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Review  |  Open Access  |  11 Jan 2024

What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?

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J Transl Genet Genom 2024;8:1-12.
10.20517/jtgg.2023.39 |  © The Author(s) 2024.
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With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology of this psychiatric disorder remains elusive. There is an evident genetic component of schizophrenia, with heritability estimates lying at 60%-80%. While genome-wide association studies have identified 120 gene loci associated with schizophrenia risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The recent emergence of whole exome sequencing (WES) technologies has facilitated the identification of rare sequence variants, including some protein-truncating variants that have significant effects on risk. Three key large-scale WES studies have demonstrated that rare sequence variants in the genes SETD1A, CACNA1G, CUL1, GRIA3, GRIN2A, HERC1, RB1CC1, SP4, TRIO, XPO7, and AKAP11 confer substantial risk for schizophrenia. These genes are highly expressed in central nervous system neurons and their products participate in diverse molecular functions including synaptic transmission, transcriptional regulation, and ubiquitin ligation. The understanding of these functional roles illuminates putative molecular mechanisms which may lead to schizophrenia-like phenotypes. It will also be possible to develop model systems in which the effects of impaired function of these genes can be further explored. Genetic studies of rare variants to date suggest that glutamatergic system dysregulation, chromatin modification, and the ubiquitin-proteasome system play key roles in schizophrenia aetiology.


Schizophrenia, exome sequencing, rare sequence variants, protein-truncating variants, glutamatergic dysfunction, ubiquitin-proteasome system


Schizophrenia is a severe and chronic psychiatric disorder with a population prevalence in the order of 1%, whose aetiology remains elusive[1,2]. It has long been clear that genetic factors can contribute to risk, and twin, family, and adoption studies estimate the heritability of schizophrenia to lie between 60%-80%[3,4]. The most comprehensive genome-wide association study (GWAS) to date implicated 287 significant risk variants and these signals were fine-mapped to 120 genes[4]. As is expected for a trait likely to be under strong negative selection, the common variants identified by GWAS are associated with a relatively small risk for schizophrenia (median OR < 1.2)[5]. There can also be a lack of clarity as to which genes are implicated and the nature of the change in gene function that leads to increased risk. A number of extremely rare copy number variants (CNVs) have been found to have large effects on schizophrenia risk, and for these, the risk is clearly associated with either a decrease (for deletions) or an increase (for duplications) in gene dosage[6]. However, in general, with the exception of the NRXN1 deletion, these CNVs implicate large regions of the genome, so it is unclear which specific genes are implicated.

Whole exome sequencing (WES) offers advantages over GWAS and other previously employed approaches for a number of reasons. It is able to detect extremely rare inherited and de novo variants, some of which may have large effects on risk. Of these rare variants, some can be characterised as having an effect on the gene such that it cannot produce a useful product. These may be termed loss of function (LOF) variants, although some authors use the term protein-truncating variants (PTVs). If such variants are found to be convincingly associated with disease, then it is reasonable to make the claim that impaired functioning of the gene, with a reduction in its product, increases the risk of disease. Overall, this may assist in developing insights into pathogenesis. Another advantage of WES is that, when such an effect is identified, it becomes possible to study animal models in which gene function is impaired, allowing a comprehensive investigation of impacts ranging from molecular mechanisms up to behavioural phenotypes.

This focussed review explores the 11 genes recently implicated in schizophrenia risk by the first large-scale WES studies, carried out on thousands of cases and controls as well as trios consisting of cases and their parents[7-9]. For all of these genes, PTVs were shown to confer a substantial effect on risk and reached exome-wide levels of statistical significance, although in the case of one gene, AKAP11, this was achieved only in a joint analysis of schizophrenia and bipolar disorder. A more recent custom sequencing study confirmed AKAP11 as a risk gene for schizophrenia and supported the involvement of most of the other genes, as well as identifying a novel gene, SRRM2, as achieving exome-wide significance[10]. However, both this study and a study of exome-sequenced participants in the UK Biobank found PTVs in one of the genes from the original set of WES genes, CACNA1G, to be relatively common in controls, casting doubt on whether it is, in fact, a schizophrenia risk gene[11]. Through the assimilation of information from WES studies, gene profiles, and relevant model systems, this review investigates what research into rare sequence variants can tell us about the aetiology of schizophrenia.


A number of sequencing studies have suggested several genes to be possibly involved in schizophrenia pathophysiology[12]. To focus this investigation, we restrict attention to the 11 genes implicated at exome-wide significance by the first three large WES studies referred to above. These implicated genes that have been found to confer schizophrenia risk are SETD1A, CACNA1G, CUL1, GRIA3, GRIN2A, HERC1, RB1CC1, SP4, TRIO, XPO7, and AKAP11. Having identified these genes as being well evidenced through systematic, large-scale studies, we went on to carry out an exhaustive review of the available literature for each of them in order to gain insights into their functions and their possible relevance to schizophrenia pathogenesis. The genes are listed in Table 1 and a detailed account of their functions related to schizophrenia is provided below.

Table 1

Summary of genes implicated in schizophrenia pathogenesis through large-scale exome sequencing studies

Gene symbolGene namePutative role in schizophrenia pathogenesis
SETD1ASET domain containing 1A, histone lysine methyltransferaseRegulates gene expression
CACNA1GCalcium voltage-gated channel subunit alpha1 GInvolved in neuronal excitation
CUL1Cullin 1Encodes component of an E3 ubiquitin ligase complex
GRIA3Glutamate ionotropic receptor AMPA type subunit 3Involved in ionotropic glutamatergic transmission
GRIN2AGlutamate ionotropic receptor NMDA type subunit 2ACodes for NMDA receptor subunit
HERC1HECT and RLD domain containing E3 ubiquitin protein ligase family member 1Encodes an E3 ubiquitin ligase
RB1CC1RB1 inducible coiled-coil 1Involved in neurodevelopment
SP4Sp4 transcription factorModulates expression of NMDA receptor subunit genes
TRIOTrio Rho guanine nucleotide exchange factorHas a role in glutamatergic transmission
XPO7Exportin 7Role unclear
AKAP11A-kinase anchoring protein 11Possibly involved in neuronal plasticity, target of E3 ubiquitin ligases


SETD1A (SET Domain Containing 1A), previously referred to as KMT2F, encodes a histone lysine-methyltransferase, which is a catalytic subunit of the highly conserved mammalian Set/COMPASS complex[13]. This complex mediates mono-, di- and trimethylation of the lysine 4 residue on the histone H3 protein (H3K4)[9]. These histone marks are associated with gene activation and implicate SETD1A as a transcription regulator[13,14]. SETD1A is particularly responsible for H3K4 trimethylation (H3K4me3), which is a chromatin modification that has been reported to be found at the transcription start sites of active genes[15,16]. Downstream effects of this transcriptional regulation include modulation of cortical synaptic dynamics and axonal branching[9,13]. In addition to being implicated in schizophrenia risk, SETD1A variants are also associated with other neurodevelopmental disorders and early-onset epilepsy[13,17]. Given these results and the fact that SETD1A is expressed in the developing brain, it seems likely that SETD1A plays a significant role in the development and maintenance of healthy brain function[17].


CACNA1G (Calcium Voltage-Gated Channel Subunit Alpha-1G Subunit) encodes the CaV3.1 subunit of the low-voltage-activated T-type calcium channel[18]. These voltage-sensitive calcium channels facilitate calcium ion entry into excitable neuronal cells, as well as being involved in calcium-dependent processes, including cell division, cell death, gene expression, and neurotransmitter release[19]. These T-type calcium channels are highly expressed in deep cerebellar nuclei and Purkinje neurons. These neurons are specific to the cerebellar cortex and appear to be involved in cognition and emotion[20,21]. Along with being a schizophrenia risk gene, CACNA1G is also associated with the risk of severe intellectual or developmental disability. To date, most research into CACNA1G has been conducted on spinocerebellar ataxia-42, a disorder characterised by cerebellar atrophies and cognitive developmental defects[20].


CUL1 (Cullin 1) encodes a scaffolding protein, which is a core component of the SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligase complex[22]. The SCF complex is invariably composed of scaffolding protein CUL1, RING finger protein RBX1, and adaptor protein SKP1, as well as a variable F-box component[23]. This complex mediates the ubiquitination and subsequent degradation of proteins regulating cell-cycle progression, signal transduction, and cell proliferation[23,24]. CUL1 is the most extensively characterised member of the cullin (CUL) protein family, and aberrant expression of this protein has been shown to induce SCF E3 ligase dysfunction[23,25]. The existing literature investigating CUL1 is largely focussed on its implication in various cancers, including breast cancer metastasis, colorectal cancer, ovarian cancer, and melanoma[22-24].

E3 ubiquitin ligases are vital components of the ubiquitin-proteasome system (UPS), which is fundamental for protein degradation in neurons[26]. Furthermore, there is strong evidence that the UPS fulfils a key role in synaptic transmission[26]. The UPS fulfils its autophagy functions via a cascade of reactions depicted in Figure 1, primarily involving E1 ubiquitin-activating enzymes and E2 ubiquitin-conjugating enzymes in addition to E3 ubiquitin-protein ligase enzymes[26]. Three major classes of E3 ligases exist, the HECT domain-containing E3s, RING domain-containing E3s, and RBR family E3s, whereby the SCF complex implicating CUL1 belongs to the RING E3 ligases[27]. Overall, E3 ligases determine ubiquitination specificity and transfer ubiquitin to the target proteins[27].

What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?

Figure 1. The cascade of reactions involved in the UPS. (A) The ubiquitination cascade involves the E1, E2, and E3 ubiquitin ligases and produces a polyubiquitinated end-product. (B) The polyubiquitinated protein is then located by the proteasome which degrades and deubiquitinates the protein. Created with


The protein product encoded by GRIA3 (Glutamate Ionotropic Receptor AMPA Type Subunit 3) is the GluA3 subunit of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate)-type ionotropic glutamate receptors (AMPARs)[28]. Overall, AMPARs are the predominant excitatory neurotransmitter receptors in mammalian brains and play a key role in hippocampal synaptic long-term potentiation and transmission[29]. Specifically, the GluA3 AMPAR subunit has been suggested to shape the synaptic transmission properties and activity-dependent plasticity of synapse end bulbs, the presynaptic region of neurons that releases neurotransmitters into the synaptic cleft[30]. Located on chromosome Xq25, alternative splicing at the GRIA3 locus results in different isoforms of GluA3, which may cause their signal transduction properties to vary[31]. X-linked Intellectual Developmental Disorder is also known to be associated with GRIA3[32].


GRIN2A (Glutamate Ionotropic Receptor NMDA Type Subunit 2A) is a particularly compelling schizophrenia risk gene as it has also been a significant GWAS hit for the disorder, as well as being implicated in eliciting clinical effects relating to the N-methyl-D-aspartate receptor (NMDAR)[12]. This gene encodes the 2A subunit of the NMDAR, which is a member of the glutamate-gated ion channel protein family alongside AMPARs and kainite receptors[12,33]. NMDARs are heterotetramers consisting of two glycine-binding GRIN1 and two glutamate-binding GRIN2 subunits, of which there are four variants (GRIN2A-GRIN2D)[33]. Mutations in each GRIN subunit gene have been shown to cause encephalopathies that tend to be initially diagnosed as epilepsy, autism, or schizophrenia[34]. Otherwise known as GluN2A, GRIN2A is the most abundant GRIN2 subunit in the central nervous system (CNS) and is thought to play a crucial role during postnatal brain development[35]. Functionally, NMDARs are characterised by calcium permeability and they mediate a component of excitatory synaptic transmission in the CNS[35]. GRIN2A mutations and polymorphisms have previously been implicated in a variety of developmental brain disorders, including epilepsy and mental retardation[35].


The HERC1 (HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase Family Member 1) gene encodes another component of the UPS, specifically an E3 ubiquitin ligase. This member of the HERC protein family belongs to the HECT domain-containing class of E3s. In addition to its role in autophagy via the UPS, HERC1 has also been shown to be involved in membrane transport processes via guanine nucleotide exchange factor (GEF) activity and its ability to bind to clathrin[36]. Moreover, the HERC1 ubiquitin ligase regulates cellular proliferation and migration via the RAF/MEK/ERK signalling pathway and the RAF-dependent MKK3/p38 signalling pathways, respectively[37]. In humans, HERC1 mutations are known to cause a variety of intellectual disability syndromes with or without cerebellar abnormalities[38]. Affected individuals are often diagnosed with macrocephaly, motor development delay, and epilepsy, in addition to intellectual disability[39].


The protein encoded by RB1CC1 (RB1 Inducible Coiled-Coil 1) is a DNA-binding transcription factor (TF), commonly referred to as FIP200[40]. It is responsible for activating the expression of the retinoblastoma 1 (RB1) gene by binding to the GC-rich region found upstream of the promoter[41]. Additionally, it interacts with various signalling pathways to regulate cellular processes in a coordinated fashion, including cell-cycle progression, differentiation, and senescence, as well as neural migration and neurodegeneration[42]. Overall, there is strong evidence supporting the role of RB1CC1 as a tumour suppressor as it enhances the expression of RB1, a gene in which mutational inactivation can lead to cancer[41].


SP4 (Specificity Protein 4 Transcription Factor) encodes a TF which is a member of the Sp/KLF family of TFs[43]. Similarly to RB1CC1, it recognises GC-rich sequences around the promoters of various genes and activates transcription; however, SP4 TFs are restrictively expressed in neuronal cells[43]. Common and rare variants in SP4 have been elucidated as risk factors for schizophrenia, possibly through distinct pathological molecular mechanisms[44]. The SP4 gene has been proposed to play a crucial role in hippocampal development and function and has also been associated with bipolar disorder in humans[45].


TRIO (Trio Rho Guanine Nucleotide Exchange Factor) encodes a guanine nucleotide exchange factor (GEF), which facilitates the activation of Rho GTPases[46]. The TRIO RhoGEF protein regulates GEF-dependent and Rho GTPase-powered cytoskeletal rearrangements and membrane trafficking, the two processes required for neurite growth and development[47]. Neurites are specific functional structures, which form when post-mitotic neurons differentiate into mature neurons in response to developmental signals[47]. Furthermore, TRIO serves a role in glutamatergic neurotransmission and long-term potentiation (LTP) alongside its paralog Kalirin[48]. As a form of synaptic plasticity, LTP strengthens glutamatergic synapses, which is postulated to be a mechanism underlying memory and learning[49]. TRIO LoF mutants have been shown to affect dendritic branching, axon guidance, and synaptic transmission[46,50]. A number of studies have implicated TRIO in autism spectrum disorder and intellectual disability[46].


To date, XPO7 (Exportin-7) is one of the least characterised genes of the exportin family genes, with relatively little being known about its function[51]. Like other exportins, XPO7 mediates the nuclear export of proteins with broad specificity and does so via GTP-dependent binding of cargo inside the nucleus[52]. The encoded protein is a RAN GTPase and thus is also referred to as RAN Binding Protein 16. In addition to facilitating cargo export, XPO7 also acts as a nuclear import receptor for proteins with nuclear localisation signals[52]. Recent studies have elucidated XPO7 as a novel senescence regulator[53]. Given that senescence is a stress response that limits the replication capacity of old, damaged and preneoplastic cells, this gene’s role in cancer and neoplastic formation is being increasingly researched[51].


AKAP11 (A-Kinase Anchoring Protein 11) encodes the AKAP11 protein, also known as AKAP220, which acts as a scaffolding protein[7]. This scaffolding protein binds to the regulatory subunits of the protein kinase A (PKA) holoenzyme, with the purpose of restricting PKA to discrete intracellular compartments[7,54]. This provides spatiotemporal regulation of PKA activity, as well as enabling substrate-specific targeting for phosphorylation and dephosphorylation[7]. Due to this characteristic, AKAP11 is also classified as an autophagy receptor, mediating PKA activation, which in turn regulates cellular metabolism[54]. Overall, the PKA protein is involved in a wide range of biological processes, one of which is neuronal plasticity, which has relevance for the investigation into neurodevelopmental disorders[12]. Nonetheless, the role of AKAP11 in the brain and its biological role in psychiatric diseases remain largely uncharacterized[12].


Investigations of these 11 genes and the functional roles of the gene products throw light on a variety of molecular mechanisms that may contribute to the schizophrenia pathophysiology. Since the association with schizophrenia is due to variants that cause loss of function of these genes, relevant in vitro and in vivo models can be established involving either heterozygous or homozygous knockouts[12]. By exploring these newly established models and revisiting existing ones, further inferences about potentially implicated molecular pathways can be made. In particular, to date such investigations implicate chromatin modification, glutamatergic system dysregulation and ubiquitin-proteasome system (UPS) impairment as putative molecular mechanisms involved in the aetiology of schizophrenia.


The identification of GRIN2A and SP4, both of which encode protein products implicated in NMDAR formation and functionality, adds further weight to the evidence from previous studies suggesting that impairment of NMDAR functioning is associated with symptoms observed in schizophrenia. Acute administration of the NMDAR antagonists phencyclidine (PCP) or methamphetamine (METH) can induce schizophrenia-like symptoms in human controls and regressive symptoms in schizophrenia patients[12,43,55]. In wild-type rodents, repeated METH administration induces NMDAR dysfunction and leads to a reduction in Grin2a expression[56]. Likewise, anti-NMDAR autoantibody encephalitis can produce symptoms resembling those observed in schizophrenia[34]. These autoantibodies cause receptor internalisation from the plasma membrane of neurons, resulting in NMDAR hypofunction[34]. In experimental mouse models, both PCP and anti-NMDAR autoantibodies induce NMDAR hypofunction in excitatory neurons and elicit schizophrenia-like symptoms, including memory deficits[34].

The Sp4 hypomorphic mouse is a further valuable model that aids our understanding of the putative NMDAR-specific hypoglutamatergic function underlying schizophrenia[43]. The mouse Sp4 gene is expressed abundantly in the hippocampal CA1 region. Relative to wild-type mice, Sp4 hypomorphic mice display impaired LTP in the hippocampal CA1 and impaired spatial learning and memory, which mimic cognitive deficits seen in schizophrenia[43]. Following the publication of the SCHEMA results and confirmation of SP4 as a schizophrenia risk gene, further investigations into Sp4 hypomorphic mice were conducted[44]. The hippocampal vacuolisation observed in these mice with reduced Sp4 expression was found to be associated with the deficits in LTP as well as the observed sensorimotor gating, learning, and memory deficits[44,57].

GRIA3 codes for GluA3, an AMPAR subunit, and dysfunction of AMPARs has also been implicated in schizophrenia aetiology, although this has been less extensively investigated. Knockout models of this gene in mice have been established and studied, yielding results that show impairment in excitatory neurotransmission in the medial prefrontal cortex (mPFC) and reduced neuronal activity[58]. In mice, heterozygous deletion of Gria3 was associated with aggressive behaviour, which could be alleviated by the injection of an adeno-associated virus vector expressing GluA3 into the mPFC[58].


With the discovery of rare LOF variants in SETD1A conferring a large increase in risk for schizophrenia, epigenetic dysregulation gained attention as an important mechanism in the pathogenesis of the disorder[8]. The Setd1a haploinsufficiency mouse model (Setd1a+/-) has been investigated extensively in order to throw light on the epigenetic mechanisms presumed to be involved in schizophrenia pathophysiology[59].

Setd1a+/- mice have been shown to have approximately a 50% decrease in Setd1a protein in frontal brain regions[60]. The effects of this haploinsufficiency in the mPFC and striatum of the Setd1a+/- mice were also investigated, yielding valuable results[59]. Single-cell RNA sequencing revealed that the H3K4me3-dependent transcriptional function of Setd1a differed between cell types and neuronal subtypes in these brain regions[59]. In the mPFC, the decrease in H3K4me3 correlated with a decrease in gene expression in excitatory neurons, particularly in Foxp2+ neurons[59]. In these mPFC-localised neurons, morphological defects including dendrite morphology defects and exocytosis impairment have been observed[59-61]. In addition, schizophrenia-like behavioural phenotypes, including impaired sociality, sensorimotor gating defects, and deficits in working memory, were observed in these Setd1a+/- mice[59-61]. However, there are some discrepancies between the behavioural phenotypes observed in Setd1a+/- mice as part of the different studies that have been conducted, which may be attributable to differing genetic backgrounds or behaviour-testing protocols[59].

Investigations into the Setd1a haploinsufficiency mouse model have also revealed an involvement of Setd1a in excitatory synaptic plasticity. In the mPFC of Setd1a+/- mice, excitatory synaptic transmission was observed to be attenuated in layer 2 and 3 (L2/3) pyramidal neurons (PNs)[61]. While postsynaptic SETD1A is crucial for the functionality of excitatory synapses, the reduction of Setd1a in L2/3 PNs further caused a reduction in the probability of glutamate release from presynaptic terminals[61]. Changes in the short-term plasticity of Setd1a+/- mice have been elucidated through observation of increases in short-term depression[17]. These observations suggest that the observed alteration of signalling processes and synaptic plasticity in these haploinsufficiency mouse models may be contributing factors to cognitive symptoms[17]. Overall, these findings relating to SETD1A suggest that schizophrenia risk may be mediated by abnormal synaptic development and function, arising as a result of aberrant epigenetic modifications[57].


The ubiquitin-proteasome system (UPS) plays a fundamental role in neuronal homeostasis via protein degradation[26]. Localised at synapses, the UPS has been implicated in synaptic development, maintenance, and plasticity. Given these implications, dysfunction of this degradation system has been related to various neurological disorders[26]. Components of the UPS are found to be mis-regulated in numerous diseases and E3 ligases may be of particular interest given their role in specifying ubiquitination targets for degradation[62]. The schizophrenia risk genes HERC1, CUL1, and AKAP11 all have a role in the UPS.

The tambaleante (tbl) mutant mouse is an extensively characterised model organism that carries a spontaneous mutation in the HERC1 E3 ubiquitin ligase[26,63]. The tbl mouse was first described as a model of adult cerebellar ataxia, which is caused by Purkinje neuron death in the cerebellum[38]. NMDARs and GABA neurotransmitters are essential in Purkinje neuron development[21]. Cerebellum-related spatial learning alterations are observed in tbl mutant mice, as well as impairments in hippocampal learning and memory[38]. In addition to having a profound impact on the growth and maintenance of the cerebellar and hippocampal structures, Herc1 has also been implicated in the amygdala through tbl mouse studies[63]. The amygdala plays a crucial role in associative learning, which is impaired in tbl mice[63]. These learning deficits are associated with a lower density of glutamatergic synaptic vesicles in the lateral amygdala and hippocampus of tbl mice[39,63]. These glutamatergic synapses are a component of dendritic spines. E3 ligases of the UPS have previously been implicated in the maintenance of the size and density of such spines on neurons of the lateral amygdala[63]. These results collectively suggest that HERC1 E3 ubiquitin ligase may play a role in the regulation of postsynaptic dendritic spinogenesis and the maintenance of homeostasis within presynaptic terminals[63].

As noted previously, CUL1 is an invariable component of the SCF E3 ubiquitin ligases. Few genetic models exist that have specifically investigated CUL1, but models exploring overall SCF complex alterations are available. It has been shown in mice that engineered ubiquitin variants that target the Cul1 binding site work to inhibit SCF ubiquitin ligases[62]. However, no investigation into behavioural phenotypes or brain-related morphological and functional defects was undertaken in this study. Total knockout of F-box protein Fbxw7 in mice induces alterations of the overall SCF complex, manifesting in vascular development abnormalities in the brain and ultimately causing embryonic lethality[25]. FBXW7 is a well-characterised variant of the F-box protein, the variable component of the SCF complex, and has been implicated in neurodevelopment and neurodegeneration[27]. Despite the current lack of brain-specific investigations focussed on CUL1, results from the existing studies suggest that alterations in the SCF complex may have implications for neurodevelopment and neurological functions.

A recent study investigating FBXW7 implicated AKAP11 as a target of SCF complex-mediated degradation. The FBXW7 component of the SCF complex binds to target substrates via a phosphodegron consensus motif and is found on proteins targeted by the UPS for proteasomal degradation[25]. Such FBXW7-binding phosphodegrons were located on AKAP11 proteins, suggesting that the SCF complex E3 ligase may be involved in maintaining levels of this neuronal synapse plasticity regulator[12,64].


The use of WES has led to the initial identification of 11 genes in which very rare PTVs confer substantially increased risk of schizophrenia: SETD1A, CACNA1G, CUL1, GRIA3, GRIN2A, HERC1, RB1CC1, SP4, TRIO, XPO7, and AKAP11[7-9]. The exploration of model systems targeting some of these genes suggests putative convergent neurobiological and molecular mechanisms that seem to be impaired in schizophrenia[12]. A role for glutamatergic system dysregulation is supported by the association with schizophrenia of PTVs in GRIA3, GRIN2A, and SP4 and is augmented by studies of NMDAR antagonists, NMDAR autoantibodies, Sp4 hypomorphic mouse models, and Gria3 knockout models. While considerable research in this area of schizophrenia pathophysiology has been carried out, the majority of animal studies investigating NMDAR antagonists have specifically focussed on effects in adulthood[56]. Further studies could be conducted that allow for the examination of behavioural changes and neural circuit impacts throughout early developmental stages[56]. Disruption of chromatin modification by Setd1a dysfunction has effects on neuronal structure and function, again including glutamatergic neurons, among others. The involvement of HERC1, CUL1, and AKAP11 suggests that impairment of the UPS could also be a component of schizophrenia pathogenesis, and in particular, the impairment of E3 ligases encoded by HERC1 and CUL1 seems to elicit dysfunction in this degradation mechanism[62,63]. Interestingly, predating the identification of these genes, a number of studies had suggested that there might be abnormalities of the UPS associated with schizophrenia, and these findings were recently reviewed, although the authors concluded that it was difficult to determine whether such abnormalities were a cause or a consequence of the illness[65]. Previous GWAS results have highlighted glutamatergic genes and the UPS but not particularly chromatin modification[4].

Our current knowledge of the biological mechanisms that are affected by these schizophrenia risk genes has been largely limited to animal models and the translational applicability of these to humans may be limited[17]. Future studies could be conducted as multi-scale studies, which maintain investigations into animal models while incorporating disease modelling based on human induced pluripotent stem cells (iPSCs)[66]. Such multi-scale studies have the potential to facilitate clarification of the molecular pathology, enable cross-species verification, and initiate the development of clinically valid biomarkers with translational potential to patients[66].

For a number of the implicated genes, little is understood about their role to date. This situation is certain to change as further functional studies are carried out, focussing on phenotypes that seem especially relevant to schizophrenia. As we gain more knowledge, it seems possible that we may be able to develop a more coherent understanding of the mechanisms that can be involved in schizophrenia pathogenesis, hopefully condensing around a relatively small number of key processes.


WES studies have proven to be of significant value in revealing schizophrenia risk genes, with future studies likely to contribute further to our understanding of the molecular mechanisms that may be involved in schizophrenia pathophysiology. Elucidating key processes that are disordered in schizophrenia holds the potential to lead to improvements in treatment and a shift towards targeting underlying biological causes.


Authors’ contributions

Carried out the literature searches and drafted the main manuscript: Heinzer L

Assisted in the writing process: Curtis D

Availability of data and materials

Not applicable.

Financial support and sponsorship


Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval

Ethical approval was obtained by the researchers carrying out the cited studies.

Consent for publication and copyright

Not applicable.


© The Author(s) 2024.


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Cite This Article

OAE Style

Heinzer L, Curtis D. What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?. J Transl Genet Genom 2024;8:1-12.

AMA Style

Heinzer L, Curtis D. What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?. Journal of Translational Genetics and Genomics. 2024; 8(1): 1-12.

Chicago/Turabian Style

Heinzer, Lea, David Curtis. 2024. "What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?" Journal of Translational Genetics and Genomics. 8, no.1: 1-12.

ACS Style

Heinzer, L.; Curtis D. What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?. J. Transl. Genet. Genom. 2024, 8, 1-12.

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