Perhaps more importantly, identifying variants convincingly associated with a given clinical phenotype will suggest biological mechanisms and new endophenotypes. That is, it may be fruitful to develop endophenotypes based on the biological function of validated polymorphisms. This is now beginning, with follow-up studies of the 108 loci implicated by the PGC consortium. A recent article fine-mapped structural variation within the major histocompatibility complex, discovering CNVs that severely affect gene expression of C4A and C4B in the brain (Sekar et al., 2016). When taken to a mouse model C4 activity mediated synaptic pruning during postnatal development. This GWAS-based finding has been translated to a neurobiological mechanism which, if true, would implicate C4 expression and possibly synaptic pruning in the etiology of schizophrenia. As the C4-related mechanisms are better understood, it should be possible to derive candidate endophenotypes for them. Indeed, we may come to think of our current arsenal of endophenotypes as obsolete and unlinked to genetic variants of measureable effects, replacing it with a new set of endophenotypes developed on the basis of known genetic effects.
