We performed sequential analyses using the following approaches: LoF-intolerant genes. We tested the enrichment of the LoF-intolerant genes described by ExAC21. This set comprised all genes defined in the ExAC database as having a probability of LoF intolerance (pLI) statistic higher than 90%. Although these genes do not form part of cohesive biological processes or phenotypes, they have previously been found to be highly expressed across tissues and developmental stages21. Also, they are enriched for hub proteins72, which makes them interesting candidates for involvement in the ‘evolutionary canalization’ processes that have been proposed to lead to pleiotropic, complex disorders73.CNS-related genes. These gene sets were compiled in our recent study30 and include 134 gene sets related to different aspects of CNS function and development. These include, among others, gene sets that have been implicated in schizophrenia by at least two independent large-scale sequencing studies8,31: targets of FMRP32, constituents of the N-methyl-D-aspartate receptor (NMDAR74) and activity-regulated cytoskeleton-associated protein complexes (ARCs75,76), as well as CNS and behavioral gene sets from MGI database version 635.Genes identified by data-driven analysis. The final systems genomic analysis
