Consideration of plausible genetic architectures for schizophrenia and implications for analytic approaches in the era of next generation sequencing.

The results of linkage and association studies imply that there are no common, dominantly active variants which have a substantial effect on the risk of schizophrenia. However, there are rare structural variants with a major effect and it is argued that results to date are not incompatible with the existence of large numbers of individually rare sequence variants with major effect, since these would not have been detected by the methods used to date. It is also argued that the epidemiology is consistent with a contribution from recessively acting variants and that likewise these might have gone undetected. It is shown that methods of analysis specifically designed to detect recessive variants through testing departure from Hardy-Weinberg equilibrium offer substantial increases of power over conventional methods. It is recommended that analytic approaches aim to detect very rare variants with major effect and that specific attempts are made to detect recessively acting loci.