The molecular interactions of DISC1 and NKCC1-dependent GABA depolarization have potential implications for understanding the mechanism of DISC1-associated genetic risk for mental illnesses. We tested this possibility directly in a clinical genetic study of variations in DISC1 and in SLC12A2 (the gene encoding human NKCC1) and risk for schizophrenia. Three independent case control datasets of patients with schizophrenia and healthy controls, all of European ancestry, were studied (n = 2961 individuals). Common haplotype tagging SNPs in DISC1 and in SLC12A2 were identified and genotyped (Figures 7A to 7B); allele and genotype frequencies between cases and controls were compared independently and in a combined dataset (Table S2). A SNP (rs1000731) in DISC1 and a SNP (rs10089) in SLC12A2 showed significant epistatic effects in the two larger datasets (Scottish: P = 0.032; German: P = 0.0294; Figure 7C; Table S2). Importantly, these same SNPs interacted significantly on risk for schizophrenia in the combined, three-sample dataset (P = 0.0017). Individuals who were minor allele carriers at both rs10089 in SLC12A2 and rs1000731 in DISC1 were positively associated with risk for schizophrenia compared with
