Risk variants identified by GWAS are individually likely to be of modest effect which poses challenges for clinical follow up studies. These are not insurmountable, but are at the present time dependent on the availability of detailed phenotypic information from subjects involved in GWAS studies or the ability to re-contact subjects for additional studies. Recent efforts in schizophrenia, demonstrate the application of a phenotype refinement approach, in this case identifying a disturbed neural connectivity phenotype in carriers of the risk allele at ZNF804A using a neuroimaging approach (Esslinger et al., 2009). If disorders are highly polygenic it could be possible to group participants into classes based on total burden of risk variation or contribution from different functional pathways. Such groupings could than be used within a disorder, or across current diagnostic boundaries, to investigate clinical profiles, cognitive functioning, drug response or clinical outcome. By extension, such approaches could also be applied to investigate gene-environment interaction in risk. The optimum approach would be integration of genetic and epidemiological research to investigate, prospectively, the effects of risk genes and gene-environment interaction in prospective studies or within high-risk groups.
