Candidate gene studies have been a major focus in schizophrenia research with the SZGene database listing >1400 studies since 1965 (Allen et al., 2008). In contrast, there are ~2200 PubMed citations for “schizophrenia randomized controlled trials”. Until five years ago, genetic studies could investigate only an extremely small proportion of the genome due to genotyping and cost limitations. Investigators thus had to focus on small numbers genetic markers, genes, and samples. In hypothesis-driven candidate gene studies, targets were selected based on ideas about pathophysiology or gene location under a linkage peak (Cichon et al., 2009). For most biomedical disorders (including schizophrenia), the results of these studies were inconsistent or confusing (Ioannidis et al., 2001). It is unclear whether this reflects poor choices of candidate genes or inadequate assessment (i.e., small samples or incomplete coverage of common genetic variation).
