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Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer's and Parkinson's disease

2007-11-26, Li, Yonghong, Grupe, Andrew, Rowland, Charles, Holmans, Peter, Segurado, Ricardo, Abraham, Richard, Jones, Lesley, Catanese, Joseph, Ross, David, Mayo, Kevin, Martinez, Maribel, Hollingworth, Paul, Goate, Alison, Cairns, Nigel J., Racette, Brad A., Perlmutter, Joel S., O'Donovan, Michael C., Morris, John C., Brayne, Carol, Rubinsztein, David C., Lovestone, Simon, Thal, Leon J., Owen, Michael J., Williams, Julie

Late-onset Alzheimer's disease (LOAD) and Parkinson's disease (PD) are the most common neurodegenerative disorders and in both diseases susceptibility is known to be influenced by genes. We set out to identify novel susceptibility genes for LOAD by performing a large scale, multi-tiered association study testing 4692 single nucleotide polymorphism (SNPs). We identified a SNP within a putative transcription factor binding site in the NEDD9 gene (neural precursor cell expressed, developmentally down-regulated), that shows good evidence of association with disease risk in four out of five LOAD samples [N = 3521, P = 5.38x10(-6), odds ratio (OR) = 1.38 (1.20-1.59)] and in addition, we observed a similar pattern of association in two PD sample sets [N = 1464, P = 0.0145, OR =1.31 (1.05-1.62)]. In exploring a potential mechanism for the association, we observed that expression of NEDD9 and APOE show a strong inverse correlation in the hippocampus of Alzheimer's cases. These data implicate NEDD9 as a novel susceptibility gene for LOAD and possibly PD.