Beyond the GWAS in schizophrenia

The identification of the genetic factors that influence susceptibility to neuropsychiatric illness has proven challenging. Currently, several approaches are being utilized to enhance the potential of these studies. Most commonly, a ‘discovery’ genome wide association study (GWAS) with a focus on a single clinical diagnostic group such as schizophrenia, with subsequent replication in independent cohorts is the standard for the field. A major challenge for this approach is the necessity for increasingly large sample sizes, presumably due to modest effect sizes and genetic heterogeneity, with commensurate increased heterogeneity of study samples. A complementary approach is to seek support for genetic loci by collecting additional phenotypic data, often termed endophenotypes, which suggest that specific genetic variants have significant effects on key biological or clinical parameters that are more closely linked to gene function. For example, studies demonstrating that a putative schizophrenia risk variant in ZNF804A influences phenotypes assessing brain structure or function as measured by neuroimaging or neurocognitive studies (Esslinger et al, 2009; Lencz et al, 2010).In this issue of EMBO Molecular Medicine, Grube et al (2011) report on a variant of this approach, the so‐called phenotype‐based genetic association study (PGAS). These authors tested the relationship of genetic variation in the KCNN3 gene; a gene that codes for the calcium‐activated potassium channel SK3, previously implicated in cognitive function (Blank et al, 2003), but only inconsistently linked with schizophrenia, to a number of …