To set the systems genomics results in context and to ensure that we were not missing enrichment in other gene sets by our hypothesis-driven approach, we undertook a purely data-driven analysis of a larger comprehensive annotation of gene sets from multiple public databases, totaling 6,677 gene sets (Methods and Supplementary Table 10). Six gene sets survived FWER correction for the full 6,677 gene sets and showed independence through conditional analyses. The LoF-intolerant gene set was the most strongly enriched, followed by the two most strongly associated functional gene sets we had specified in our hypothesis-driven CNS gene set analysis (FMRP targets and MGI abnormal behavior genes). The other three sets were calcium ion import (GO:0070509), membrane depolarization during action potential (GO:0086010) and synaptic transmission (GO:0007268). These are highly overlapping with the independently associated sets from our primary CNS systems genomics analysis. Indeed, if we repeat the data-driven comprehensive gene set analysis while adjusting for the six independently associated CNS gene sets, the only surviving enrichment term is the LoF-intolerant genes. These results are consistent with those from CNV analysis30 in
