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demonstrated the significance of DISC1 pathway genes within the regulome as well, showing for instance,
[73]
significant associations between rare variations found in DISC1 and GRIN2B and opioid dependence .

Other candidate genes and pathways
Several other candidate genes have been implicated in SCZ, with a wide variety of functions. Rare variations
in nuclear distribution E homolog 1 (NDE1), a gene that plays a role in microtubule formation, mitosis,
[74]
and neuronal migration . One investigation identified variant S214F, which was significantly associated
[74]
with SCZ based on Fischer’s exact test. This variant is deleterious to the function of the NDE1 protein .
The targeted sequencing of Northern Swedish SCZ patients revealed that NDE1 is significantly associated
[70]
with SCZ diagnosis . Dysfunction in myelination of axons, has also been implicated in SCZ patients. A
rare variant in a receptor subunit for a myelin-associated inhibitor known as RTN46 was shown to have a
[75]
modest association with SCZ . This subunit has been demonstrated to play a role in synapse formation
and is located on chromosome 22 in a mutational hotspot associated with SCZ. Upon further investigation,
[75]
this variant was found to affect synaptogenesis by decreasing growth cone collapse . Imputation analysis
of GWAS data found both common and rare variants in ADAMTSL3 gene, a constituent of the extracellular
[76]
matrix . An additional investigation found four rare variants located in noncoding regions near the
[77]
MIR185 gene, which codes for a microRNA with many functions .
There is an overlap in many of the genes found to contain rare variation in SCZ with other neuropsychiatric
and neurodevelopmental disorders like ASD. GRIN2B is a gene that is regulated by the DISC1 protein,
implicating dysfunction in glutamateric signaling in SCZ neuropathology. In a study on ASD and SCZ, the
investigators found an excess of rare variants, over 200 non-synonymous variants. Many of these rare variants
[78]
had deleterious effects on genes associated with neurite outgrowth, Rett syndrome, and intellectual deficits .
Further investigations of the genetic overlap between SCZ and ASD have also demonstrated that the rate of de
[79]
novo mutations in ASD spectrum disorder and SCZ patients was higher than that of controls .

Wes fOR CODINg VaRIaNTs
WES is a method of sequencing that focuses on coding regions of the genome. It is cheaper than WGS, making
it possible to sequence more samples, while potentially increasing the signal to noise ratio. However, the power
[39]
of a WES study will depend on the number of samples and the amount of variation in the genes of interest .
By excluding de novo mutations and filtering of these variants in GWAS or WES can help to further narrow
[80]
down the search for rare causative variants or as a means of grouping variants for association analyses .
Here, we review the WES studies for investigating rare coding variants associated with SCZ [Table 2].

Case-control WES studies
WES has been widely used in case-control studies to search for candidate genes associated SCZ. In a WES
study of 4,264 SCZ cases and 9,343 controls, investigators found a significant association between loss of
function mutations in SETDIA and SCZ. SETDIA is a gene that is associated with developmental disorders,
which is further underscored by the fact that loss of function mutations in this gene are rare within the
[81]
general population . Damaging and disruptive ultra-rare mutations were found to be enriched in cases of
SCZ. Investigators observed de novo nonsynonymous mutations in two genes previously identified as SCZ
candidate genes, TAF13 and SETD1A. Additionally, A single ultra-rare variant in NRXN1 was identified to
[82]
[83]
be associated with SCZ . Giacopuzzi et al. sequenced an Italian cohort of 180 persons diagnosed with
SCZ and detected 45 brain-expressed genes with deleterious effects. Four variants in four candidate genes
(ANO2, FMN1, MEGF8 and GAD1) were determined to have rare or novel missense mutations which were
not detected in control patients. The results indicate that high levels of homozygosity are associated with
[83]
increased rare recessive variations in genes that convey a higher risk of SCZ . WES studies of common
and rare variants in SCZ risk loci can be used to elucidate psychiatric drug targets and improve treatment