Fourth, the largest and most carefully conducted schizophrenia common variant association study does not provide empirical support for 21 of the 25 historical candidate genes as genetic risk factors for schizophrenia. 11 Two historical candidate genes (DRD2 and GRM3) have genome-wide significant evidence for common variant association with schizophrenia 11 although the candidate gene literature did not support these associations. Two additional candidate genes (TNF and NOTCH4) have genome-wide significant associations with schizophrenia. 11 These genes are in the extended MHC, a complex region with high gene density and extensive linkage disequilibrium, and the MHC-schizophrenia association may not implicate these genes. The candidate gene literature missed these associations although these should have been the most accessible common variant findings: the MHC was the first genome-wide significant GWAS signal for schizophrenia 42–44 and 11% of high-quality SNPs (6,570 of 57,891) in the extended MHC region exceeded genome-wide significance. 11 These false negatives from the pre-GWAS era likely resulted from extremely low statistical power and limited genotyping.
