Elucidating the relationship between DISC1, NDEL1and NDE1 and the risk for schizophrenia:: Evidence of epistasis and competitive binding

DISC1 influences 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 theNDEL1 gene or the relationship betweenNDEL1 andDISC1 in SZ. We genotyped sixNDEL1 single-nucleotide polymorphisms (SNPs) in 275 Caucasian SZ patients and 200 controls and tested for association and interaction between the functional SNP Ser704Cys inDISC1 andNDEL1. We also evaluated the relationship betweenNDE1 andDISC1 genotype and SZ. Finally, in a series ofin vitro assays, we determined the binding profiles of NDEL1 and NDE1, in relation toDISC1 Ser704Cys. We observed a single haplotype block withinNDEL1; the majority of variation was captured byNDEL1 rs1391768. We observed a significant interaction between rs1391768 andDISC1 Ser704Cys, with the effect ofNDEL1 on SZ evident only against the background ofDISC1 Ser704 homozygosity. Secondary analyses revealed no direct relationship betweenNDE1 genotype and SZ; however, there was an opposite pattern of risk forNDE1 genotype when conditioned onDISC1 Ser704Cys, withNDE1 rs3784859 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 thatNDEL1 significantly influences risk for SZ via an interaction withDISC1. We propose a model where NDEL1 and NDE1 compete for binding with DISC1.