The brain-derived neurotrophic factor (BDNF) is a secretory polypeptide distributed in the central nervous system (CNS), as in other organs, and involved in many cellular processes that regulate behavior. BDNF is a member of a large family of growth factors called neurotrophins, which regulate proliferation, differentiation, survival and death of neuronal and glial cells (Chao, 2003). In the brain, BDNF is expressed by glutamatergic neurons and glial cells but apparently not by inhibitory neurons. A remarkable number of studies in the last two decades demonstrate that BDNF is released at the synapse where it affects synaptic plasticity producing critical changes in cognitive functions, learning and memory (Lu and Martinowich, 2008; Nieto et al., 2013). Cognitive dysfunctions and abnormalities in the underlying brain processes are considered, respectively, core clinical symptoms and biological features in the pathophysiology of psychiatric disorders (Millan et al., 2016).
The current conceptualization of major psychiatric disorders relies on the so-called neurodevelopmental hypothesis, which emphasizes that early altered maturation of the brain and related behavior unfold as phenotypic manifestations of highly heritable characters, that are strongly modulated by environmental factors and, in the end, increase the risk of full-blown disease manifestation (Weinberger, 1987). In fact, multiple evidence suggest that cognitive impairment, intellectual disability, autism, schizophrenia and other psychiatric disorders are characterized, at certain time-points in development, by subtle alterations of brain morphology and physiology, including aberrant synaptic plasticity (Millan et al., 2016). Therefore, it is not surprising that BDNF has been associated with several of those neurodevelopmental disorders (NDD). However, BDNF has a widespread and non-specific action in the CNS, making it difficult to distinguish whether BDNF has a causal role or just appears as epiphenomenon of the disease. Nevertheless, its substantial involvement in neurodevelopment, synaptic regulation and plasticity points to BDNF as a suitable candidate to explain part of the pathophysiology (hopefully, pathogenesis) of different NDD, such as schizophrenia.
Schizophrenia is one of the most debilitating psychiatric disorders, affecting almost 1% of the general population. Schizophrenia has a highly heritable, complex, polygenic architecture, where multiple and non-specific environmental factors interact to unmask subtle brain and behavioral alterations hastening disease onset. To date, the largest genome-wide association study (GWAS) of schizophrenia (Psychiatric Genomics Consortium, Schizophrenia Working Group, 2014), partly confirming the historical relevance of BDNF, spotted the BDNF genomic locus as enriched in common single-nucleotide polymorphisms (SNPs) nominally associated with the disease (P-value < 10−4), but not reaching genome-wide statistical threshold (α = 5 × 10−8). Since a large portion of the estimated heritability of schizophrenia is not accounted by recent GWAS, it cannot be excluded that such studies were underpowered to detect the genetic signal at the BDNF locus. The apparent mismatch between multiple evidence and GWAS findings sustains the debate about the biological translation of GWAS findings, compelling scientist to recognize that the understanding of biochemical and physiological mechanisms may overrule case-control genetic association studies. The latter may be limited by the uncertainty of the phenotype in the psychiatric nosography or by the assumption of a strictly additive genetic model. Although they would deserve greater attention, these considerations go beyond the scope of the present review. Here, we will briefly recapitulate the biology of BDNF and explore its role in the pathophysiology of schizophrenia. We focus on functional genetics and on studies mainly related to the effects of the rs6265 non-synonymous polymorphism. We also review epigenetic and environmental influences, which may account for the largest fraction of BDNF effects in the CNS in modulating the risk and the pathophysiology of schizophrenia. Owing to space constraints, a selection of critical works on the subject matter will be cited.
The cell biology of brain-derived neurotrophic factor
BDNF is synthesized as a pre-proneurotrophin that is cleaved into pro-BDNF and further processed by furin to mature BDNF (hereafter, BDNF) (Song et al., 2017). BDNF undergoes a high regulated endocellular biosynthetic process and is packed in dense-core vesicles (Lessmann and Brigadski, 2009), almost exclusively localized to the pre-synaptic compartment and secreted in response to extracellular and intracellular signals. Neurons also release pro-BDNF, which is in part converted to BDNF by the tissue plasminogen activator/plasmin system. BDNF has high affinity for the tropomyosin-related kinase B (TrkB) receptor, through which it exerts trophic structural and physiological functions across the CNS, promoting synaptic plasticity and connectivity, neurite outgrowth, neuronal survival, prevention of apoptosis and long-term potentiation. On the other hand, pro-BDNF exerts opposite biological functions by stimulating the p75 neurotrophin receptor (p75NTR), which can promote the reduction of dendritic arborization, apoptosis and long-term depression. Because of the opposite functions of BDNF and pro-BDNF, the systems that regulate the pro-BDNF/BDNF ratio may be critical in influencing the overall output on the CNS. Additionally, it is now accepted that BDNF is synthesized and secreted also in post-synaptic dendrites, eliciting autocrine responses, and in microglia (Chung et al., 2015) involving synaptic remodeling and pain modulation (Coull et al., 2005).
The BDNF gene has a complex structure encompassing at least 11 different exons in humans, and nine in rodents, with nine alternative promoters in both species. Fine-tuning of alternative splicing is likely to be related to the spatial-temporal localization of BDNF transcripts and in the end to behavior (Hing et al., 2018). Indeed, it has been shown that the length of the 3’UTR could determine the localization of BDNF mRNA in mice (An et al., 2008), and that transcripts containing exons I and IV are localized to the soma while those with exons II and VI to the dendrites (Chiaruttini et al., 2008). Importantly, the experimental disruption of promoter regions dramatically affects behavior in mice. Disruption of promoter IV impaired GABAergic activity and produced depression- and anhedonia-like behaviors (Sakata et al., 2009; Sakata et al., 2010), whereas disruption of promoter I has been linked with aggressive behavior (Maynard et al., 2016). These studies suggest that the complex splicing of the BDNF gene is crucial to allow spatial-temporal regulation of BDNF synthesis, thus providing an explanation for the diverse phenotypes that have been associated with the genetic variation.
Among the genetic variants in human BDNF, rs6265 represents one of the most studied SNP in psychiatric genetics. Rs6265 lies within the BDNF pro-region domain and produces a non-synonymous substitution at codon 66: C → T/Valine → Methionine (Val66Met). Despite being located in the cleaved pro-region of BDNF, the functional polymorphism rs6265 Val66Met has a profound impact on BDNF cellular biology. The SNP has been linked to BDNF subcellular trafficking and behavior in both human and mice. Historically, empirical evidence pointed to the Met allele as the one conferring the disadvantaged phenotypes either at cellular, structural, physiological and behavioral level (Table 1).
In cultured hippocampal neurons, Val-BDNF is localized to both the cell body and dendrites, whereas Met-BDNF is largely absent from distal dendrites and the synapse (Egan et al., 2003). Indeed, at cellular level, the Met allele is supposed to disrupt the activity-dependent secretion of BDNF by inhibiting sorting of BDNF into dense-core vesicles (Egan et al., 2003). Specifically, it is currently believed that Met-BDNF disrupts the interaction with intracellular transport molecules such as sortilin (Chen et al., 2005; Chen et al., 2006) and translin, which bind the polymorphism location (Chiaruttini et al., 2009). Consistently, experimental studies have shown that the Met-BDNF results in an approximate 18% decrease in activity-dependent secretion in transfected cells carrying one Met allele and a 29% decrease in those transfected with two Met alleles (Chen et al., 2006). However, the constitutive secretion of mature BDNF is not affected by the polymorphism, and basal amounts of BDNF can still be released into the synapse (Chen et al., 2006). The BDNF prodomain itself is a ligand that is secreted in response to neuronal activity, where the Met66 substitution is associated with changes in neuronal morphology. Specific mechanisms have been proposed involving other ligands (Anastasia et al., 2013)–such as SorCS2– probably relevant for dopaminergic circuitry (Glerup et al., 2014). This evidence suggests that multiple mechanisms may affect the BDNF pathway, resulting in altered cell biochemistry.
Cellular biology of BDNF is vast and has been thoroughly studied and reviewed in many articles to which we refer for further reading (Lu and Martinowich, 2008; Nieto et al., 2013; Song et al., 2017; Hing et al., 2018). We will now proceed focusing on the relationship between the genetics of BDNF and its implication for neurodevelopmental, cognitive and behavioral impairment in schizophrenia.
BDNF genetics and schizophrenia
BDNF has been widely investigated in light of the neurodevelopmental hypothesis of schizophrenia, given its role in the development and in the physiology of the CNS. Indeed, BDNF expression is temporally regulated (Hill et al., 2012; Briana and Malamitsi-Puchner, 2018) in promoting neuronal survival and synaptic plasticity (Kojima and Mizui, 2017; Song et al., 2017). BDNF signaling may critically affect the structure and functioning of several neural circuits, being involved in the modulation of multiple neurotransmitter systems, including the dopaminergic (Krebs et al., 2000; Baker et al., 2005), serotoninergic (Martinowich and Lu, 2008) and GABAergic systems (Brünig et al., 2001; Minzenberg et al., 2010), all closely related to schizophrenia. In this regard, disrupted BDNF-TrkB signaling during critical developmental periods may perturb normal development of these systems, leading to physiological dysregulation and vulnerability to schizophrenia (Buckley et al., 2007; Nieto et al., 2013).
Genome-wide association study
We will now briefly review the main aspects of BDNF genetics in GWAS. Schizophrenia is a heritable NDD, believed to arise from complex gene-environment interactions. A number of genes have been associated to schizophrenia-spectrum disorders from family and twins’ studies. However, no single association has been proved necessary or sufficient to produce the disease, compelling scientists to investigate the pleiotropic, non-deterministic consequences of genetic manifestation during development, rather than causality.
GWASs have come to support the genetic liability of schizophrenia (Psychiatric Genomics Consortium, Schizophrenia Working Group, 2014). According to GWAS, genetic risk for schizophrenia is mostly accounted by the widespread small effect contributions of thousands of common genetic variants. The best-known GWAS on schizophrenia, involving 36 989 cases and 113 075 controls, has spotted 108 genomic loci including more than 350 putative risk genes for schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics C, 2014). BDNF gene is not included among these loci. However, the genomic region spanning BDNF and BDNF antisense RNA gene (BDNF-AS), is rich in SNPs with infra-threshold association with schizophrenia (P-value < 1 × 10−4), among which rs6265, the most widely studied genetic variation for the disorder in pre-GWAS era (P-value = 7.95 × 10−5). Of note, in a recent re-analysis of GWAS data (total of 40 675 cases and 64 643 controls) (Pardiñas et al., 2018), rs6265 is the SNP with the strongest association with schizophrenia within the locus, with the C allele (Val-BDNF) associated with increased risk for the disorder [odds ratio (OR) = 1.054, P-value = 1.36 × 10−5]. These data puzzle researchers, since the Met-BDNF allele is the one usually believed to confer disadvantage (Table 1). However, given that in the first schizophrenia GWAS the association of the BDNF locus with the disease was much less significant (P-value = 0.0184), it may be reasonable to expect that rs6265, or other SNPs in this locus, could reach GWAS-significant association with schizophrenia in future studies with greater sample sizes.
The rs6265 single-nucleotide polymorphism
We will now review the main aspects of BDNF genetics associated with the non-synonymous variant rs6265. See Table 1 for a selection of studies on this topic. We here follow the overarching hypothesis that an improved understanding of a complex NDD, such as schizophrenia, should go in parallel with the unloading of physiological mechanisms, bridging the genotype into the phenotype. Indeed, while the Val66Met polymorphism may not be a major unidirectional risk-conferring agent, there is mounting evidence that rs6265 modulates a range of biological and clinical features. To reconcile previous allele-specific findings with risk-allele liability, we may consider the issue of high phenotypic heterogeneity, which might be related to unknown epistatic gene-gene (G × G) or gene-environment (G × E) interactions. In addition, we can hypothesize that the effect of the rs6265 SNP on risk for schizophrenia is compensated by an opposite effect of other variants inherited with it, which would conciliate research showing deleterious effect of the rs6265 T–Met-coding–allele with GWAS findings suggesting a protective role. Indeed, given recent findings implying that common variants associated with schizophrenia are in loci under background selection and characterized by loss of function intolerance (Pardiñas et al., 2018), the BDNF association with schizophrenia could be linked to these ‘less deleterious’ variants, possibly in linkage disequilibrium with rs6265. However, we recognize that the proper inquiry about genotype manifestation into phenotype should invoke the developmental perspective, being the temporal sparsity of possible G × E an insuperable limitation, at this time, to disentangle the generative bias toward the phenotype (Müller, 2007). The Val66Met polymorphism, as well as any common genetic variation, may be a pleiotropic modulator of disease-associated phenotypes, where multiple genetic variants simultaneously inherited might modify the BDNF-TrkB signaling balance in a probabilistic way (Lin et al., 2013). To this regard, recent evidence showing that chromatin loop formation may mediate the mechanism of risk of schizophrenia-associated variants (Won et al., 2016) makes intriguing to explore the potential link between a schizophrenia locus on chromosome 9 (index SNP: rs11139497, OR: 1.07, GWAS, P-value: 3.09 × 10−9) (Schizophrenia Working Group of the Psychiatric Genomics C, 2014) and NTRK2, the gene codifying for the TrkB receptor, ~2.5 Mb far from the index SNP of this locus.
The Val66Met polymorphism has also been associated with brain morphology in magnetic resonance studies. As reviewed elsewhere (Nieto et al., 2013; Notaras et al., 2015), findings are mixed and not conclusive. The Met allele may account for a reduction in volume of bilateral hippocampi. Indeed, hippocampal structure and function may be abnormal at the microscopic level as a consequence of altered biochemistry. Experimental studies have pointed to the Val66Met polymorphism causing morphological abnormalities at the synapses level, both in humans and rodents (Egan et al., 2003; Chen et al., 2006). Met-BDNF knock-in mice showed reduced hippocampal volumes, as well as morphological anomalies of hippocampal neurons (Chen et al., 2006), at the dendritic level, with a lowering of the complexity of the arborization (Chen et al., 2006). Intriguingly, the Met/Met genotype is associated with reduced spine density but an increase in spine length (Liu et al., 2012). Additionally, Met/Met mice showed reduced level of BDNF, impaired neurogenesis and synaptic plasticity in hippocampus (Bath et al., 2012). Behaviorally, these cellular phenotypes are associated with alterations in hippocampal functions such as spatial memory (Yu et al., 2012) and the expression of contextual fear (Chen et al., 2006). Consistent morphological changes have been observed within the prefrontal cortex (Glantz and Lewis, 2000; Kolluri et al., 2005) and hippocampus (Harrison and Eastwood, 2001; Harrison, 2004) of patients with schizophrenia. Interestingly, in humans, working memory-related hippocampal regional cerebral blood flow showed a differential association with rs6265 genotypes in different diagnostic groups. In medication-free patients with schizophrenia bearing the Met allele, blood flow is decreased, whereas the opposite is observed in healthy controls (Eisenberg et al., 2013). Although a causal link between BDNF and schizophrenia is still missing, the convergence on BDNF pathway of different insults may trigger brain circuit alterations related to the disease, likely interacting with genetic variation.
Given its effects on neuronal morphology, rs6265 has been widely investigated for the association with cognitive dysfunction, which is a core symptom of schizophrenia. The effects of the BDNF Val66Met polymorphism on cognition have been extensively documented in healthy individuals. In particular, episodic memory and executive function appear to be impaired in healthy individuals carrying the Met allele (Hariri et al., 2003; Ho et al., 2007; Beste et al., 2011; Richter-Schmidinger et al., 2011). Episodic memory was substantially impaired in Met/Met healthy controls, schizophrenia probands and siblings as compared to the other genotype groups (Egan et al., 2003; Dempster et al., 2005). Impairment of executive function due to failure of prefrontal cognition is a hallmark of the disorder (Andreasen et al., 1998) and the Val66Met polymorphism has been suggested affecting the deficit (Lu et al., 2012). Among patients with schizophrenia, the Val/Val carriers showed better performance at the n-back task, whereas patients with bipolar disorder and Val/Val genotype showed poorer scores in the Wisconsin Card Sorting Test (Rybakowski et al., 2006). These findings suggest that the Val66Met polymorphism may have differential effects on prefrontal cognition between neuropsychiatric disorders (Rybakowski et al., 2006), likely interacting with other factors. Further to this, the Met allele has been associated with impairments in attentional processing, visuospatial ability and cognitive inflexibility in patients diagnosed with schizophrenia, as reviewed elsewhere (Nieto et al., 2013).
The rs6265 polymorphism has also been associated with severity of both affective and non-affective symptoms. In particular, depressive symptoms have been reported to be more severe in patients with schizophrenia carrying the Met allele (Jönsson et al., 2006; Sun et al., 2013). Aside from mood variations, the Met allele carriers have also been found to be burdened with more severe positive symptom, such as delusions (Han et al., 2008; Zhai et al., 2013) and hallucinatory behavior (Suchanek et al., 2013). Furthermore, it was reported that the Met allele carriers were more likely to develop positive-like symptoms (Alemany et al., 2011) and cognitive and brain abnormalities (Aas et al., 2013) when they experienced childhood abuse, and higher self-reported paranoia when exposed to mild social stress (Simons et al., 2009), supporting the possibility of gene-environment interactions involving the rs6265 SNP. Indeed, consistent with a potential role of cognitive control in stress adaptation, a recent imaging study has detected a significant increase in interregional connectivity between anterior cingulate and prefrontal cortex in rs6265 Met-carriers and in individuals with increased familial risk for schizophrenia, during a cognitive control task (Schweiger et al., 2019).
Interestingly, the Val/Val genotype, which was considered the protective genotype before being found as potentially conferring risk for schizophrenia in the latest GWAS study, has been associated with comorbid obsessive-compulsive symptoms in schizophrenia patients (Hashim et al., 2012). Other reports suggest that schizophrenia patients carrying the Val/Val genotype are at risk of experiencing more severe symptoms than patients carrying at least one Met allele (Ho et al., 2007; Numata et al., 2007; Chang et al., 2009; Suchanek et al., 2013), including evidence for sex-biased association, where male patients carrying the Val/Val genotype had more severe positive, negative and general symptoms (Golimbet et al., 2008). Moreover, it has been suggested that Val66Met polymorphism may determine different profiles of response to treatment with antipsychotics (Hong et al., 2003). Although previous studies failed to report significant associations with treatment response to antipsychotics (Anttila et al., 2005; Xu et al., 2010), in another work Val/Val patients turned out to be over-represented among responders to antipsychotics (Zai et al., 2012). As recently reviewed (Han and Deng, 2018), BDNF Val66Met may play a critical role in metabolic disorders associated with antipsychotic treatment in patients with schizophrenia, and indeed rs6265 has been independently associated with eating disorders (Bonaccorso et al., 2015) obesity and type 2 diabetes (Takeuchi et al., 2011).
Such mixed findings may be driven by unknown G × G and G × E interactions, so that individuals carrying a certain allele may be at risk for some pathological conditions but protected from others, depending on the genetic background and the environmental context. GWAS results should be interpreted within a probabilistic and non-deterministic framework. GWAS findings are indeed about common variants conferring small risk for schizophrenia: only if we sum thousands of small-effect variants we obtain a non-zero odd ratio that the individual will develop the disease, being not possible to predict whether this will happen or not. Although the variants within the BDNF locus do not survive GWAS statistical threshold, even conferring small risk, BDNF has a number of recognized functions, related to neuronal physiology, which support future investigations on this gene, and its putative interactome. Of note, an important interactor of BDNF that is likely to regulate BDNF expression (Modarresi et al., 2012) might be the BDNF-AS, whose sequence lies close to BDNF gene. In conclusion, it is plausible that many epistatic and environmental factors may act modulating BDNF pathway, contributing to disease pathophysiology and determining behavioral manifestations.
Brain-derived neurotrophic factor epigenetics and schizophrenia
Being BDNF a gene crucial for highly dynamic processes like brain development and activity, epigenetic mechanisms are likely to play an important role in the regulation of the expression of this gene, potentially interacting with other environmental factors in affecting risk for schizophrenia. Epigenetic mechanisms encompass DNA methylation, histone modification and chromatin conformation, which regulate DNA accessibility and gene expression (Punzi et al., 2018). DNA methylation is the most widely studied mechanism in schizophrenia. It consists in the transfer of a methyl residue to the carbon 5 of those cytosine nucleotides mainly followed by a guanine in the DNA strand 5’ → 3’ (Punzi et al., 2018). DNA methylation changes are relevant for neurodevelopment and underlie the transition between pre-natal and post-natal human brains (Jaffe et al., 2016). Furthermore, a signature of differentially methylated CpGs has been identified in patients with schizophrenia compared to healthy controls in large samples of post-mortem human brains (Jaffe et al., 2016). DNA methylation is known to be under genetic control but is also sensitive to environmental factors, which in turn may affect regulation of gene expression (Ibi and González-Maeso, 2015).
It has been demonstrated that epigenetic mechanisms intervene in the activity-dependent secretion of BDNF. For example, an increased synthesis of BDNF in mouse neurons after depolarization correlates with a decrease in CpG methylation within the regulatory region of the BDNF gene. Moreover, increased BDNF transcription involves dissociation of the MECP2-histone deacetylase-Sin3A repression complex from its promoter, suggesting that DNA methylation-related chromatin remodeling is important for activity-dependent gene regulation that may be critical for neural plasticity (Martinowich et al., 2003).
BDNF expression is also sensitive to the early life environment and to hypoxic stressors (Schmidt-Kastner et al., 2012) and, consistently, hypoxia-related obstetric complications have been reported to interact with BDNF in affecting risk for schizophrenia, but independently from rs6265. Specifically, birth hypoxia has been associated with reduced BDNF levels in cord samples, taken at delivery, of individuals who developed schizophrenia later in life (Cannon et al., 2008), and another BDNF genetic variant, ss76882600 (rs56164415) has been found to interact with serious obstetric complications to increase the risk for schizophrenia up to 12 times (Nicodemus et al., 2008). Although the sample size was small, Nicodemus et al.’s (2008) finding is consistent with the location of the interacting genetic variant in the promoter of a BDNF transcript highly expressed in placenta. Given the relevance of genetic interactions with obstetric complications and placenta biology in schizophrenia (Ursini et al., 2018), further studies are needed to investigate this and other G × E relationships, which may account for the largest part of BDNF downstream effects. In particular, it may be particularly relevant to investigate the role of epigenetic mechanisms in modulating the relationship between genetic variation of BDNF, environmental risk factors and the risk for schizophrenia.
In a proof-of-concept study of the modulatory effects exerted by the environment and putatively mediated by the genetics of BDNF, it has been found that the rs6265 genotype, together with DNA methylation within this polymorphic site, might interact with obstetric complications to influence phenotypes relevant for schizophrenia. In particular, the C → T/Val → Met substitution at the SNP rs6265 creates/abolishes a CpG site, so that the Val allele presents a CpG site in the DNA sequence while the Met allele does not. The structural variation itself allows that the effect of the Val allele might be modified by methylation, whereas the Met allele remains hidden to the methylation machinery (Ursini et al., 2016). In this study, methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects was associated with hypoxia-related obstetric complications and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation was associated with exposure to obstetric complications and impaired working memory accuracy, while these relationships were opposite in ValMet subjects. Also, rs6265 methylation and obstetric complications interacted in modulating working memory-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the two genotype groups. Consistently, rs6265 methylation had a different association with schizo- phrenia risk in ValVal and ValMet individuals (Ursini et al., 2016). These results suggest that environmentally-sensitive DNA methylation modulates the effect of genetic variation of BDNF on risk for schizophrenia. However, whereas this possibility is intriguing and biologically relevant, it needs to be confirmed in a mechanistical setting, extended to the study of other epigenetic processes acting in brain and, perhaps, in placenta.
Brain-derived neurotrophic factor expression levels in the brain and in the blood
It is well-known that BDNF can cross the blood-brain barrier (Pan et al., 1998), which encouraged the investigation of BDNF expression levels in both brain and blood tissues. Contrary to previous studies reporting reduced BDNF expression in brain regions (Takahashi et al., 2000; Weickert et al., 2003; Mellios et al., 2009), recent evidence suggested that BDNF mRNA expression does not differ between patients with schizophrenia and healthy controls in large samples of post-mortem human brains (Cheah et al., 2017; Jaffe et al., 2018). However, thanks to blood samples accessibility, studies measuring serum level of BDNF have thrived, supported by the evidence that serum and plasma BDNF levels are highly correlated with those in cerebrospinal fluid (Pillai et al., 2010). Meta-analysis of such studies has highlighted a role for reduced BDNF level as a potential biomarker for schizophrenia (Green et al., 2011). BDNF levels were reduced in drug-naïve patients with schizophrenia and first episode of psychosis (Green et al., 2011; Yang et al., 2019), and lower levels have been associated with poorer cognitive functions in chronic patients, first episode and at-risk mental state (Heitz et al., 2018; Man et al., 2018; Yang et al., 2019), but not associated with the Val66Met polymorphism (Skibinska et al., 2018). Interestingly, age-related decrease of gene expression is steeper in patients compared to healthy controls, with no evidence of medication dosage effect (Green et al., 2011). Blood expression of BDNF in psychiatric disorders has been recently reviewed, also at exon level (Cattaneo et al., 2016).
The age-related decline of BDNF in the blood is consistent with the dynamic observed in the brain (Weickert et al., 2003; Mellios et al., 2009). However, it remains unclear whether the decline is accelerated by disease progression in patients, or it is a reflection of lower basal levels occurred earlier during the development and lagging behind for the rest of the life. Stratifying the general population for genetic risk for schizophrenia before disease onset (e.g., decile of the polygenic risk score) and following longitudinally groups with different genetic load may help to answer whether the dynamic of BDNF gene expression is related to disease pathogenesis. Unknow regulatory mechanism may occur. For example, BDNF interactome has been weakly explored through gene co-expression analysis, despite co-expression data being released (Pergola et al., 2019).
BDNF is a neurotrophic factor with widespread functions in the CNS, from synaptic plasticity to energy homeostasis (Marosi and Mattson, 2014). Given its role in regulating brain development and neuronal activity and survival, it represents an ideal candidate gene for schizophrenia. Many hypothesis-driven studies have highlighted the association of BDNF with phenotypes relevant for schizophrenia, in humans and mice; however, evidence of a causative role of BDNF specific to schizophrenia is still missing.
BDNF locus is not associated with schizophrenia in the largest GWAS to date, even though the nominal association (P-value < 10−4) would deserve credit in a hypothesis-driven interrogation of case-control samples. Furthermore, the ORs of SNPs in BDNF locus have a similar magnitude compared with those in GWAS-significant loci. Indeed, it has been shown that the risk conveyed by multiple small effect sub-threshold loci is larger than the risk conveyed by GWAS significant loci only (Boyle et al., 2017). In the BDNF locus, one of the SNP with the strongest association with the disease is the widely studied Val66Met rs6265 polymorphism, but–surprisingly–the T (Met-coding) allele, known to be associated with impaired activity-dependent secretion of BDNF, turned out to be the protective allele. This is compatible with the possibility that rs6265 compensates the effect of other genetic variants in linkage disequilibrium, thus mitigating their effect on schizophrenia risk; if this is true it may be worth searching for rare haplotypes in this locus that could have a high effect size on the risk for the disease. On the other hand, the complex structure of the BDNF locus and the fine-tuned regulation of BDNF secretion may represent the results of natural selection that have excluded genotypes that strongly affect gene function at this locus. In other words, a paradoxical (indeed coherent with the modern synthesis of natural selection) situation may exist, for which this gene is so important for brain development and activity, and then for schizophrenia, that humans cannot afford having genetic variants or haplotypes, which–per se–dramatically impact BDNF function. Indeed, preliminary evidence exists on the role of epigenetic factors in modulating BDNF expression and the relationship between environmental factors, BDNF genetic variation and brain phenotypes. Following these considerations, we should be careful in pursuing a ‘GWAS or nothing attitude’, pushing for reproducible mechanistic explanation in lieu of valuing robust genetic association.
Therefore, the final word on the relationship between BDNF and schizophrenia will only originate from the evaluation of the efficacy of therapeutic or preventive strategies modulating BDNF signaling. Despite the high number of studies on BDNF, the development of such strategies will likely require further understanding of the BDNF biology and of the epigenetic regulation of BDNF and its interactome during development.
This work is partially supported by P50 MH094268 grant to G.U.
Conflicts of interest
There are no conflicts of interest.
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