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Wgs fOR geNOmIC VaRIaNTs
WGS can lead to the identification of associations between genomic variants and SCZ [Table 2]. It can be
used to identify small variants, including SNV and small insertions and deletions (INDELs), in coding and
noncoding regions. Since the entire genome is sequenced, WGS is also a comprehensive tool for detecting
large structural variants such as CNVs.

Small variants
WGS has given investigators the ability to investigate the association between rare small variations and
disease. One investigation found deleterious missense mutations in the SHANK2 and SMARCA1 genes which
play a role in the post-synaptic density and neurogenesis [102] . An investigation of a large Chinese family with
several members diagnosed with SCZ found that the genetic model of inheritance was autosomal dominant
and one missense variant in RELN, a gene involved in neuronal migration, was significantly associated with
SCZ [103] . The missense variant in RELN was found to co-segregate with the disorder and to be disruptive
to protein function WGS of monozygotic twins discordant for SCZ indicates multiple genetic risk factors
for SCZ [104] . The rate of de novo mutations was correlated with paternal age at the time of conception. A
combination of inherited and de novo rare mutations seems to confer an increased risk of developing SCZ.

Structural variants
The 22q11.2 deletion syndrome is a common genetic disorder, which is associated with a 25-fold increase in
the risk of psychotic disorders, like SCZ [105] . In order to study the effects of 22q11.2 deletions on phenotype
and develop better diagnostic assessments, the International Brain and Behavior Consortium developed
a framework for investigations of the genetics of this disorder using data from patients and unaffected
adults [106] . The model assumes that remaining haploid copies of segments of 22q11.2 deletion sites will
demonstrate an increased number of variants in individuals affected by SCZ or psychotic disorders. The
combined model also tests for SNPs, for and rare structural variants, which exist outside of deleted 22q11.2
regions. The findings showed that patients with SCZ had significantly more CNVs than undiagnosed
individuals [106] . 22q11.2 deletions alone cannot explain the risk of developing SCZ. Investigators performed
WGS in a group of nine unrelated patients, and demonstrated a greater burden for rare variants in cases
than in controls in neurofunctional gene sets [107] . Burden analysis also revealed a large association between
22q11.2 microdeletions and rare variations in non-coding RNA genes as well. A familial study detected
associations between variations in COMT and PRODH with cognitive impairments. Both the COMT and
[107]
PRODH genes are located in the 22q11 deletion region [105] . Merico et al. performed WGS on 9 unrelated
Canadian patients with SCZ to investigate the impact of 22q11.2 deletions on gene expression. The
investigators identified rare variants in coding regions that were predicted to have damaging effects under
a haploinsufficiency model. They found that the patients with SCZ had more deleterious rare variations
in neuronal genes associated with neural projection as well as neuronal function. The investigators then
investigated the association between SCZ and rare variants in genes that are affected by DGCR8, a gene
involved in miRNA biogenesis. They found that patients with 22q11.2 deletions, where the function of
DGCR8 was affected, were at greater risk of developing SCZ. These results lend further credence to the
miRNA hypothesis of SCZ [107] .

WGS was also applied to family studies to discover variants or modifications that could explain the
variability of SCZ phenotypes. Khan et al. [108] performed WGS to search for CNVs in 91 families with
members diagnosed as schizophrenic. They found that there was an average of 9 rare CNVs per patient.
Intronic deletions were found to be 3 times greater than exonic deletions. The transmission rates for rare
exonic CNVs from unaffected parents to affected children were higher than for unaffected children [108] . A
WGS study on 660 proband trios found rare CNVs in 14 loci that overlapped with SCZ risk genes in nine
children seven offspring of persons who had attempted suicide. Forty-five of the patients that previously
attempted suicide were found to have CNVs in 65 genes known to be involved in neural development [109] .