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Page 12 of 20 Rhoades et al. J Transl Genet Genom 2019;3:1. I https://doi.org/10.20517/jtgg.2018.26

with intellectual disability in SCZ patients. Variations in several genes implicated in ASD were found to
overlap with those associated with SCZ. The supervised learning method, gradient boosted trees, was used
to determine whether combinations of inherited and de novo variants could be used to predict the risk of
[89]
SCZ in WES data from 2,545 patients with SCZ and 2,545 controls . The investigators reported that the
algorithm was 85% accurate in identifying patients diagnosed with SCZ. The results support the polygenic
model of SCZ. The investigators further argue that the results support the “threshold hypothesis”, whereby
SCZ is mainly a result of the accumulation of inherited mutations from an unaffected parent in susceptibility
genes beyond a threshold.

Family WES studies
Familial studies can be advantageous in studying highly heritable disorders where the loci associated
[90]
with diseases have been identified . This strategy is likely to increase the signal of rare causal variants
which may otherwise be dampened by the presence of common variants in association studies or burden
analyses [40,90] . A previous WES study of 53 family trios of the first episode sporadic patients diagnosed as SCZ
showed that rare de novo variants were 10 times more likely contain non-synonymous mutations than those
[91]
inherited from parents . In another investigation of de novo mutations in 14 trios, the researchers found
[92]
the ratio of nonsense to missense mutations was higher than expected based on previous studies . They
concluded that de novo mutations likely accounted for the missing heritability in SCZ. Family studies can
also be used to help identify genetic variants associated with complex disease within the general population.
Investigators found consensus in de novo variations in the PTPRG, SLC39A13, and TGM5 genes between in
[93]
5 proband trios and 12 out of 48 unrelated cases of SCZ . Family cohort studies can aid the understanding
of the heritability of SCZ within families. In a WES study of an Indian family, the investigators found the
variants in TIMP2 and PIWIL3 genes are segregated with family members who had been diagnosed with
[94]
SCZ . Pharmacological targets can also be elucidated through family cohort studies. In an investigation of
an affected Indian family, WES revealed a rare heterozygous missense mutation in the TAAR1 gene, present
only in the affected family members. This mutation affects a disulfide bond critical for the G protein-coupled
[95]
receptor and may have relevance to the discovery of pharmacological interventions for SCZ . A separate
investigation of two cases and one control in a family identified four rare variations in UNC13B were unique
[96]
to affected individuals . In a study of three families affected by SCZ, PDCD11 was found to have recurrent
[97]
variations and three variants were determined to be deleterious . ATP1A3 is associated with alternating
[98]
hemiplegia of childhood and was previously demonstrated to be associated with ASD. Chaumette et al.
used WES to determine whether rare variations in this gene are associated with risk of childhood-onset SCZ
in an American cohort. They found three variants, two de novo and one a non-synonymous, in the ATP1A3
gene and three rare variants in an interacting gene FXYD1. These genes were associated with a greater risk
[98]
of SCZ . ITGB4 gene is involved in cellular interactions and is highly expressed in neural stem cells and
precursors. A gene-wise weighted burden test conducted using Bulgarian proband trios failed to find any
gene that achieved exome wide significance, however, ITGB4 was the most “highly ranked” based on its
[99]
signed log P-value .
Family WES studies can be used to identify pathways associated with a greater risk for developing SCZ.
A study of a familial cohort combined WES and identity by descent model to map alleles associated with
greater risk of SCZ [100] . Non-synonymous variants that were associated with greater risk for SCZ and were
also enriched in pathways involved in the extracellular matrix and the development of neuronal projections.
Although, future investigations might consider whether this variation might contribute to certain cognitive
[96]
[101]
or behavioral symptoms . Timms et al. investigated rare variants associated with the NMDA receptors
in 5 families whose pedigrees demonstrate several persons affected by SCZ. They found rare variations in
21 genes, two of which were found in GRM5, a metabotropic glutamate receptor. Both variants affect the
extracellular domain. Rare variants were also determined to occur in the PPEF2 and LRP1B genes as well [101] .