Schizophrenia is a serious mental illness, involving disruptions in
thought and behavior, with a worldwide prevalence of about one percent. Although
highly heritable, much of the genetic liability of schizophrenia is yet to be
explained. We searched for susceptibility loci in multiplex, multigenerational
families affected by schizophrenia, targeting protein-altering variation with
in silico predicted functional effects. Exome sequencing
was performed on 136 samples from eight European-American families, including 23
individuals diagnosed with schizophrenia or schizoaffective disorder. In total,
11,878 non-synonymous variants from 6,396 genes were tested for their
association with schizophrenia spectrum disorders. Pathway enrichment analyses
were conducted on gene-based test results, protein-protein interaction (PPI)
networks, and epistatic effects. Using a significance threshold of
FDR<0.1, association was detected for rs10941112
(P=2.1×10−5;
q-value=0.073) in AMACR, a gene
involved in fatty acid metabolism and previously implicated in schizophrenia,
with significant cis effects on gene expression
(P=5.5×10−4), including
brain tissue data from the Genotype-Tissue Expression project (minimum
P=6.0×10−5). A second
SNP, rs10378 located in TMEM176A, also shows risk effects in
the exome data (P=2.8×10−5;
q-value=0.073). Protein-protein interactions among
our top gene-based association results (P<0.05;
n=359 genes) reveal significant enrichment of genes
involved in NCAM-mediated neurite outgrowth
(P=3.0×10−5), while
exome-wide SNP-SNP interaction effects for rs10941112 and rs10378 indicate a
potential role for kinase-mediated signaling involved in memory and learning. In
conclusion, these association results implicate AMACR and
TMEM176A in schizophrenia risk, whose effects may be
modulated by genes involved in synaptic plasticity and neurocognitive
performance.