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Page 8 of 20 Rhoades et al. J Transl Genet Genom 2019;3:1. I https://doi.org/10.20517/jtgg.2018.26

genome. Targeted resequencing can be used to identify rare variants in candidate genes associated with SCZ
[Table 2]. One strategy is to sequence a few extreme cases and then compare the rare variants identified in
cases with a few controls. The other strategy is to use a few extreme cases to identify rare variants in novel
[64]
genes and perform a sequencing on a large cohort, targeting the potential candidate gene .
Disrupted-in-Schizophrenia 1
Disrupted-in-Schizophrenia 1 (DISC1) is a candidate gene implicated in multiple major psychiatric disorders
including SCZ, BD and MDD. It was originally reported in a linkage analysis of a translocation (1;11) (q42;q14)
[65]
co-segregated with SCZ, BD, and MDD in a large Scottish pedigree . Several additional independent
studies have also reported associations between DISC1 variants with other psychiatric disorders,
endophenotypes, and neurophysiological traits [66-68] . Rare missense mutations in DISC1 have been identified
in patients with SCZ, BD, and MDD. In a previous study, a targeted resequencing was used to sequence the
[69]
DISC1 locus (528 Kb) in 1,542 samples . Two-thousand and ten rare variants (MAF < 1%) were found, and
[69]
489 variants were located in regulatory regions while 36 mapped to coding exons . One variant, rs16856199,
in DISC1 was found to be significant in a region-wide association test and burden analysis revealed an excess
of rare regulatory variants in MDD patients. In addition, a rare missense mutation R37W in an MDD patient
was found to be transmitted to two affected offspring.

DISC1 pathway
DISC1 functions as a scaffold protein in a large pathway comprised of two networks of genes, termed the
“DISC1 Interactome” and “DISC1 Regulome”. The “Interactome” describes a set of proteins that interact
directly with the DISC1 protein, whilst the “Regulome” designates a set of genes that are regulated by
DISC1 protein. Both networks converge on pathways critical for various neurodevelopmental processes
and therapeutic targets of of SCZ, BD, and MDD. Genetic analyses of patients with psychiatric disorders
have identified additional mutations in DISC1 pathway genes. For example, the GWAS studies have found
common variants in SCZ candidate genes like, PDE4B, and sequencing of DISC1 and genes within the
DISC1 pathway has revealed an excess of rare missense variants in SCZ cases versus controls [70,71] . Variations
within the DISC1 pathway can have numerous effects on cognition as well as neurodevelopmental processes
and signaling. Perturbations in the DISC1 pathway could represent an important susceptibility pathway in
the development of SCZ.

In a recent study, a targeted resequencing analysis of 59 “DISC1 Interactome” and 154 “DISC1 Regulome”
[72]
genes was performed in 654 cases with SCZ, BD or MDD, and in 889 healthy controls . Burden analysis
showed the gene translin-associated factor X-interacting protein 1 (TSNAXIP1) was enriched for rare
damaging mutations in SCZ and MDD cases relative to controls. SKAT analysis showed an increased
burden of singleton disruptive variants in the “DISC1 Regulome” in SCZ patients. There are significant
associations between rare functional variants in the interactome with measures of cognitive performance.
DISC1, MAP1A, CIT, and DST were found to be associated with cognitive ability based on burden analysis.
Taken together these data suggest that genes in the “Regulome” and “Interactome” play a role in the etiology,
[72]
progression, and severity of symptoms in SCZ .

Targeted resequencing has been applied to sequence DISC1 and its interactors for SCZ and other
[71]
neurodevelopmental disorders in other studies. Kenny et al. sequenced patients with ASD and SCZ in 215
synaptic genes including DISC1 Interactome genes known to be important to synaptic function. A significant
burden of loss of function variants were found among combined cases of ASD and SCZ patients, which
[71]
[70]
demonstrates that dysregulation at the synapse is an important feature of ASD and SCZ . Moens et al.
investigated rare coding variants in 10 DISC1 Interactome genes in 486 SCZ patients and 514 healthy
controls from a Northern Swedish population. They found that rare mutations with MAF of 0.01 or less
were found more often in SCZ cases than in controls. Unrelated studies of drug dependence have also