuitry,85 with Bdnf heterozygote (+/ − ) mice showing impairments in contextual fear memory.86 Although extinction learning is affected in BDNF+/ − mice,87 Bdnf haploinsufficiency tends to affect especially the extinction learning of older mice.88 Providing evidence that activity-dependent secretion of BDNF, and not developmental abnormalities resulting from a BDNFdeficient environment, modulates function of the fear circuitry, 66Met homozygote knock-in mice similarly show deficits in contextual, but not cue-elicited, fear memory20 and extinction learning.60 Providing evidence for a conserved role of the 66Met allele in the fear circuitry, human 66Met allele carriers also show extinction learning deficits60 and generalize cued fear responses maladaptively across contexts.89 Stronger patterns of activation of the amygdala during an affective startle reflex paradigm have also been observed among 66Met allele carriers,90 whereas overactivation of the anterior cingulate cortex, brainstem and insula has been observed among 66Met carriers when presented with fear-related and emotionally salient facial expressions.91 Cumulatively, these studies suggest that 66Met carriers show dysregulated activation of brain regions involved in fear processing and autonomic arousal, which may predispose or increase risk of fear-related disorders such as PTSD. In spite of an expanding literature base suggesting that the Val66Met polymorphism modulates function of the fear circuitry in both mouse and man,60 there is only limited evidence to suggest that the Val66Met polymorphism is associated with PTSD—partly due to a lack of research on the topic. Early studies found no association of the 66Met allele with PTSD status, but were compromised of small sample sizes ranging from 65 to 106 patients.92–94 More recently, however, a study of 576 war veterans of Caucasian descent (370 of whom carried a PTSD diagnosis) revealed that a subgroup of PTSD patients with psychotic symptoms more frequently carried the 66Met allele relative to non-psychotic PTSD patients or veteran controls.95 Similarly, a study of 461 United States Army Special Operations soldiers found that the frequency of the Met/Met genotype and 66Met allele was three- and twofold higher within the probable-PTSD group than controls.96 Complementing these studies, the 66Met allele has also been shown to predict poorer response to an 8-week exposurebased therapy program among a cohort of 55 patients carrying a diagnosis of PTSD,97 suggesting that the 66Met allele may also have a role in the treatment of this disorder. Although only a handful of studies assessing a role of the Val66Met polymorphism in PTSD have been published, there is consistency in that the 66Met allele has been associated with the prevalence or treatment of this disorder in all of these studies. Further, the fact that extinction learning is disrupted in both man and mouse is a good evidence for a conserved role of this genetic variant within the fear circuitry.60 However, given the small number of clinical studies on the topic, further studies comprising larger samples are warranted to draw a conclusion about the role of the Val66Met polymorphism in susceptibility to PTSD. Mood disorders Investigations into the molecular mechanisms of depression and bipolar disorder, two mood disorders characterized by affective dysregulation, cognitive dysfunction and anhedonia, have © 2015 Macmillan Publishers Limited

BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

5 consistently implicated BDNF function in the pathophysiology and treatment of these disorders. For instance, serum BDNF levels are lower among depression patients and may recover to levels more consistent with controls following antidepressant treatment.98 This finding coincides with observations that BDNF may be involved in the molecular actions of mood-stabilizing therapeutics.99,100 For example, direct infusion of BDNF to the midbrain reduces the immobility of rats on the forced swim test, a behavioral model of learned helplessness, by up to 70%,101 whereas performance of Val66Met polymorphism knock-in mice on this test is also disrupted and is not rescued by fluoxetine.20 Val66Met knock-in mice also show reduced ketamine-induced prefrontal synaptogenesis,26 and fluoxetine-induced hippocampal plasticity,24 respectively, suggesting that the 66Met allele may be associated with treatment resistance. A human endophenotype of depression, neuroticism, has also been screened for association with the Val66Met polymorphism, and while results between studies have been inconsistent,102 one study (n = 2333) found that the 5HTTLPR variant interacted with the 66Met allele to increase neuroticism.103 The Val66Met polymorphism has also been linked to the presence of depressive symptoms in other disorders such as schizophrenia104 and neurological conditions such as Alzheimer’s disease,105 which when taken as a whole suggests a role for BDNF in the pathogenesis of mood disorders.106,107 Despite these findings, the role of the Val66Met polymorphism in mood disorders remains unclear. Depression has been associated with BDNF gene haplotypes104 as well as both the 66Met allele in geriatric depression108,109 and wild-type 66Val allele110 between studies. However, reports that the 66Met allele is not overrepresented among depression probands appears to be the most prevalent result within the literature.111–113 Studies assessing association of the Val66Met polymorphism with bipolar disorder have also reported no significant association in singlemarker analyses,114 which is consistent with the results of two meta-analyses of 3236 (ref. 115) and 3143 (ref. 116) cases, respectively. In contrast, reports of association117 or preferential transmission of the 66Val allele in both children118 and adults119,120 have also been published. Population stratification aside,115 a possible explanation for this discrepancy could be that the Val66Met polymorphism may only convey susceptibility to mood disorder according to sex. In support of this view, there is (variable) evidence that serum BDNF concentrations of Val66Met carriers are modulated by sex,121,122 whereas a meta-analysis of 2812 cases and 10 843 controls found that the association between depression and the Met/Met genotype and 66Met allele may be selective to males.123 However, one study reported the opposite by finding that the 66Met allele was overrepresented with depression among females, but selectively among those with a history of childhood adversity.124 Given the role of stress in mood disorder susceptibility, it may be that the Val66Met polymorphism is associated with mood disorders through altered hypothalamic-pituitary-adrenal axis activity. This may sensitize 66Met allele carriers to the negative effects of stress, which may explain discrepant results from association studies given that few have stratified their samples for a history of stress. Both humans125–127 and Val66Met knock-in mice128 have been reported to show evidence of hypothalamic-pituitary-adrenal axis dysregulation either at baseline or following challenge, suggesting physiological susceptibility to stress. Furthermore, it has been reported that stressful life events are significantly more frequent among first-episode depression patients carrying the Val/Met and Met/Met genotype.129 Further to this, the effect of childhood sexual abuse on adult depressive symptoms in otherwise healthy individuals also appears to be moderated by Val66Met genotype, with 66Met allele carriers being more susceptible than Val/Val genotype controls.130 In this regard, it may be of value for future Val66Met studies to consider stratifying their analysis for both main effects of sex (or high–low estrogen phases,39,131 which may © 2015 Macmillan Publishers Limited

mediate sex differences) and exposure to stressful life events. This may resolve the effect of these two factors, and their putative interaction,126 in the modification of risk and clinical phenotype of stress-inducible psychiatric disorders such as PTSD and depression. While suggestive that the Val66Met polymorphism is unlikely to conform to the parameters of a simple genetic model,115 the results of these risk-determination studies do not preclude the possibility that the Val66Met polymorphism may determine certain clinical phenotypes. A role of the Val66Met polymorphism in the efficacy of antidepressant therapeutics is one such clinical feature that has been relatively well explored. Antidepressant medications are believed to upregulate100,132 and, at least partially, exert their effects through BDNF-mediated signaling.99,133 However, evidence linking the Val66Met polymorphism to antidepressant response has been relatively variable—potentially because of this being a skewed literature that overrepresents Asian samples relative to Caucasians (see Table 1). In this respect, as supported by meta-analysis, evidence linking the Val66Met polymorphism with therapeutic efficacy appears to be associated with data obtained from Asian samples.134 In addition to antidepressant response, there is evidence to suggest that lithium prophylaxis may also be gated according by the Val66Met polymorphism in isolation135 and via epistatic interactions with the serotonin 5HTTLPR variant;136 however, inconsistent results also persist.137 These conflicting results in both the depression and bipolar literature have lead to suggestions that type of therapeutic,111 ethnicity134 or genetic variation within the serotonin system136,138 may mediate a potentially small113 effect of therapeutic responsiveness among Val66Met carriers. Other than pharmacological treatments, it has also been hypothesized that the Val66Met polymorphism may affect the efficacy of transcranial magnetic stimulation treatments by altering BDNF-inducible synaptic plasticity,139 and there is evidence to suggest that mood disorder patients carrying the 66Met allele are not as responsive to repetitive transcranial magnetic stimulation therapy as compared with 66Val homozygotes.140 Regardless of the method, whether these observed differences in treatment responsiveness affect overall rates of long-term remission often remains unreported. Between two studies, it has been reported that late-life depression patients carrying the 66Met allele show a higher rate of remission than controls.141,142 Although 66Met allele carriers have lower perceived social support and show a trend for fewer social interactions,143 suggesting poor utilization of peer-based coping strategies, social support does not appear to mediate the putative effects of the 66Met allele with regard to maintaining 6-month remission rates.142 That said, given that these studies sampled older adults, it remains unclear if these results extend to individuals of all ages suffering from divergent forms of mood disorder. Although promising, these studies highlight the need for further investigation, especially in light of a recent meta-analysis, which suggests no role of the Val66Met polymorphism in the mediation of remission following antidepressant treatment.134 Keeping in mind the heterogeneity and ethnicity bias present within the Val66Met literature at present, in the short term it would be of value for further large-scale studies to continue exploring an association among mood disorders, their clinical phenotype and Val66Met genotype in Caucasians and other underrepresented but vulnerable subgroups (e.g., females with a history of early life stress). On the other hand, in the long term, the collection of longitudinal data may help to discern a definitive role of the Val66Met polymorphism in mediating response to and recovery from disorders of mood; data that are currently lacking but are critically required before results relating to Val66Met-mediated treatment efficacy and rates of remission can be generalized with confidence and translated to the clinic. Molecular Psychiatry (2015), 1 – 15

BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

6 Table 1.

Association of the BDNF gene Val66Met polymorphism with antidepressant response

Reference

Therapeutic

Principal mechanism

Treatment length

Major outcome (66Met vs 66Val)

Tsai et al.112

Fluoxetine

4 Weeks

No major effect on response

Choi et al.240

Citalopram

8 Weeks

↑Citalopram response among 66Met carriers

Gratacos et al.241

Not specific

Serotonin reuptake Serotonin reuptake —

Rajewska-Rager Escitalopram and Serotonin and nortriptyline norepinephrine et al.242 reuptake Yoshida et al.243 Fluvoxamine and Serotonin and milnacipran norepinephrine reuptake 244 Mirtazapine Noradrenaline Kang et al. and serotonin Fluoxetine Serotonin Zou et al.245 reuptake Fluoxetine and Serotonin and Chi et al.111 venlafaxine norepinephrine reuptake Not specific — Domschke 113 et al.

Zou et al.134

Not specific

Paroxetine and Yoshimura sertraline et al.246 247 Mirtazapine Katsuki et al. Laje et al.248

Ketamine

Xu et al.249

SSRI and venlafaxine

— Serotonin reuptake Noradrenaline and serotonin NMDAR antagonist Serotonin and norepinephrine reuptake

⩾ 6 Weeks

No major effect on response

8 Weeks

No major effect on response

1, 2, 4 and 6 Weeks

Total sample Asian MD = 110 Control = 255 Asian MD = 83 Caucasian MD = 374 Control = 342 Caucasian MD = 90

↑ Therapeutic effect on MADR scores of Val/Met genotype patients across time

Asian MD = 134

4 and 8 Weeks ↑ Plasma BDNF in Met/Met homozygotes following Asian MD = 243 treatment relative to 66Val allele carriers 6 Weeks ↑ Rate of Remission among Val/Met vs Val/Val patients. Asian MD = 295 No major effect on rate of response or HAM-D. 4 Weeks ↑Venlafaxine response among 66Val carriers Asian MD = 117 Control = 106 6 Weeks



Val66Met genotype related to AD response in melancholic depression. BDNF rs7103411/rs6265/ rs7124442 haplotype predicts worse treatment response. No effect in STAR*D.

Caucasian MD = 268 Control = 424 STAR*D *MD = 1953 Meta-analysis MD = 1115

8 Weeks

↑Antidepressant response of Val/Met vs Val/Val genotype among total and Asian samples. No effect on remission rate. No major effect on response Asian MD = 132

4 Weeks

No major effect on response

Asian MD = 84

Acute infusion ↑Response to Ketamine among 66Val Homozygotes (40 min) (short term) 4 and 6 Weeks ↑ Early response (4 weeks) to SSRI treatment among Met/Mets, but no effect at week 6

Mostly Caucasian MD = 62 Asian MD = 159

Abbreviations: AD, antidepressant; BDNF, brain-derived neurotrophic factor; HAM-D, Hamilton Rating Scale for Depression; MADRS, Montgomery Åsberg Depression Rating Scale; MD, mood disorder; NMDAR, N-methyl-D-aspartate receptor; SSRI, selective serotonin reuptake inhibitor; STAR*D, Sequenced Treatment Alternatives to Relieve Depression.

Eating disorders Eating disorders, including anorexia nervosa, bulimia nervosa, binge eating and obesity, are widely accepted to have a genetic component.144,145 Genes believed to produce products involved in the regulation of feeding behavior have been extensively screened for incidence and the clinical phenotype of eating disorders.146 Early work with Bdnf conditional147,148 and heterozygous (+/ − ) knockout mice suggested that BDNF may have a role in the pathogenesis of eating disorders, especially given that the latter have been reported to develop hyperphagia,149 matureonset obesity,150 adipocyte hypertrophy when overweight151 and insulin resistance.152 Interestingly, it has been shown that Bdnf +/ − mice increase meal sizes if fed a high-fat diet,150 a finding that may be related to binging behavior. Subsequent studies identified that BDNF has an important role in regulating the activity of regions within the hypothalamus that may mediate energy homeostasis,148,153 whereas central infusion of BDNF was found to curb food intake in rats154 and maladaptive feeding behavior in overweight Bdnf +/ − mice.151 Although humans are rarely heterozygote for the BDNF gene, one study reported the case of an 8-eight-year-old female who carried a rare de novo chromosomal inversion of part of chromosome 11 that resulted in monoallelic expression of BDNF.155 This patient showed many of Molecular Psychiatry (2015), 1 – 15

the phenotypes exhibited by Bdnf +/ − heterozygote mice, including hyperphagia, obesity and impaired cognitive function. Patients suffering from WAGR syndrome, who suffer from deletions of parts of chromosome 11, also develop hyperphagia and obesity when deletions of the BDNF gene occur.156,157 Taken rogether, these clinical cases and animal studies provide good evidence for the role of BDNF in the modification of normal feeding behavior and subsequent regulation of weight. Being a relatively common genetic mechanism of altered BDNF function, it is not surprising that the Val66Met polymorphism has been associated with psychopathology associated with aspects of weight regulation and feeding behavior.158 The 66Met allele and Met/Met genotype has been associated with minimum body mass index (BMI) in healthy adults as well as risk of developing both anorexia nervosa (AN) and bulimia nervosa (BN) both within and between studies (see Table 2 for summary). Promisingly, several of these studies have been multicenter studies comprising relatively large samples (e.g., n = 1142 eating disorder cases for psychiatric association studies,159 and up to n = 20 270 healthy adults for BMI association160). Although there has been some variability between studies, the Val66Met eating disorder literature has been relatively consistent compared with other psychiatric disorders, and large-scale replication studies © 2015 Macmillan Publishers Limited

BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

7 Table 2.

Association of the BDNF gene Val66Met polymorphism with BMI and eating disorders

Reference

Disorders assessed

Major outcome (66Met vs 66Val)

Ribases et al.250

↓ Minimum BMI and association of ANrestrictive subtype with 66M allele

Caucasian ED = 143 (AN = 64; BN = 70) Control = 112

66Met allele associated with all assessed AN subtypes and BN

Caucasian ED = 1142 (AN = 753; BN = 389) Control = 913 Asian (Japanese) ED = 198 (AN = 72; BN = 118) Control = 222

de Krom et al.251

AN AN-restrictive AN-purging/binging BN AN AN-restrictive AN-purging/binging BN AN AN-restrictive AN-purging/binging BN BN-purging BN-NP AN

Friedel et al.252

AN BN

No association with risk of AN or BN

Gunstad et al. Monteleone et al.165

BMI in healthy adults BN BED

↓ BMI associated with Met/Met genotype ↑ Weekly frequency and severity of binging behavior in Met/Met homozygotes

161

Rybakowski et al.162 Shugart et al.254

AN AN-restrictive AN-purging/binging AN BMI in healthy adults

Arija et al.255

BMI/risk of ED in adolescents

↑ Clinical severity in 66Met carriers No preferential transmission of the Val66Met SNP in AN No Association with Risk of AN ↓ BMI associated with Met/Met genotype relative to 66Val carriers ↓ Caloric intake in 66Met allele carriers with ongoing risk of ED (507 kcal per day) No association with risk of AN

Ribases et al.159 Koizumi et al.158

253

Dardennes et al.

256

AN AN-restrictive AN without binging AN without BN BMI in healthy adults

Ando et al.

Hong et al.160 Brandys et al.229 257

Perkovic et al.

AN BMI in healthy adults

Val/Met genotype associated with total ED sample, AN-restrictive and BN-purging subtypes No association with risk of AN

↓ Body fat % in 66Met allele carriers in the Korea Association Resource (KARE) sample Val66Met genotype correlates with BMI No association with risk of AN in case– control study No effect of Val66Met polymorphism on BMI

Total sample

Caucasian AN = 195 Control = 580 Caucasian ED = 198 (AN = 118; BN = 80) Controls = 96 Healthy adults = 481 Caucasian ED = 210 (BN = 126; BED = 84) Control = 121 Family trios = 114 AN = 149 Control = 100 Healthy adults = 3631 Caucasian children = 258 Asian AN = 689 Controls = 573 Asian healthy adults = 20 270 Caucasian AN = 235 Controls = 643 Caucasian healthy adults = 339

Abbreviations: AN, anorexia nervosa; BDNF, brain-derived neurotrophic factor; BED, binge eating disorder; BMI, body mass index; BN, bulimia nervosa; BN-NP, bulimia nervosa non-purging; ED, eating disorder.

that have comprised both case–control studies and family trios provide support for a potential role of the 66Met allele in risk of developing these disorders. Nevertheless, it remains unclear if preferential transmission of the 66Met allele is involved in risk of eating disorders, with one study reporting preferential transmission of a − 270C/66Met haplotype to AN-restrictive probands,159 while another reported no evidence of such preferential transmission,161 exemplifying the need for further family-based research within this disorder. In the short term, further research is required to ascertain whether a persistent role of the Val66Met polymorphism in eating disorder phenotypes and pathology exists outside of risk—a research theme that has been relatively underexplored sans a study assessing personality risk factors for eating disorders among 66Met allele carriers.162 In the long term, it would be of value to identify a mechanism by which the Val66Met polymorphism may be involved in the pathogenesis of AN and BN. From a conceptual perspective, as eating disorders are more common among females,163 the putative interaction of ovarian sex steroid hormones and BDNF expression during development164 make the interaction of these two factors a promising molecular pathway within the eating disorder literature. Further, the association of the 66Met allele with binging behavior,165 which appears to be modulated by dietary restriction,166 is another potential pathway worthy of investigation. © 2015 Macmillan Publishers Limited

Schizophrenia and psychosis Schizophrenia is a psychotic-spectrum psychiatric disorder with a complex etiology that is both polygenic and environmentally modulated. The evidence suggesting that the 66Met allele is associated with risk of developing schizophrenia is relatively weak,167 with most studies reporting no evidence that the Val66Met polymorphism is significantly overrepresented among schizophrenia patients relative to controls.168–173 Multimarker analyses that have assessed haplotypes and variants in LD with the Val66Met polymorphism are promising for risk determination,104,174 but remain inconsistent.173,175–178 Adding to the heterogeneity of results observed between studies, there have also been reports that the 66Val allele may be preferentially transmitted from heterozygous parents179 or that the 66Val allele or Val/Val genotype may be risk conferring174,180 in schizophrenia, although a recent meta-analysis reported the opposite.115 That said, most meta-analyses have reported no significant association of the Val66Met polymorphism with schizophrenia in either Asians or Caucasians.170,175–178 Ultimately, given that only a handful of studies have reported positive associations between Val66Met genotype or allelotype, and considering that ‘big data’ approaches such as the Psychiatric Genomics Consortium181 have failed to produce robust evidence that the Val66Met polymorphism is associated with schizophrenia, it is unlikely that the Val66Met Molecular Psychiatry (2015), 1 – 15

BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

8 polymorphism is a major etiological factor related to the development of this illness or related disorders. That said, one recent report used the multifactor-dimensionality reduction method to identify several risk-conferring haplotypes for paranoid schizophrenia that comprised both NTRK2 variants, the gene encoding BDNF’s high-affinity TrkB receptor, and the BDNF Val66Met polymorphism.182 This result suggests that perhaps the 66Met allele is only risk conferring in those individuals carrying other genetic variants that may affect BDNF-TrkB signaling, and possibly those with an increased risk of schizophrenia. In support of the latter, 66Met allele carriers with a high genetic risk of developing schizophrenia show decreased prefrontal brain function,183 whereas 66Met allele carriers with high schizotypal traits show worse probabilistic association learning than those with low schizotypal traits.184 Taken together, these results suggest that the Val66Met polymorphism may only increase risk of schizophrenia when inherited on a high-risk background. However, given the large number of inconclusive results, these studies should be replicated before being used as evidence for a genetic role of the Val66Met polymorphism in the onset of schizophrenia. Risk aside, the Val66Met polymorphism has been shown to modulate several clinical features of schizophrenia. For instance, there have been several positive reports that the 66Met allele may be related to age of onset of schizophrenia, an effect that has been replicated in independent Armenian,167 Asian185 and AfricanAmerican186 samples and appears to be compounded by cannabis use among females.187 The Val66Met polymorphism has also been found to associate with the presence of depression-related symptoms104,188,189 and with aspects of the positive symptom class of schizophrenia in patients,190 as well as with psychosis-like experiences in healthy controls with a history of childhood abuse.191 Therapeutic efficacy also appears to be gated by the Val66Met polymorphism,192,193 with risperidone response being moderated by epistatic interactions with the BDNF (GT)n dinucleotide and C-270T variants.194 Given that the Val66Met polymorphism is associated with cognitive impairment in healthy controls,5 the 66Met allele has also been associated, albeit variably, with selective deficits in executive function,195 working memory196 and visuospatial processing197 in schizophrenia probands. Deficits in episodic memory have also been reported among medial–prefrontal cortex Val66Met patient carriers,198 as well as decreased hippocampal cerebral blood flow relative to controls during a working memory task.199 However, other studies have failed to replicate an effect of the 66Met substitution on hippocampal function specifically among schizophrenia patients.3,41 Given numerous conflicting reports, but assuming an effect of the Val66Met polymorphism within this disorder, these studies suggest that the 66Met allele may act as a modulator of clinical phenotype independent of any effect on risk. We recently published an exhaustive review on this topic, and direct the reader to such should a more comprehensive discussion of the Val66Met polymorphism and its relevance to schizophrenia be of interest.200 Suicidal behavior Suicidal behavior (SB), defined as ideation, attempts at or completion of suicide, is believed to have a genetic component.201 Suicide is a common cause of premature death; however, those currently suffering from a psychiatric disorder,202 or who have relatives with a history of SB,203 appear to be particularly susceptible to SB. Interestingly, the genetics that predisposes development of psychiatric disorders do not appear to entirely account for the genetic risk of SB.201,204,205 Although a causative agent for SB remains elusive, a converging array of evidence ranging from post-mortem206–208 to blood biomarker209,210 studies suggests that dysregulation of the BDNF system may be associated with SB.211 However, the relationship between the Val66Met Molecular Psychiatry (2015), 1 – 15

polymorphism and SB remains controversial, with both positive and null effects of the 66Met allele having been reported within the literature. Many of the positive associations reported between the Val66Met polymorphism and SB have come from samples of patients suffering from a predisposing psychiatric disorder, with attempted suicide being associated with the 66Met allele212,213 or Met/Met214 genotype among several independent samples comprised of mood disorder patients. Frequency of the Met/Met genotype has also been associated with attempted suicide among schizophrenia probands.215 Of concern, the 66Met allele has been linked to lethality among depressed patients who attempt suicide216 and the utilization of violent suicide methods among female carriers of a 66Met allele.217 Adding credence for a role of BDNF in SB, a recent meta-analysis reported that the 66Met allele was significantly associated with history of suicide attempt,218 while another reported that the 66Met allele was associated with attempted but not completed suicide.219 Contradicting these findings, there have also been reports that the wild-type 66Val allele is associated with SB in bipolar disorder,220 or that haplotypes inclusive of the 66Val allele are associated with aspects of SB such as ideation.221 One prominent study found that only the Val/Val genotype was associated SB among individuals with a history of child abuse,222 suggesting not only a multifaceted role of the Val66Met polymorphism in SB pathology but also the need to explore complex gene–environment interactions in suicide research. When taken with null reports of Val66Met polymorphism status among suicide completers,223 suicidal thoughts among adolescents224 and suicide attempt in mood-disordered patients,108,225 it becomes clear that further research examining the Val66Met polymorphism and its role in SB is required. Further, and in light of positive associations, it remains unclear how the Val66Met polymorphism may be related to SB. Thus, genetic association studies have provided evidence for the involvement of the polymorphism in SB, but have not provided detail of the mutation’s mechanism of action in the production or maintenance of SB. An approach for future research, therefore, may be to identify the biological, cognitive and psychosocial substrates that mediate the relationship between the Val66Met polymorphism and SB (Figure 3); a theme that has yet to be the topic of primary research. In the long term, it may then be possible to use these intermediate phenotypes to more accurately refer patients to preventative services and treatments before the onset of strong ideation. UNRESOLVED ISSUES Analysis, population stratification and sampling factors The number of inconsistent, and contradictory, reports within the literature assessing the effects of the Val66Met polymorphism in both healthy and clinical samples emphasizes (1) the need to identify additional factors that are involved in the relationship between aberrant BDNF function and a resulting phenotype; (2) that phenotypes may be subtle and are susceptible to nuisance variance and noise. Differences in allelic frequency of the Val66Met polymorphism between ethnicities226 and subpopulation groups227 paired with the observation that Caucasians appear to be more susceptible to the effects of the 66Met allele,228 furthermore, suggests ethnicity-specific effects of this variant, an argument that has already been used to explain the diversity of clinical features that have variably been linked to Val66Met genotype between studies. Considering the surge in research examining the role of the Val66Met polymorphism in brain structure, function and disease over the past decade (see Figure 1), a lack of understanding of the effects of ethnicity and genetic background on Val66Met phenotypes represents a central limitation in interpreting experimental results and translating them into feasible clinical treatments. Further, as the 66Met allele is less common in Caucasian relative to Asian populations,227 © 2015 Macmillan Publishers Limited

BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

9 cellular level or whether they affect the molecular phenotype induced by the 66Met substitution.

Figure 3. The Val66Met polymorphism has been linked to suicidal behavior; however, reports of discrepant and null effects of the 66Met allele suggest that other factors may mediate the relationship between this variant and suicidal behavior. The intermediary factors that facilitate the relationship between suicidal behavior and the Val66Met polymorphism have not been widely investigated and remain undefined. Ergo, identification of the biological and psychosocial mediators of suicidal behavior that derive from being a 66Met allele carrier, may provide the opportunity to more accurately determine risk of suicidal behavior, permit the formulation of early interventions specific to those carrying the risk allele of this variant and lead to improved clinical management of individual cases. HPA, hypothalamic-pituitary-adrenal axis.

many European and North American studies group 66Met heterozygote and homozygote probands together into a single group for comparison against Val/Val homozygotes.50 This process of genotype grouping has resulted in two inherent biases within the literature as a whole, namely that (1) there is an ethnicity bias within the literature that has assessed all three genotype groups and that (2) genotype, relative to allelotype, effects remain understudied—especially among Caucasian samples. Given evidence of a gene–dosage effect of the Val66Met polymorphism from animal studies,20 future studies should consider sampling strategies that would increase representation of the Met/Met genotype, and not just the 66Met allele, to ensure that a main effect of genotype is not unintentionally missed. Confirming that groups are adequately sampled via a priori power analysis may also help to address reports of increasing regression towards the mean with respect to the effect sizes observed in some Val66Met replication studies. Likewise, meta-analyses must be careful to stratify their analyses for ethnicity but should also be mindful of early reports, which constitute a ‘winner’s curse’ as these may also skew the results if not removed.229 Ensuring that these statistical and sampling biases are addressed within the Val66Met literature is a priority, and may help to resolve an effect of the Val66Met polymorphism where inconsistent results persist. Other BDNF gene variants Also worthy of discussion is the undefined role of other BDNF gene variants, and their possible interactions in controlling the molecular actions of the Val66Met polymorphism. Outside of rare variants, several of the more common BDNF gene variants appear to be in strong LD with the Val66Met SNP in psychiatric populations. Given that single-marker association studies often fail to reach significance, haplotype blocks can offer increased statistical power for detecting subtle BDNF-mediated phenotypes but may also provide important clues as to whether other variants located within promoter regions, polyadenylation sites or CpG islands may be having an effect in psychiatric illnesses when inherited in tandem with the Val66Met polymorphism. As other BDNF transgene mice have yet to be generated, phenotyped and then crossed with Val66Met knock-in mice, it remains unclear whether these other BDNF gene variants are functional at the © 2015 Macmillan Publishers Limited

A role for the Val66Met variant in cognitive deterioration? Over the current review, several unresolved questions and gaps in the literature have been identified that may be resolved through the use of a longitudinal design, namely assessments of remission from mood disorders and assessments of the therapeutic efficacy of antidepressants. In addition to this recommendation, there is a need to examine how BDNF phenotypes develop and change over time. BDNF has a role in healthy aging, and has been suggested to have a role in neurodegenerative disorders such as Alzheimer’s disease.230 Aging may therefore exacerbate susceptibility to alterations in the expression or secretion of BDNF, possibly arising through a process where latent cognitive reserve is depleted as a factor of healthy aging. Despite knowing that the Val66Met polymorphism has a role in modulating hippocampal function and several other cognitive functions as already reviewed,5,228 little is known about whether Val66Met genotype mediates changes in cognition over time as a result of aging or length and severity of psychiatric illness—factors that may underscore cognitive decline. Indeed, preliminary evidence suggests that memory dysfunction, especially transposition errors on a backward recall task, may arise in older but not younger 66Met allele carriers,231 suggesting that cognitive phenotypes may emerge as a factor of age in Val66Met carriers. Likewise, changes in brain morphology over 3 and 4 years have been associated with the Val66Met polymorphism in schizophrenia232 and bipolar233 patients, respectively, and it would be interesting to extend these studies over a longer duration while continuing extensive cognitive testing. Determining whether the Val66Met polymorphism mediates long-term cognitive deterioration as a result of psychiatric illness or aging is therefore a critical question to be further resolved within the Val66Met literature, and could help to tailor treatment strategies to vulnerable groups. Complex interactions Another major limitation of the Val66Met literature as a whole is a lack of understanding of environmental and genetic factors, which further regulate the molecular, behavioral and clinical phenotypes associated with this genetic variant. Whether one is studying anxiety disorders or SB, the Val66Met clinical literature is consistently inconsistent. Although some of this variability is likely due to differences in etiology within disorders and clinical subtypes, complex interactions have been used as a common explanation for non-concordant results between studies but remain relatively unexplored. Over a decade of research has robustly identified a range of environmental factors that control the expression of, and phenotypes related to, BDNF, including stress, drug abuse, exercise, environmental enrichment and sex steroid hormones. Many of these factors have been unexplored at both the basic and clinical level within the Val66Met literature as potential interaction factors, both at baseline and in psychiatric populations. Likewise, other common genetic variants, including those within the serotonergic2,234 and dopaminergic systems,1 have been scarcely investigated as interaction factors or covariates —in spite of strong evidence that BDNF controls the development and physiology of these systems.235–239 Many of these environmental and genetic factors have also been identified as factors associated with the onset of mental illness themselves, and if a coherent role for the Val66Met polymorphism in psychiatry is to emerge within the literature, it is imperative that further research is conducted that addresses these gaps. CONCLUSION Over the past decade, the underlying neuroscience of the BDNF Val66Met polymorphism has begun to develop to a point where Molecular Psychiatry (2015), 1 – 15

BDNF Val66Met and psychiatric disorder susceptibility M Notaras et al

10 insight into the polymorphism’s role in neuropsychiatric disorders is beginning to be better understood. However, while the Val66Met polymorphism has been shown to be associated with the prevalence or clinical features of certain anxiety, affective, eating and psychotic disorders, the persistence of inconsistent results draws attention to small effect sizes, heterogeneous sampling and experimental shortcomings. Further, the results of these studies also challenge the conventional view that the 66Met allele is selectively risk conferring, and draws attention to the idea that the wild-type 66Val allele may also contribute risk to particular phenotypes or among certain population groups. If experimental findings are to be translated to clinical treatments, a better understanding of the mechanisms and interactions of the Val66Met polymorphism at the molecular, individual and population levels are required. Transgenic Val66Met knock-in mice should not be overlooked as a viable translational model to assess complex interactions of clinical relevance given their recapitulation of many human phenotypes. In summary, the collective Val66Met polymorphism literature suggests a complex and multifaceted role of BDNF function in neurocognition and psychiatric disorder susceptibility. Whether BDNF is a viable therapeutic target for the treatment of cognitive dysfunction or psychiatric disorders remains a contentious topic, yet continued study of the Val66Met polymorphism holds value by providing insight into the effects of altered activity-dependent BDNF signaling on brain structure, function and disorder. CONFLICT OF INTEREST The authors declare no conflict of interest.

ACKNOWLEDGMENTS MN is a recipient of an Australian Postgraduate Award. RH is supported by a Career Development Fellowship from the National health and Medical Research Council of Australia (NHMRC). MvdB is supported by an NHMRC Senior Research Fellowship.

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