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Heinzer et al. J Transl Genet Genom 2024;8:1-12 https://dx.doi.org/10.20517/jtgg.2023.39 Page 9

DISCUSSION
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 . The exploration of model systems targeting some of these genes suggests
[7-9]
putative convergent neurobiological and molecular mechanisms that seem to be impaired in
[12]
schizophrenia . 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
[56]
investigating NMDAR antagonists have specifically focussed on effects in adulthood . Further studies
could be conducted that allow for the examination of behavioural changes and neural circuit impacts
[56]
throughout early developmental stages . 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 . Previous GWAS results have highlighted glutamatergic genes and the UPS but not particularly
[65]
[4]
chromatin modification .
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
[17]
limited . 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) . Such multi-scale studies have the potential to facilitate clarification of the molecular pathology,
[66]
enable cross-species verification, and initiate the development of clinically valid biomarkers with
[66]
translational potential to patients .
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.

CONCLUSION
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.

DECLARATIONS
Authors’ contributions
Carried out the literature searches and drafted the main manuscript: Heinzer L
Assisted in the writing process: Curtis D