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DISC1influences susceptibility to psychiatric disease and related phenotypes. Intact functions of DISC1 and its binding partners, NDEL1 and NDE1, are critical to neurodevelopmental processes aberrant in schizophrenia (SZ). Despite evidence of an NDEL1–DISC1 protein interaction, there have been no investigations of theNDEL1gene or the relationship betweenNDEL1andDISC1in SZ. We genotyped sixNDEL1single-nucleotide polymorphisms (SNPs) in 275 Caucasian SZ patients and 200 controls and tested for association and interaction between the functional SNP Ser704Cys inDISC1andNDEL1. We also evaluated the relationship betweenNDE1andDISC1genotype and SZ. Finally, in a series ofin vitroassays, we determined the binding profiles of NDEL1 and NDE1, in relation toDISC1Ser704Cys. We observed a single haplotype block withinNDEL1; the majority of variation was captured byNDEL1rs1391768. We observed a significant interaction between rs1391768 andDISC1Ser704Cys, with the effect ofNDEL1on SZ evident only against the background ofDISC1Ser704 homozygosity. Secondary analyses revealed no direct relationship betweenNDE1genotype and SZ; however, there was an opposite pattern of risk forNDE1genotype when conditioned onDISC1Ser704Cys, withNDE1rs3784859 imparting a significant effect but only in the context of a Cys-carrying background. In addition, we report opposing binding patterns of NDEL1 and NDE1 to Ser704 versus Cys704, at the same DISC1 binding domain. These data suggest thatNDEL1significantly influences risk for SZ via an interaction withDISC1. We propose a model where NDEL1 and NDE1 compete for binding with DISC1.

human molecular genetics

Elucidating the relationship between               DISC1, NDEL1               and               NDE1               and the risk for schizophrenia: Evidence of epistasis and competitive binding