to SCZ risk using a risk profile generated from the SNPs within these genes. This pattern of results is not consistent with robust or notable collective contribution of common variation within the hypothesis-driven candidate genes to schizophrenia based on the ISC data. However, it is possible that subsets of the heterogeneous list of historical candidate genes are enriched for smaller ISC p-values. We thus tested the two over-arching, “meta-hypotheses” which have been highly influential – notions of schizophrenia as a disease of the synapse and as a neuro-developmental disease. To our knowledge, these two larger-scale ideas have not been tested for empirical support in aggregate. We found no evidence to support a genetic basis for these two hypotheses in perhaps the most comprehensive analysis yet conducted. In addition, we specifically evaluated eight of the ten most studied historical candidate genes and the ISC GWAS results provide no support for common genetic variation associated with schizophrenia. We note that the strongest ISC GWAS findings were in the MHC region. Genes from the expanded MHC region do appear in the hypothesis-driven candidate gene literature. Most notably, NOTCH4 had genome wide significant SNPs in the ISC data and was highly studied (24 times;
