3 ± 11 4

years) and 1378 healthy controls (54 0% female;

3 ± 11.4

years) and 1378 healthy controls (54.0% female; mean age 51.1 ± 17.0 years) for which genotype data at the four FEZ1 SNPs were available ( Table S1A). No significant results were detected on susceptibility to schizophrenia for each of the four FEZ1 SNPs, which is consistent with the result from the ZHH cohort ( Table S1A). The platform used to genotype GAIN (Affymetrix 6.0 chip) did not include the DISC1 Ser704Cys marker but has a perfect proxy for this SNP (rs1754605; r2 = 1.0). We then performed a backward selleck screening library stepwise regression to test for an interaction between the proxy SNP for DISC1 Ser704Cys and FEZ1 rs12224788 ( Figure 6C). As this approach was to serve as a replication of the findings in the ZHH data set, we included only the FEZ1 SNP with statistical evidence of epistasis (FEZ1 rs12224788) in the GAIN sample regression model ( Table S1B). Variables retained in the best fit model included FEZ1 genotype (Beta = 0.72; p = 0.041), DISC1 genotype (Beta = 0.53; p = 0.044), and the interaction term FEZ1 × DISC1 (Beta = −0.45; p = 0.039). While the significant interaction is consistent with results from the ZHH data set, the Beta term is negative, suggesting a somewhat different pattern of

interaction in the GAIN sample as compared with the ZHH sample. Specifically, χ2 analyses revealed only a trend-level association for the C allele at FEZ1 PD0332991 price rs12224788 in DISC1 Ser homozygotes (χ2 = 1.53; df = 1; p = 0.12; OR = 1.2) and a significant association for the FEZ1 GG genotype in the context of a DISC1 Cys background (χ2 = 2.83; df = 1; p = 0.05; OR = 0.77; Figure 6B). While not identical, this pattern of risk association related to the interaction is consistent with that found through in the ZHH sample. We also performed a series of χ2 tests in the same way to test for a potential interaction between our NDEL1 risk SNP (rs1391768) ( Burdick et al., 2008) and each of the four FEZ1 SNPs using the ZHH sample. We carried out four separate χ2

analyses with one for each FEZ1 SNP, while conditioning the sample on NDEL1 rs1391768 status. The results from these analyses provided no significant evidence of interaction among these four FEZ1 SNPs and NDEL1 rs1391768 (all p > 0.10; Figure S6D and data not shown). Taken together, these genetic interaction results from clinical cohorts mirror the biochemical and cell biological findings of a synergistic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, in regulating neuronal development in the animal model. Cumulative evidence supports a significant neurodevelopmental contribution to the pathophysiology of schizophrenia and other major mental disorders (Lewis and Levitt, 2002, Rapoport et al., 2005 and Weinberger, 1987), yet underlying molecular mechanisms are far from clear. DISC1 has emerged as a general risk factor for schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism, and Asperger syndrome (Chubb et al., 2008 and Muir et al., 2008).

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