Abstract
By meta-analyzing rare coding variants in whole-exome sequences of 4,264 schizophrenia cases and 9,343 controls, de novo mutations in 1,077 trios, and array-based copy number variant calls from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare damaging variants in a subset of 3,230 “highly constrained” genes previously identified as having near-complete depletion of protein truncating variants. Furthermore, rare variant enrichment analyses demonstrate that this burden is concentrated in known autism spectrum disorder risk genes, genes diagnostic of severe developmental disorders, and the autism-implicated sets of promoter targets of CHD8, and mRNA targets of FMRP. We further show that schizophrenia patients with intellectual disability have a greater enrichment of rare damaging variants in highly constrained genes and developmental disorder genes, but that a weaker but significant enrichment exists throughout the larger schizophrenia population. Combined, our results demonstrate that schizophrenia risk loci of large effect across a range of variant types implicate a common set of genes shared with broader neurodevelopmental disorders, suggesting a path forward in identifying additional risk genes in psychiatric disorders and further supporting a neurodevelopmental etiology to the pathogenesis of schizophrenia.
