Human Molecular Genetics Advance Access originally published online on May 10, 2008
Human Molecular Genetics 2008 17(16):2462-2473; doi:10.1093/hmg/ddn146
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Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: Evidence of epistasis and competitive binding
1 Department of Psychiatry Research, The Zucker Hillside Hospital, North Shore–Long Island Jewish Health System, Glen Oaks, NY, USA 2 Department of Psychiatry, Albert Einstein College of Medicine, New York, NY, USA 3 The Feinstein Institute for Medical Research, Manhasset, NY, USA 4 Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA 5 Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA 6 Department of Health Chemistry, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan 7 Department of Neuroscience, Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed at: The Zucker Hillside Hospital, North Shore–Long Island Jewish Health System, 75-59 263rd Street, Glen Oaks, NY 11004, USA. Tel: +1 7184708167; Fax: +1 7183431659; Email: kburdick{at}lij.edu
Received February 1, 2008; Accepted May 7, 2008
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 the NDEL1 gene or the relationship between NDEL1 and DISC1 in SZ. We genotyped six NDEL1 single-nucleotide polymorphisms (SNPs) in 275 Caucasian SZ patients and 200 controls and tested for association and interaction between the functional SNP Ser704Cys in DISC1 and NDEL1. We also evaluated the relationship between NDE1 and DISC1 genotype and SZ. Finally, in a series of in vitro assays, we determined the binding profiles of NDEL1 and NDE1, in relation to DISC1 Ser704Cys. We observed a single haplotype block within NDEL1; the majority of variation was captured by NDEL1 rs1391768. We observed a significant interaction between rs1391768 and DISC1 Ser704Cys, with the effect of NDEL1 on SZ evident only against the background of DISC1 Ser704 homozygosity. Secondary analyses revealed no direct relationship between NDE1 genotype and SZ; however, there was an opposite pattern of risk for NDE1 genotype when conditioned on DISC1 Ser704Cys, with NDE1 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 that NDEL1 significantly influences risk for SZ via an interaction with DISC1. We propose a model where NDEL1 and NDE1 compete for binding with DISC1.
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