Abstract
The use of quantitative endophenotypes in genetic studies may provide greater power, allowing for the use of powerful statistical methods and a biological model for the effects of the disease-associated genetic variation. Cerebrospinal fluid (CSF) amyloid beta (Aβ) levels are promising endophenotypes for late-onset Alzheimer’s disease (LOAD) and show correlation with LOAD status and Aβ deposition. In this study, we investigated 29 single nucleotide polymorphisms (SNPs) positive in AlzGene (http://www.alzgene.org) meta-analyses, for association with CSF Aβ levels in 313 individuals. This study design makes it possible to replicate reported LOAD risk alleles while contributing novel information about the mechanism by which they might affect that risk. Alleles in ACE, APOE, BDNF, DAPK1, and TF are significantly associated with CSF Aβ levels. In vitro analysis of the TF SNP showed a change in secreted Aβ consistent with the CSF phenotype and known Alzheimer’s disease variants, demonstrating the utility of this approach in identifying SNPs that influence risk for disease via an Aβ-related mechanism.
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Acknowledgments
This work was supported by the National Institute on Aging (P50-AG05681, J.C.M.; P01-AG03991, J.C.M.; P01-AG026276, J.C.M.; R01-AG16208, A.M.G.; P30-N5057105, D.M.H.; 1-TL1-RR024995-01 and 1-KL2-RR024994-01, Washington University) the Barnes Jewish Foundation and the American Health Assistance Foundation (A.M.G.). This publication was made possible in part by grant number UL1 RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. J.S.K.K. is a Hope Center Fellow supported by the Hope Center for Neurological Disorders and National Institutes of Health Grant T32 MH14677. The authors gratefully acknowledge the individuals who participated in this study. The authors also acknowledge the contributions of the Genetics, Clinical, Psychometric, and Biostatistics Cores of the Washington University Alzheimer’s Disease Research Center.
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Kauwe, J.S.K., Wang, J., Mayo, K. et al. Alzheimer’s disease risk variants show association with cerebrospinal fluid amyloid beta. Neurogenetics 10, 13–17 (2009). https://doi.org/10.1007/s10048-008-0150-4
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DOI: https://doi.org/10.1007/s10048-008-0150-4