The final possibility is that much of schizophrenia risk is due to rare, moderate-to-high penetrance variants whose population frequencies reside somewhere below the threshold of detection of genome-wide screens. Due to the complex patterns of schizophrenia heredity, and the relative lack of families with Mendelian schizophrenia syndromes, this cannot account fully for schizophrenia susceptibility. On balance, however, the data presented here are most consistent with this interpretation. First, we find no evidence of association for common SNPs, but clear evidence that a fraction of cases are due to very rare, very highly penetrant structural variants. One interpretation of this pattern is that selection for reliable cognitive function has been sufficiently strong to keep the genome free of common variants that predispose to schizophrenia, and that it is only rare deleterious variants that influence risk [49]. This model for schizophrenia genetics presents clear challenges to the hope that genetics will rapidly reveal new therapeutic opportunities or partition patients up into a small number of clinically manageable subgroups.
