Abstract
Late-onset Alzheimer’s disease (LOAD) is known to have a complex, oligogenic etiology, with considerable genetic heterogeneity. We investigated the influence of genetic interactions between genes in the Alzheimer’s disease (AD) pathway on amyloid-beta (Aβ) deposition as measured by PiB or AV-45 ligand positron emission tomography (PET) to aid in understanding LOAD’s genetic etiology. Subsets of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts were used for discovery and for two independent validation analyses. A significant interaction between RYR3 and CACNA1C was confirmed in all three of the independent ADNI datasets. Both genes encode calcium channels expressed in the brain. The results shown here support previous animal studies implicating interactions between these calcium channels in amyloidogenesis and suggest that the pathological cascade of this disease may be modified by interactions in the amyloid–calcium axis. Future work focusing on the mechanisms of such relationships may inform targets for clinical intervention.
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Acknowledgments
This research was supported in part by the Vanderbilt/National Institute of Mental Health Neurogenomics Training grant (T32 MH65215), the Vanderbilt Medical Scientist Training Program (T32 GM07347), and the Recruitment for Genetic Aging Research (P30 AG036445). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We gratefully acknowledge Michael Sivley, Shashwath Meda, and Lan Jiang for programming and scripting help. Data collection and sharing for this project was funded by ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Amorfix Life Sciences Ltd; AstraZeneca; Bayer HealthCare; BioClinica, Inc; Biogen Idec Inc; Bristol-Myers Squibb Company; Eisai Inc; Elan Pharmaceuticals Inc; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; GE Healthcare; Innogenetics, N.V.; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc; Merck & Co, Inc; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc; Servier; Synarc Inc; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation of the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514.
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The authors have no actual or potential conflicts of interest including any financial, personal, or other relationships with other people or organizations that could inappropriately influence (bias) our work.
Ethical standards
The experiments detailed above comply with the current laws of the USA, where they were performed. Appropriate approval and procedures were used concerning human subjects.
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For the Alzheimer’s Disease Neuroimaging Initiative. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data, but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
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Supplementary material 1 Table 1 43 genes from the KEGG AD pathway included in discovery dataset with chromosome number (PDF 319 kb)
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Koran, M.E.I., Hohman, T.J. & Thornton-Wells, T.A. Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography. Hum Genet 133, 85–93 (2014). https://doi.org/10.1007/s00439-013-1354-8
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DOI: https://doi.org/10.1007/s00439-013-1354-8