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Table 1. Summary of genes implicated in schizophrenia pathogenesis through large-scale exome sequencing studies
Gene Gene name Putative role in schizophrenia pathogenesis
symbol
SETD1A SET domain containing 1A, histone lysine methyltransferase Regulates gene expression
CACNA1G Calcium voltage-gated channel subunit alpha1 G Involved in neuronal excitation
CUL1 Cullin 1 Encodes component of an E3 ubiquitin ligase complex
GRIA3 Glutamate ionotropic receptor AMPA type subunit 3 Involved in ionotropic glutamatergic transmission
GRIN2A Glutamate ionotropic receptor NMDA type subunit 2A Codes for NMDA receptor subunit
HERC1 HECT and RLD domain containing E3 ubiquitin protein ligase family Encodes an E3 ubiquitin ligase
member 1
RB1CC1 RB1 inducible coiled-coil 1 Involved in neurodevelopment
SP4 Sp4 transcription factor Modulates expression of NMDA receptor subunit genes
TRIO Trio Rho guanine nucleotide exchange factor Has a role in glutamatergic transmission
XPO7 Exportin 7 Role unclear
AKAP11 A-kinase anchoring protein 11 Possibly involved in neuronal plasticity, target of E3
ubiquitin ligases

SETD1A
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
[13]
complex . This complex mediates mono-, di- and trimethylation of the lysine 4 residue on the histone H3
protein (H3K4) . These histone marks are associated with gene activation and implicate SETD1A as a
[9]
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
CACNA1G (Calcium Voltage-Gated Channel Subunit Alpha-1G Subunit) encodes the Ca 3.1 subunit of the
V
low-voltage-activated T-type calcium channel . These voltage-sensitive calcium channels facilitate calcium
[18]
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 . These T-type calcium channels are
[19]
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
[20]
cerebellar atrophies and cognitive developmental defects .

CUL1
CUL1 (Cullin 1) encodes a scaffolding protein, which is a core component of the SKP1-CUL1-F-box-
protein (SCF) E3 ubiquitin ligase complex . The SCF complex is invariably composed of scaffolding
[22]
protein CUL1, RING finger protein RBX1, and adaptor protein SKP1, as well as a variable F-box
component . This complex mediates the ubiquitination and subsequent degradation of proteins regulating
[23]
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