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[110]
Piluso et al. investigated de novo CNVs in cis-regulatory elements using NGS data from 46 family trios
where at least one member was diagnosed with SCZ. They found de novo CNVs in genes associated with
SCZ, intellectual disability, neuronal, migration, and neural development: CNTNAP2, MAGI1, TSPAN7,
CAV1, CAV2, MET, and ZIC1. Two de novo mutations were found to affect the hs1043 and hs582 regulatory
elements [110] .

CHalleNges
One challenge of investigating the genetics of SCZ is that many of the variants, which seem to confer
susceptibility to SCZ or to have demonstrated an association with SCZ overlap with other neuropsychiatric
illnesses including BD and MDD. In an investigation of over 19,000 cases of SCZ and BD, the investigators
identified 219 SNPs that achieved genome-wide significance. These variants were found within 6 regions of
the genome, two which were previously associated with SCZ, MHC, MAD1L1; two previously associated
with BD, TRANK1, IFI44L, one gene that was based on previous work was associated with both diseases,
CACNA1C; and a novel risk gene, PIK3C2A, also associated with both SCZ and BD. None of the 6 genes
identified demonstrated a significant difference in terms of odds ratio between SCZ or BD, which further
demonstrates the genetic overlap between the polygenic nature of these disorders [111] . The complex genetics
of SCZ has also been demonstrated by the fact that it is difficult to distinguish between SCZ, schizoaffective,
schizotypal, and non-affective psychotic disorders, which is sometimes referred to as the SCZ spectrum. In
an investigation of the polygenic nature of SCZ spectrum disorders, the investigators calculated polygenetic
risk scores for each subject based on the genome-wide significance of SNP in cases vs. controls. Individuals
who lacked a psychiatric diagnosis had significantly lower scores than those of cases who were diagnosed
on the spectrum [112] . SCZ and ASD also share a number of similar endophenotypes with respect to
executive function, cognition, and sensory deficits [113] . Alterations in the morphology and neurochemistry
of several neuroanatomical regions are common to both SCZ and ASD, including the prefrontal cortex,
anterior cingulate, posterior cingulate, claustrum, and right parahippocampal gyrus among others [114-116] . In
terms of genetic overlap, studies have found increased number of de novo splice site mutations and CNVs
associated with both SCZ and ASD [117,118] . The common susceptibility genes associated with SCZ and ASD
are post synaptic density associated genes like DLG2, NRXN1, and BDNF [119-121] . Factors relating to prenatal
development represent another point similarity in the etiology of ASD and SCZ, particularly with respect to
inflammation and neuroinflammation [121,122] . It is also worth noting that maternal infection and autoimmune
disorders are associated with greater risk of developing ASD and SCZ [14,123] .

Another challenge is determining the role of environmental factors. The rate of the immune system’s
exposure to bacteria is higher early in life and decreases with age. Impaired immune response in persons
has been hypothesized to play a role in the development of SCZ [113,124] . However, most studies implicate
maternal infection as a greater risk factor than postnatal immune insults [14,125] . Inferior social status is an
environmental factor that may also play role in the increased risk of SCZ diagnoses [108] . These differences
in environmental conditions between racial and ethnic minorities may result in neurobiological changes
as well. In two Canadian investigations of clients at risk for psychosis and SCZ and healthy controls,
researchers found that immigrants demonstrated increased dopamine release from the striatum relative to
non-immigrants [126,127] . However, the mean genetic variability did not differ among the ethnic groups [128] .
The racial or ethnic differences in the incidence of SCZ diagnosis are studies, which have shown that
socioeconomic status and perceived honesty of the patient may influence diagnoses. In one investigation
interviewers diagnosed 19% of white participants as schizophrenic, however study interviewers diagnosed
nearly half of the black participants [129] . Socioeconomic factors, age, substance use, and reports of symptoms
such as hallucinations differed between the two groups. However, investigators found that the client’s race
still increased the likelihood of SCZ diagnosis three-fold [129] . A literature review concerning the black
Caribbean populations in the UK found several possible explanations for the increased incidence of SCZ in