Table 1 provides a summary of molecular-genetic findings. What is striking is that most (89%) of the 153 cells are empty. The discovery-based analyses involving genome-wide testing of the approximately 527,000 SNPs, 17,000 genes, 85,000 exome chip rare variants, and 27 million sequenced variants produced only a few findings. By current convention, none can be considered valid discoveries in the absence of replication. Although one advantage of the discovery-based approach is the opportunity to capitalize on novel etiological insights that might arise from unexpected effects (see how Ford in this issue interpreted the delta power DEFA4/DEFA6 finding in light of the hypothesized role of inflammation to the pathophysiology of schizophrenia), unreplicated “discoveries” appear more plausible if they can be linked to the endophenotype through a known biological mechanism. Of the 11 genes in Table 1 identified through genome-wide studies, four appear likely to affect brain function. MYEF2, myelin expression factor 2, stands out because of the importance of myelin sheathing to nerve conduction. PARD3, PNPLA7, and GBX2 concern brain function. The latter three represent tentative discoveries based on rare variants, and all are in need of replication.
