Abstract
The abnormal deposition of amyloid-β protein in the brain plays an important role in Alzheimer’s disease (AD), being considered a potential clinical biomarker. To investigate genetic associations with amyloid-β we used biomarker data and genome-wide variants from individuals with AD and mild cognitive impairment in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We used a standard linear model and retested the associations with a mixed linear model to correct the residual sample structure. Both methods’ results showed two identical significant SNPs associated with the A β-42 levels in CSF (rs2075650 at intron region TOMM40 with p-value ≥ 1 × 10–16 and rs439401 in the intergenic region of LOC100129500 and APOC1 with p-value ≥ 1 × 10-9) and highlighted APOC1 and TOMM40, which are well-known genes previously associated with AD. Extending our analysis, we considered possible candidate genes mapped to SNPs with p-value ≥ 1 × 10-6 to explore gene-set enrichment e gene-gene network analysis, which reveals genes related to synaptic transmission, transmission of nerve impulses, cell-cell signaling and neurological processes. These genes require fine mapping and replication studies to allow more detailed understanding of how they may contribute to the genetic architecture of AD.
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Acknowledgments
Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: Abbott; the Alzheimer’s Association; the Alzheimer’s Drug Discovery Foundation; Amorfix Life Sciences, Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec, Inc.; Bristol-Myers Squibb Co.; Eisai, Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Co.; 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 Corp.; Pfizer, Inc.; Servier; Synarc, Inc.; Takeda Pharmaceutical Co. The Canadian Institutes of Health Research is providing funds to support the ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for 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 Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514.
This study received financial support from the following academic bureaus and Brazilian funding agencies: Centro de Informática-CIN, LIKA-JIKA, UFPE, FACEPE and CNPq.
IG Costa acknowledges fundings received from Interdisciplinary Center for Clinical Research (IZKF) Medical Faculty RWTH Aachen.
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Data used in the 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 its design and implementation and/or provided data but did not participate in the analysis or writing of this report. A complete listing of the ADNI investigators can be found at: http://adni.loni.ucla.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
M. B. R. Souza and G. S. Araújo contributed equally to this work.
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Souza, M.B.R., Araújo, G.S., Costa, I.G. et al. Combined Genome-Wide CSF Aβ-42’s Associations and Simple Network Properties Highlight New Risk Factors for Alzheimer’s Disease. J Mol Neurosci 58, 120–128 (2016). https://doi.org/10.1007/s12031-015-0667-6
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DOI: https://doi.org/10.1007/s12031-015-0667-6