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Page 2 Heinzer et al. J Transl Genet Genom 2024;8:1-12 https://dx.doi.org/10.20517/jtgg.2023.39

[1,2]
whose aetiology remains elusive . It has long been clear that genetic factors can contribute to risk, and
[3,4]
twin, family, and adoption studies estimate the heritability of schizophrenia to lie between 60%-80% . The
most comprehensive genome-wide association study (GWAS) to date implicated 287 significant risk
[4]
variants and these signals were fine-mapped to 120 genes . 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
[5]
risk for schizophrenia (median OR < 1.2) . 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
[6]
duplications) in gene dosage . 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 . For all of these genes, PTVs were shown to confer a substantial effect on risk and reached
[7-9]
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
[10]
genes, as well as identifying a novel gene, SRRM2, as achieving exome-wide significance . 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
[11]
whether it is, in fact, a schizophrenia risk gene . 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.

INDIVIDUAL RISK GENES IMPLICATED IN SCHIZOPHRENIA THROUGH WES
A number of sequencing studies have suggested several genes to be possibly involved in schizophrenia
pathophysiology . To focus this investigation, we restrict attention to the 11 genes implicated at exome-
[12]
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.