Elsevier Editorial System(tm) for Biological Psychiatry Manuscript Draft Biological Psychiatry Association between Genes of Disc1 Interactors and Schizophrenia Supports the Role of the Disc1 Pathway in the Etiology of Major Mental Illnesses

BACKGROUND: Disrupted in Schizophrenia 1 (DISC1) is currently one of the most interesting candidate genes for major mental illness, having been demonstrated to associate with schizophrenia, bipolar disorder, major depression, autism, and Asperger's syndrome. We have previously reported a DISC1 haplotype, HEP3, and an NDE1 spanning tag haplotype to associate to schizophrenia in Finnish schizophrenia families. Since both DISC1 and NDE1 display association in our study sample, we hypothesized that other genes interacting with DISC1 may also have a role in the etiology of schizophrenia. METHODS: We selected 11 additional genes encoding components of the "DISC1 pathway" and studied these in our study sample of 476 families including 1857 genotyped individuals. We performed SNP and haplotype association analyses in two independent sets of families. For markers and haplotypes found to be consistently associated in both sets, the overall significance was tested using the combined set of families. RESULTS: We identified three SNPs to be associated with schizophrenia in PDE4D (rs1120303, p = 0.021), PDE4B (rs7412571, p = 0.018) and NDEL1 (rs17806986, p = 0.0038). Greater significance was observed with allelic haplotypes of PDE4D (p = 0.00084), PDE4B (p = 0.0022 and p = 0.029) and NDEL1 (p = 0.0027) that increased or decreased schizophrenia susceptibility. CONCLUSIONS: Our findings with other converging lines of evidence support the underlying importance of DISC1-related molecular pathways in the etiology of schizophrenia and other major mental illnesses. Response to Reviewers: Response to reviewers’ comments