A recent development in the genetic architecture of schizophrenia suggested that an omnigenic model may underlie the risk for this disorder. The aim of our study was to use polygenic profile scoring to quantitatively assess whether a number of experimentally derived sets would contribute to the disorder above and beyond the omnigenic effect. Using the PGC2 secondary analysis schizophrenia case-control cohort (N = 29,125 cases and 34,836 controls), a robust polygenic signal was observed from gene sets based on TCF4, FMR1, upregulation from MIR137 and downregulation from CHD8. Additional analyses revealed a constant floor effect in the amount of variance explained, consistent with the omnigenic model. Thus, we report that putative core gene sets showed a significant effect above and beyond the floor effect that might be linked with the underlying omnigenic background. In addition, we demonstrate a method to quantify the contribution of specific gene sets within the omnigenic context.