The above three examples concern over-representation of genes within a functionally defined gene set. Complementing these, the best example of convergence of multiple genetic hits within a well-established biochemical pathway is the neuregulin 1 (NRG1)–ERBB4–PI3K–AKT1 pathway. Although it is important to point out that none of these genes are significant in the large GWAS studies, there is evidence for association of all four genes to schizophrenia, and for epistasis between them (Emamian et al., 2004; Harrison and Law, 2006; Hatzimanolis et al., 2013; Law et al., 2012; Nicodemus et al., 2010; Norton et al., 2006). This is a key pathway regulating cellular growth and activity (Mei and Nave, 2014; Vanhaesebroeck et al., 2010; Zheng et al., 2012). Its role in schizophrenia illustrates the point made earlier that the risk SNPs may preferentially affect certain isoforms of each gene; for example, type IV NRG1 (Law et al., 2006; Paterson et al., 2014; Tan et al., 2007), the CYT-1 isoform of ERBB4 (Law et al., 2007), and the p100δ isoform of the catalytic subunit of PI3K (Law et al., 2012). This isoform
