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Zinc finger proteins in psychiatric disorders and response to psychotropic medications

Squassina, Alessioa,,c; Meloni, Annaa; Chillotti, Caterinab; Pisanu, Claudiaa,,d

doi: 10.1097/YPG.0000000000000231
Review Articles
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Zinc finger proteins are a large family of abundantly expressed small motifs that play a crucial role in a wide range of physiological and pathophysiological mechanisms. Findings published so far support an involvement of zinc fingers in psychiatric disorders. Most of the evidence has been provided for the zinc finger protein 804A (ZNF804A) gene, which has been suggested to be implicated in schizophrenia and bipolar disorder. This evidence has been corroborated by a wide range of functional studies showing that ZNF804A regulates the expression of genes involved in cell adhesion and plays a crucial role in neurite formation and maintenance of dendritic spines. On the other hand, far less is known on other zinc finger proteins and their involvement in psychiatric disorders. In this review, we discussed studies exploring the role of zinc finger proteins in schizophrenia, bipolar disorder, and major depressive disorder as well as in pharmacogenetics of psychotropic drugs.

aDepartment of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari

bUnit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy

cDepartment of Psychiatry, Dalhousie University, Halifax, NS, Canada

dDepartment of Neuroscience, Unit of Functional Pharmacology, Uppsala University, Uppsala, Sweden

Received 5 April 2019 Accepted 18 June 2019

Correspondence to Alessio Squassina, PhD, Section of Neurosciences and Clinical Pharmacology, Department of Biomedical Sciences, School of Medicine, University of Cagliari, sp 6, 09042, Cagliari, Italy Tel: +39 070 6754323; fax: +39 070 6754320; e-mail: squassina@unica.it

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Introduction

Zinc finger proteins are a large family of small motifs that contain finger-like protrusions and require one or more zinc ions to stabilize their structure (Laity et al., 2001). These small domains usually contain combinations of cysteine and histidine residues that coordinate the binding of the zinc ion (Vilas et al., 2018). While the zinc ion is important to stabilize the structure of the protein, the finger-like protrusions are able to bind different molecules such as DNA, RNA, and other macromolecules as well, with a different specificity based on the amino acid sequence of the domains. Being one of the most expressed family of domains, it is not surprising that zinc fingers play a crucial role in a wide range of functions, including regulation of gene expression, apoptosis and protein folding (Laity et al., 2001; Vilas et al., 2018; Abbehausen, 2019).

Cys2His2 represents the classical and most abundant zinc finger domain (Laity et al., 2001; Krishna et al., 2003). Cys2His2 zinc finger motifs, which present two β-sheets and one α-helix (Zhang et al., 2011), can bind DNA with high specificity (Vilas et al., 2018), although they can also bind RNA and other molecules. Cys2His2 zinc fingers motifs are present in over 700 proteins in the human genome, many of which are transcription factors (Laity et al., 2001; Cassandri et al., 2017; Vilas et al., 2018). Other zinc finger motifs differ in cysteine/histidine combinations and present different numbers of cysteine and histidine residues, such as Cys-Cys-His-Cys (CCHC) or Cys-Cys-His-His (C2H2). Zinc finger proteins have been suggested to play a role in a variety of physiological (Cassandri et al., 2017) and pathophysiological mechanisms, including immune regulation (Fu and Blackshear, 2017), cancer progression (Jen and Wang, 2016), aging (Vilas et al., 2018), and neurological diseases (Liu et al., 2015). More recently, genome-wide association studies (GWAS) led the basis for hypothesizing a role of zinc finger proteins in the susceptibility to psychiatric disorders such as schizophrenia (SCZ), bipolar disorder, and major depressive disorder (MDD). The most robust evidence has been provided for variants located in the zinc finger protein 804A (ZNF804A) gene, whose association with psychiatric disorders has been replicated in several studies that will be discussed in the next sections of this review. Although the precise function of ZNF804A is currently unknown, recent studies suggest that this protein is implicated in neurite formation and maintenance of dendritic spines (Deans et al., 2017). Besides ZNF804A, other zinc finger proteins have been implicated in susceptibility to psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. However, many of these findings still require replication in independent samples or further studies to evaluate the specific molecular mechanisms underlying the associations. In this narrative review, we discussed the available literature exploring the involvement of zinc finger proteins in predisposition to SCZ, bipolar disorder, MDD, as well as treatment outcomes of psychotropic drugs. We searched for articles in English on PubMed (Medline), with no date limitation, using different combinations of the following terms: ‘zinc finger proteins’, ‘zinc finger genes’, ‘ZNF804A’, ‘bipolar disorder’, ‘major depressive disorder’, ‘schizophrenia’, ‘pharmacogenetics’, ‘mood stabilizers’, ‘antipsychotics’, and ‘antidepressants’. A specific focus was put on: (1) genes replicated in independent samples or (2) genes for which functional analyses or evidence from different converging molecular approaches have been provided.

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Zinc finger proteins and psychiatric disorders: unraveling the role of ZNF804A

Association between genetic variants located in the ZNF804A gene and psychiatric disorders

The most relevant results from human studies are reported in Table 1. The first GWAS to show association between ZNF804A and psychiatric disorders was carried out in SCZ (O’Donovan et al., 2008). In this study, authors ran a multistage GWAS by genotyping 479 SCZ cases and 2937 controls from the Wellcome Trust Case Control Consortium and selected those with P value <10–5 for replication in two distinct, larger cohorts (sample 1: 1664 cases, 3541 controls; sample 2: 4143 cases, 6515 controls). The rs1344706 single nucleotide polymorphism (SNP) (risk allele=T), located in the second intron of the ZNF804A gene, was significant in all the samples analyzed, and the most significant in the meta-analysis of the different stages (P=1.61×10–7). Interestingly, a strongest association was obtained when patients with either SCZ and bipolar disorder (9173 cases in total and 12934 controls) were combined and compared with healthy controls (P=9.99×10–9).

Table 1

Table 1

After this first landmark study, several subsequent investigations and meta-analyses provided additional evidence for a role of ZNF804A in susceptibility to SCZ (for a recent comprehensive review, see Chang et al., 2017), and bipolar disorder (Sun et al., 2015; Zhang et al., 2016b), while a lower number of studies has been conducted in MDD patients (Amare et al., 2019). Most of the evidence has been reported for the rs1344706 variant, but more recent studies also suggested the involvement of other intronic SNPs located in the same gene (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Furthermore, copy number variations and other structural variations of the ZNF804A gene have been associated with SCZ (Steinberg et al., 2011) as well as with other psychiatric diseases (Griswold et al., 2012; Talkowski et al., 2012).

Studies conducted in non-Caucasian populations provided more controversial results (Chang et al., 2017; Falola et al., 2017). A case-control study conducted in 1330 Han Chinese patients with SCZ, 1045 with MDD, and 1235 healthy controls (Wang et al., 2018) evaluated 13 SNPs within ZNF804A (including rs1344706) reporting an association between the rs12476147 SNP and SCZ (adjusted P=0.0078). While rs1344706 was not associated with either SCZ or MDD, a haplotype block including SNPs rs1247647 and rs1344706 was associated with both disorders (Wang et al., 2018). Another study reported a significant association between another variant in the ZNF804A promoter (rs359895) with SCZ in Han Chinese population (Li et al., 2011). The largest meta-analysis of genetic studies so far conducted in Asian populations to investigate the role of ZNF804A genetic variants in SCZ and bipolar disorder was carried out by Huang et al. (2016). The study, including a total of 13452 cases and 17826 healthy controls, only showed a nominal one-tailed association between rs1344706 and SCZ [results for the A allele on the complementary strand were reported: odds ratio (OR)=1.05, one-tailed P=0.043], but the association was strengthened in when SCZ and bipolar disorder patients where combined (OR=1.57, one-tailed P=0.02). A nominal association between the nonsynonymous SNP rs1366842 and SCZ was also reported (OR=1.10, P=0.01) (Huang et al., 2016). A recent study in Koreans including 921 patients with SCZ or bipolar disorder, and 502 control showed a significant association between five SNPs in ZNF804A (rs2369595, rs6755404, rs10931156, rs12476147, and rs1366842) and risk of either disorders (Baek et al., 2017).

Summarizing, findings from Caucasian samples suggest a strong association of ZNF804A with SCZ and bipolar disorder, particularly for SNP rs1344706. On the other hand, findings on Asian populations suggest that ZNF804A might play a smaller role in susceptibility to these disorders through different genetic variants.

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Functional studies on ZNF804A

Findings suggesting the potential involvement of ZNF804A in psychiatric disorders supported further investigations to better understand the molecular mechanisms in which ZNF804A could play a role (Chang et al., 2017). Because SNP rs1344706 has been most robustly associated with SCZ and bipolar disorder, several studies explored its functional properties. It has been shown that this SNP is an expression quantitative trait locus (eQTL) for ZNF804A in fetal brain, as the SCZ risk allele (allele T) reduces ZNF804A gene expression (Hill and Bray, 2012). Similar results were observed in the allelic-specific gene expression study conducted by Schultz et al. (2014). In this study, the rs1344706 risk allele (the study reported results for the A allele on the complementary strand) was associated with decreased ZNF804A expression in post-mortem prefrontal cortex samples from 35 patients with SCZ (Schultz et al., 2014). Another study was conducted in dorsolateral prefrontal cortex post-mortem brain samples from second trimester to 85-year-old patients with SCZ, bipolar disorder, and MDD as well as healthy controls (Tao et al., 2014). Authors identified a truncated ZNF804A transcript (ZNF804AE3E4), encoding a protein lacking the zinc finger domain. Also in this case, the rs1344706 T allele was shown to reduce ZNF804AE3E4 mRNA expression in fetal brain (P=0.02). Additionally, mRNA levels of ZNF804AE3E4 were decreased in SCZ (P=0.006) but increased in MDD (P<0.001) (Tao et al., 2014). However, other studies measuring ZNF804A mRNA levels in lymphoblastoid cell lines (LCLs) or post-mortem brain samples from patients with SCZ compared with healthy controls provided negative results (Okada et al., 2012; Umeda-Yano et al., 2014). These studies support the hypothesis that the rs1344706 ZNF804A variant might be functionally relevant and play a crucial role during brain development, although this mechanism might differ among different psychiatric conditions. Additionally, further studies are needed to more precisely elucidate the functional effect of rs1344706 on different ZNF804A transcripts as well as during different stages of development.

Although the precise function of ZNF804A is currently unknown, available findings suggest that this zinc finger protein might be involved in regulation of gene expression of several targets crucial for neurodevelopment. ZNF804A contains a single C2H2-type zinc finger domain able to bind DNA, RNA, and proteins (Chapman et al., 2018). In a recent study, Deans et al. (2017) explored the localization of ZNF804A protein in young neurons derived from human neural progenitor cells (hNPCs), showing that this protein colocalized with the postsynaptic marker GluN1 and postsynaptic density protein 95. Knockdown of ZNF804A in these cells attenuated neurite outgrowth and this effect was counteracted by overexpression of the adhesion protein neuroligin-4 (NLGN4) (Deans et al., 2017). Furthermore, loss of ZNF804A resulted in reduced dendritic spine density in mature neurons (Deans et al., 2017). These results support a role of ZNF804A in neurite formation and maintenance of dendritic spines. Other studies showed that knockdown of ZNF804A in hNPC or in neurons derived from human-induced pluripotent stem cells (hiPSCs), modified the expression of genes involved in cell adhesion (a mechanism critically important for neuronal migration) or in the interferon signaling pathway, respectively (Hill et al., 2012; Chen et al., 2015).

A number of studies tried to elucidate the network of genes trough which ZNF804A might exert an effect on predisposition to psychiatric disorders. Using a yeast two-hybrid genome-wide screen, Zhou et al. (2018) identified a network of ZNF804A-interacting proteins. This network was enriched for genes involved in mRNA translation (Zhou et al., 2018). The authors also used RNA immunoprecipitation-RNAseq in mice brain and showed that ZFP804A, the homolog of ZNF804A, was associated with different genes playing a role in regulation of translation as well as mitochondrial function (Zhou et al., 2018). Further evidence has been provided by a recent study that investigated changes in gene expression associated with the knockdown of ZNF804A in SH-SY5Y neuroblastoma cell line. This specific line was used as a model, being characterized by a ZNF804A expression similar to the human brain (Chapman et al., 2018). Knockdown of ZNF804A induced differential expression of genes involved in nervous system development, synaptic contact, and cell adhesion (Chapman et al., 2018). Moreover, by performing a screen of human embryonic brain and adult mouse brain cDNA libraries, the same study showed that ZNF408A interacts with different splicing factors, including RNPS1 and RBFOX2, that regulate alternative mRNA splicing in neurons (Chapman et al., 2018). A gene ontology-term analysis confirmed that proteins interacting with ZNF804A were enriched for regulation of alternative mRNA splicing via proteasome and RNA binding. These findings further support a role of ZNF804A in regulation of pre-mRNA processing as well as regulation of gene expression (Chapman et al., 2018).

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ZNF804A and response/adverse reactions to psychotropic drugs

Antipsychotics

While the involvement of ZNF804A in susceptibility to psychiatric disorders has been widely investigated, fewer studies explored the role of this gene in response to psychotropic drugs or adverse effects induced by these medications (Table 2). As in the case of susceptibility to psychiatric disorders, response to different classes of psychotropic drugs represents a complex phenotype, which is particularly challenging to investigate due to several limiting features, including interactions between genetic and environmental factors as well as differences in the scales used to measure the clinical outcome.

Table 2

Table 2

Studies conducted in both the Caucasian and Chinese population support a potential association between the rs1344706 variant and response to antipsychotics (Table 2). However, these studies were generally conducted in small samples and largely varied as regard to treatment regimen as well as evaluated outcomes. In the Chinese population, the rs1344706 polymorphism was associated with response to atypical antipsychotics [evaluated as the change in the Positive and Negative Syndrome Scale (PANSS) score after four weeks of treatment] (Zhang et al., 2012). This association was found to be independent from specific drugs, as the risk allele of rs1344706 (allele T) was associated with a lower change in the total score and in the positive symptoms subscore also when adjusting for antipsychotic type (Zhang et al., 2012). Similar results were reported by a study conducted in a sample of 144 Caucasian hospitalized SCZ patients treated with atypical antipsychotics for four weeks (Mössner et al., 2012). In this study, patients with two copies of the risk allele of rs1344706 showed a lower improvement in PANSS positive subscore compared to noncarriers. Consistently with these findings, a more recent study including 291 patients with SCZ showed a strong correlation between the number of rs1344706 risk alleles (results for allele A were reported in this study) and the number of days of hospitalization during the two years following the first disease episode (Wickramasinghe et al., 2015). Although this study did not specifically evaluate treatment response, its findings support the hypothesis that the risk allele of ZNF804A rs1344706 is associated not only with predisposition to SCZ, but also to a worse clinical outcome. To our knowledge, only one study evaluated the role of variants other than rs1344706 in response to antipsychotics (Porcelli et al., 2018). In this study, the two variants rs7597593 and rs1987025 were nominally associated with negative symptom response in a Korean sample including 176 SCZ in-patients (Porcelli et al., 2018). Overall, the hypothesis that SNPs located in the ZNF804A gene might play a role in response to antipsychotic drugs requires further investigation, due to the paucity of studies, small number of investigated variants, and relatively limited sample size.

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Antidepressants

Similarly to the response to antipsychotics, a small number of studies provided evidence supporting a potential role of ZNF804A genetic variants in response to antidepressants. Although these works mostly reported nominal associations, they were generally conducted in larger samples compared to the literature on response to antipsychotics and included a replication sample (Table 2). Besides rs1344706, which was found to be associated with antidepressants response both in the STAR*D level 1 sample (1861 patients with MDD) as well as in a European sample including 285 MDD and 84 bipolar disorder patients (Fabbri et al., 2014), other SNPs located in the ZNF804A gene (rs7590852, rs725617, and rs7603001) have been associated with either response to antidepressants or remission (Table 2) (Fabbri et al., 2014, 2017). Additionally, rs760300 was also reported to be nominally associated with psychic adverse reactions to psychotropic medications in bipolar disorder patients (Fabbri et al., 2015).

In light of the observed contribution of multiple ZNF804A SNPs, gene-based analyses might potentially be useful to further elucidate the joint contribution of these variants.

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Involvement of other members of the zinc finger proteins family in psychiatric disorders

Association between genetic variants located in zinc finger genes and psychiatric disorders

Studies exploring or implicating other members of the zinc finger protein family in psychiatric disorders have been sparse and often lacked replication (Table 1). The most promising evidence has been provided for four zinc finger proteins which are involved in a range of different functions: Zinc Finger E-Box Binding Homeobox 2 (ZEB2), myelin transcription factor 1 like (MYT1L), DNA Methyltransferase 1 (DNMT1), and zinc finger protein 750 (ZNF750). These genes have been associated with susceptibility to psychiatric disorders by at least two studies or have been implicated in processes believed to be important in the pathogenesis of psychiatric disorders.

ZEB2 presents two distinct zinc finger clusters: an N-terminal cluster containing four zinc fingers and a C-terminal one containing three zinc fingers (Khan et al., 2016). These two clusters can bind independently to DNA sequences of genes involved in cell adhesion, such as a4-integrin and E-cadherin (Khan et al., 2016). A GWAS and comprehensive meta-analysis implicated rs12991836, whose nearest gene is ZEB2, as a risk locus for SCZ (Ripke et al., 2013). These results were extended by a subsequent study including 1248 Han Chinese patients with SCZ, 1344 with bipolar disorder, 1056 with MDD, and 1248 healthy controls, which investigated the role of 10 ZEB2 variants in susceptibility to psychiatric disorders (Khan et al., 2016), showing a significant association between rs6755392 and SCZ (Khan et al., 2016). ZEB2 encodes a protein involved in epithelial differentiation, whose mutations are known to cause the rare Mowat–Wilson syndrome, which is characterized by a distinct facial phenotype, mental retardation, epilepsy, and other congenital abnormalities (Garavelli and Mainardi, 2007). In light of the important role played by this molecule during differentiation of progenitor cells in cortical neurons (McKinsey et al., 2013; Khan et al., 2016), ZEB2 appears a promising target as regard to susceptibility to SCZ.

Interesting preliminary evidence also supports a potential role for MYT1L in susceptibility to psychiatric disorders. This gene encodes a CCHC zinc finger motif which is highly expressed in developing neuronal cells (Wang et al., 2010). This type of zinc finger domain is a short cysteine-rich polypeptide that specifically binds nonmethylated CpG dinucleotides (Long et al., 2013). Copy number variations in MYTL1, which encodes a zinc finger transcription factor, were associated with SCZ in a small discovery cohort of 54 Dutch patients as well as in an additional cohort of 752 patients and 706 controls (Vrijenhoek et al., 2008). Other variants of this gene (rs3748989 and the rs1317213-rs6759709 haplotype) were associated with susceptibility to MDD in a large sample of 1139 Han Chinese MDD patients and 1140 controls (Wang et al., 2010).

Other genes containing a CCHC domain, instead of the classical Cys2His2 zinc finger motif, have been implicated in SCZ and bipolar disorder. In particular, a recent study conducted on post-mortem brain samples from 20 patients with bipolar disorder, 22 with SCZ ,and 22 controls found increased expression of DNMT1 and Tet Methylcytosine Dioxygenase 1 (TET1) in the prefrontal cortex of both SCZ and bipolar disorder patients (Dong et al., 2015). The study also showed an increased binding of DNMT1 at the promoter regions of genes previously implicated in the pathogenesis of psychiatric disorders, such as glutamate decarboxylase 1, reelin, and brain-derived neurotrophic factor, in the prefrontal cortex of SCZ and bipolar disorder patients (Dong et al., 2015). Additionally, two genetic variants located in the DNMT1 gene (rs2114724 and rs2228611) have been associated with SCZ by a study conducted in a South Indian sample including 330 patients and 302 controls (Saradalekshmi et al., 2014). An in-silico analysis conducted by the authors suggested that these two variants might be involved in regulation of an enhancer site and alternative splicing, respectively.

Finally, in Chinese, the rs8073471 SNP, located in the 5′-untranslated region of exon 2 of the ZNF750 gene, which encodes a classic C2H2 zinc finger motif, was nominally associated with SCZ in a GWAS including 746 cases and 1599 controls (Yue et al., 2011). This result was subsequently replicated by Guan et al. (2016) in an independent sample of 1471 cases and 1528 matched controls. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and has been implicated in the pathogenesis of psoriasis (Hwu et al, 2005), a known autoimmune comorbidity of SCZ (Chen et al., 2012).

Besides these four genes for which the most promising evidence has been provided, a few studies focused on the role of disrupted-in-SCZ 1 (DISC1)-binding zinc finger protein (DBZ), based on a growing body of evidence supporting a crucial role for the DISC1-DBZ network in neurodevelopment (Tohyama et al., 2015). DBZ has a predicted C2H2-type zinc finger motif and is expressed almost exclusively in brain (Tohyama et al., 2015). This protein interacts with DISC1, which has been implicated in susceptibility to mental illness (Sawa, 2019). Neurobiological studies suggest that DISC1 dysfunctions might confer susceptibility to psychiatric diseases by inducing abnormalities in neurodevelopment (Tohyama et al., 2015). Specifically, DISC1 regulates cell-cell adhesion and increases neurite outgrowth through regulation of the expression of adhesion molecules, such as β1-integrin (Tohyama et al., 2015). Conversely, the DISC1–DBZ interaction has been suggested to be fundamental to stop neurite extension (Tohyama et al., 2015). Lack of this gene in rodents has been shown to induce disturbances in the development of basket cells interneurons (Koyama et al., 2013) and oligodendrocytes (Shimizu et al., 2014), as well as alterations in dendrite and spine morphology of cortical pyramidal neurons (Koyama et al., 2015). Although these results are quite promising, contrasting or negative results have been reported by genetic investigations for either DISC1 or its zinc finger partner (Anitha et al., 2009; Sawa, 2019), suggesting that mechanisms other than common genetic variations might affect the way in which the DISC1-DBZ network may modulate the susceptibility to psychiatric disorders.

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Association between zinc finger proteins and response/adverse reactions to psychotropic drugs

Antipsychotics

Available studies investigating the role of zinc finger motifs in treatment with antipsychotics focused on adverse reactions such as antipsychotic-induced Parkinsonism (AIP) (Table 2). A GWAS conducted by Alkelai et al. (2009) in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) GWAS dataset suggested a role of the Zinc Finger Protein, Multitype 2 (ZFPM2) gene in AIP. The analysis included data for 397 patients (190 with and 198 without AIP), treated with an antipsychotic drug for a maximum of 18months and assessed for clinical efficacy and adverse effects (Lieberman et al., 2005). The ZFPM2 rs12678719 variant was among the most significant SNPs associated with AIP severity. The association was replicated by the same authors in an independent sample of 178 patients (111 African Americans and 67 Caucasians) treated with a single antipsychotic drug (clozapine, olanzapine, risperidone, or a typical antipsychotic) for at least one month (Greenbaum et al., 2012). The G allele of rs12678719 was associated with AIP in the whole sample as well as in the subsample including only African American patients. The ZFPM2 gene is located on chromosome 8 and encodes a member of the Friends of GATA (FOG family) (Fox et al., 1999). The encoded protein binds directly to different GATA transcription factors and modulates transcriptional activation either activating or repressing expression of targets in different contexts. Using DAT-SPECT, a preliminary investigation by Greenbaum et al. (2012) including 49 patients with idiopathic Parkinson’s disease showed that the AIP risk allele was associated with decreased uptake of [123I]-FP-CIT (a ligand which binds to the dopamine transporter) in the contralateral putamen. This result suggests a potential association between the rs12678719 G allele and the level of degeneration of the nigrostriatal pathway. However, the results require confirmation as well as replication in patients with AIP.

Another secondary analysis of the CATIE GWAS dataset supports a potential role of the GLI family zinc finger 2 (GLI2) gene in tardive dyskinesia, a severe and chronic effect of long-term antipsychotic exposure (Greenbaum et al., 2010). The study included data from 327 patients with SCZ treated with antipsychotic monotherapy (131 with and 196 without tardive dyskinesia). Tardive dyskinesia was defined as presence of involuntary movements of a mild degree in two or more body regions or of a moderate degree in at least one body region, at two distinct evaluations. Patients were considered not to have tardive dyskinesia in case they showed absence of any involuntary movement (Greenbaum et al., 2010). The authors reported a nominal association between the T allele of the rs3943552 SNP, located in the GLI2 gene, and an increased risk of tardive dyskinesia. The association was replicated in an independent sample of 96 Jewish Ashkenazi patients with SCZ (44 with and 52 without tardive dyskinesia) but not in a sample of 74 Jewish non-Ashkenazi patients (Greenbaum et al., 2010). GLI2 encodes a C2H2-type zinc finger transcription factor which plays an important role in regulation of the sonic Hedgehog signaling pathway (Takanaga et al., 2009). Preclinical studies showed that Gli2 modulates expression of Sox2, a transcription factor essential for the maintenance of multipotent neural stem cells (Takanaga et al., 2009). Moreover, being Shh signaling involved in midbrain dopamine neuron differentiation during embryonic development (Abeliovich and Hammond 2007), the authors speculated that a potential role of GLI2 in predisposition to tardive dyskinesia in adult life might be explained by induction of architectural changes in the dopaminergic pathway formation during brain development. Further studies will be required to confirm the role of this gene and further explore the mechanisms potentially underlying its association with tardive dyskinesia.

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Mood stabilizers

Although lithium represents the mainstay therapy in the management of bipolar disorder, the molecular networks underlying its clinical efficacy are still not perfectly known (Alda, 2015; Pisanu et al., 2016, 2018b; Walss-Bass and Fries, 2019). Findings from a recent study suggest that zinc finger protein 493 (ZNF493) might play a role in modulating response to lithium in patients with bipolar disorder (Pisanu et al., 2018a). This study integrated genome-wide transcriptomic and GWAS data from a sample of bipolar disorder patients characterized for lithium response using the ‘retrospective criteria of long-term treatment response in research subjects with bipolar disorder,’ (Grof et al., 2002; Manchia et al., 2013). LCLs from 20 bipolar disorder patients (10 responders and 10 nonresponders) were grown with or without lithium 1mM for 1 week to test the effect of treatment on gene expression. Genes differentially expressed after lithium treatment exclusively in responders were further tested for gene-based association with lithium response using GWAS data from 205 bipolar disorder patients. ZNF493 and zinc finger gene 429 (ZNF429) were significantly associated with lithium response in the gene expression and GWAS analyses. The decreased expression of ZNF493 after lithium treatment in lithium responders was also validated with real-time PCR (Pisanu et al., 2018a). Although both ZNF429 and ZNF493 encode Cys2His2 zinc finger proteins, their function has yet to be characterized. Being this the first study to support a potential role of zinc finger genes in modulating lithium response, these findings need be confirmed in independent samples.

Another study suggested a role of zinc finger proteins in liver steatosis, an adverse effect associated with treatment with valproic acid (VPA) (Wolters et al., 2017). This study analyzed changes in patterns of methylation in nuclear and mitochondrial DNA in primary human hepatocytes treated in vitro with VPA. In this study, cells were treated with VPA 15mM daily for 5days followed by a 3-day washout. Most VPA-induced methylation changes were found to be reversible after the washout. Among 31 differentially methylated regions persisting after washout, five represented zinc finger protein genes which were found to be hypermethylated [zinc finger protein 74, 750, and 865) or hypomethylated (zinc finger protein 786 and 733 pseudogene) (Wolters et al., 2017). These results suggest that zinc finger proteins might play a role in the more persistent epigenetic changes induced by treatment with VPA. However, further studies are needed to confirm and further evaluate the potential functional role of these changes on expression of targets involved in VPA-induced steatosis.

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Antidepressants

Liou et al. (2012) carried out an integrated study using mice and a human sample of MDD patients to explore the genetics of response to fluoxetine. Response to antidepressants in mice was evaluated using the forced swimming test. QTLs where then identified based on different response and two significant SNPs, located in the zinc finger protein 326 (ZNF326) gene (rs2816881 and rs10922744), were genotyped in a sample of 262 Han Chinese MDD patients. Response to 8-week treatment with fluoxetine or citalopram was defined as a decrease >50% at the 21-item Hamilton Depression Rating Scale (Liou et al., 2012). The A allele of rs2816881 and the G allele of rs10922744 were associated with positive response, suggesting that also this zinc finger gene could be involved in response to antidepressants.

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Discussion

The rs1344706 SNP located in the ZNF804A gene has been robustly associated with SCZ and bipolar disorder. In 2008, when this gene was first identified as a psychiatric disorder susceptibility gene, while it was known that it encoded a protein with zinc ion and DNA binding domains, possibly involved in modulation of gene expression, the exact function was still be to uncovered (O’Donovan et al., 2008). In the last 10years, studies exploring the functional role of this gene in post-mortem brain samples as well as different cellular models, including hNPCs and neurons derived from hiPSCs, not only confirmed the role of rs1344706 as an eQTL but also provided convincing evidence supporting a role of ZNF804A in neurodevelopment. A large body of neuroimaging studies further extended our knowledge on the putative role of ZNF804A in susceptibility to psychiatric disorders, showing that a risk genotype is associated with abnormalities in functional brain connectivity (Esslinger et al., 2009; Mohnke et al., 2014; Zhang et al., 2016a) and white matter microstructure (Ikuta et al., 2014). Although this topic has been less investigated, there is also promising evidence that genetic variants in ZNF804A might be associated with worse clinical outcome and poor response to antipsychotics (Mössner et al., 2012; Zhang et al., 2012; Wickramasinghe et al., 2015). However, due to the fact that available studies only reported small effect sizes, the clinical relevance of findings appears to be limited. Nonetheless, ZNF804A represents a promising target for future pharmacogenetic studies in SCZ and possibly mood disorders. Based on evidence suggesting that the risk-allele of ZNF804A is able to induce a downregulation of the gene both in fetal and adult brain (Hill and Bray, 2012; Schultz et al., 2014), it might be speculated that agents able to upregulate ZNF804A levels might be investigated as a potential novel treatment avenue for SCZ. However, although ZNF804A knockdown has been associated with defects in neurodevelopment by a number of authors (Deans et al., 2017; Chapman et al., 2018), studies conducted in post-mortem brain samples provided contrasting results regarding alterations in ZNF804A mRNA levels in adult patients with SCZ compared to nonpsychiatric controls (Okada et al., 2012; Tao et al., 2012; Umeda-Yano et al., 2014). Therefore, further studies aimed at exploring the dynamics of the effects of ZNF804A during development and adulthood, as well as potential differences among ZNF804A transcripts as regards to mRNA levels, would be of great help to elucidate whether this gene might represent a useful therapeutic target.

Despite the large number of efforts and the encouraging findings, there are still many unclear aspects regarding the implication of ZNF804A in psychiatric disorders. First, while the association between rs1344706 and SCZ in Caucasians has been replicated by several studies, controversial results have been reported in Asians. Available evidence suggests that ZNF804A might play a role in populations other than Europeans, although different genetic variants might be involved. Another question that remains open regards the role of this gene in other psychiatric conditions. In fact, while the genetic association between rs1344706 and SCZ or bipolar disorder has been replicated by several studies, findings are less supportive for its involvement in MDD. For instance, while some studies suggest that rs1344706 might play a role in susceptibility to MDD (Amare et al., 2019) and response to antidepressants (Fabbri et al., 2017), this variant is not among the significant hits reported by the most recent and large meta-analysis of GWAS studies of depression (including data for 246363 cases and 561190 controls; Howard et al., 2019). Because MDD represents a complex and heterogenous disorder, it could be hypothesized that ZNF804A might play a role in specific subphenotypes of depression. However, this hypothesis has yet to be explored. Specifically, it might be important to investigate the role of this gene in susceptibility to psychotic depression (Gournellis et al., 2018). Finally, further functional studies are required to understand if and through which mechanisms ZNF804A could modulate genes involved in cell adhesion, neurite formation and maintenance of dendritic spines, and what would be the role and contribution of rs1344706 in these mechanisms and in the development of SCZ.

As summarized in the previous sections, other genes encoding zinc finger motifs have been implicated in susceptibility to psychiatric disorders as well as in response to psychotropic medications. For some of these genes (e.g., ZEB2, MYT1L, and ZNF750), replication has been provided in at least one independent sample. However, most of the available studies were severely limited in terms of sample size as well as in the number of analyzed variants. Moreover, the functions of most of the investigated proteins are still uncharacterized. Another topic worth of further investigation is the role of zinc finger proteins in adverse effects induced by antipsychotics. Intriguing evidence supports a potential role of ZFPM2 in AIP (Alkelai et al., 2009) and GLI2 in tardive dyskinesia (Greenbaum et al., 2010). Further studies are needed to understand if some of the investigated markers might be useful to identify patients at the highest risk of developing adverse reaction during treatment with psychotropic drugs.

To date, no study has systematically evaluated a potential joint contribution of different zinc finger genes in predisposition to psychiatric diseases as well as treatment outcome. Future studies might implement methodologies such as gene-set analysis to explore the role of sets of genes encoding zinc finger proteins, as well as specific zinc finger proteins and their targets.

In conclusion, available findings converge on a role of ZNF804A in modulating the susceptibility to SCZ and bipolar disorder, while an increasing number of studies support the hypothesis that genes encoding other zinc finger proteins might be implicated as well. However, considering our limited knowledge on the genetics and biology of zinc fingers, further studies are warranted to elucidate the role of ZNF804A and other zinc finger protein genes in the development of psychiatric disorders and in response to psychotropic medications.

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Acknowledgements

C.P. is supported by a fellowship funded by Fondazione di Sardegna (‘Convenzione triennale 2015–2017’) and by the Autonomous Region of Sardinia (‘Legge Regionale 7 agosto 2007, n. 7 – call 2016’) grant number F72F16003090002.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

antidepressants; antipsychotics; bipolar disorder; lithium; major depressive disorder; pharmacogenetics; personalized medicine; schizophrenia; zinc finger genes; zinc finger protein 804A

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