Exome sequences of multiplex, multigenerational families reveal schizophrenia risk loci with potential implications for neurocognitive performance

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