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Mixed 161 affected patients and 69 controls FMRP, VGCCs Salvoro et al. [100]
Family 5 large families with multiple affected patients GRM5, PPEF2 & LRP1B Timms et al. [101]
WGS
Family 5 families with 3 or more affected individuals SHANK2, SMARCA1 Homann et al. [102]
Family A large Chinese family with several affected RELN2 Zhou et al. [103]
members
Family 8 families of monozygotic twins who were TTN, GCN1L1, GAD1, PLXNA2, RELN2, FEX1 Tang et al. [104]
discordant for SCZ
Family Two trios of unaffected patients with children COMT & PRODH Chung et al. [105]
with 22q11.2DS
Case-control 1,616 samples DGCR8 Gur et al. [106]
9 unrelated individuals with 22q11.2 deletions DGCR8 Merico et al. [107]
Case-control 188 patient, 376 controls HHAT Betcheva et al. [27]
Family 91 SCZ families Selected genes implicated: ABCA13, Khan et al. [108]
CNTNAP2, SHANK2, SHANK3, HHAT
Family 660 proband trios with at least one suicide NRXN1 & VIPR2 Sokolowski et al. [109]
attempt
Family 46 proband trios CNTNAP2, MAGI1, TSPAN7, CAV1, CAV2, Piluso et al. [110]
MET, ZIC1

ASD: autism spectrum disorder; BD: bipolar disorder; MDD: major depressive disorder; SCZ: schizophrenia; COS: childhood-onset
schizophrenia; WES: whole exome sequencing; WGS: whole genome sequencing

outcomes. One such investigation found 10 of 167 pharmacologically relevant gene sets were enriched for
deleterious rare variants in SCZ patients. When the investigators examined the enrichment of common
variants in pharmacologically relevant gene sets, they found that 35 of 167 gene sets were enriched among
SCZ patients. Interestingly, they found that when analyzing both common and rare variations, two gene
sets of pharmacologically relevant drugs were associated with greater risk of SCZ, drugs that are meant to
treat amoebiasis and protozoal diseases, as well as antipsychotics. Further analysis revealed 4 target genes
[84]
associated with treatment efficacy in SCZ patients .
Rare variations in genes that are intolerant to protein truncation variants have also been associated with
[85]
increased risk in several neuropsychiatric disorders including SCZ . Several pathways involved in cell cycle
arrest, heterocycle metabolic processes, and covalent chromatin modification, and histone modification are
enriched for rare functional variants. The findings demonstrated a role for dysfunction or dysregulation
of the cell cycle and histone modification in the pathology of SCZ . Rare disruptive mutations associated
[86]
with SCZ are likely to play a role as patients have higher rates of rare disruptive mutation than healthy
controls. Further investigation of three sets of genes associated with the activity-regulated cytoskeleton-
associated protein (ARC), postsynaptic density 95 protein, and calcium ion channels, revealed that the
number rare disruptive variants among these gene sets were increased in SCZ. Many of the rare disruptive
[17]
variants found were non-synonymous de novo mutations . In a case-control investigation, the scientists
found that mutational rates for the diagnosed patients were correlated with advanced parental age. However,
79% of all de novo mutations occurred on paternal chromosomes. Patient exomes showed an increased rate
in non-synonymous de novo mutations in genes associated with SCZ and synaptic function. Upon further
investigation, it was shown that the proteins resulting from these non-synonymous mutations exhibited
greater number of protein-protein interactions with synaptic proteins than was expected. Genes involved in
forming the N-methyl-D-aspartate receptor (NMDAR) and ARC complexes, which are involved in processes
underlying synaptic plasticity, were particularly enriched in non-synonymous mutations . Many of the
[87]
variations associated with SCZ are found within genes that are intolerant of damaging mutations. In a study
of 9,274 controls and 4,133 SCZ cases, the authors compared rates of copy number variants between cases
[88]
and control . Investigators also performed joint analysis to determine if there were associations between
cases and controls with respect to combinations of SNVs, copy number variants, and de novo mutations. The
authors determined that SCZ patients had a greater number of variations in genes that are intolerant of loss
of function mutations. Burden analysis also demonstrated that loss of function mutations were associated