Abstract
Background Amyloid beta (Aβ), phosphorylated tau (p-tau), and total tau (t-tau) in cerebrospinal fluid are established biomarkers for Alzheimer’s disease (AD). In other neurodegenerative diseases, such as Parkinson’s disease (PD), these biomarkers have also been found to be altered, and the molecular mechanisms responsible for these alterations are still under investigation. Moreover, the interplay between these mechanisms and the diverse underlying disease states remains to be elucidated.
Objectives To investigate genetic contributions to the AD biomarkers and assess the commonality and heterogeneity of the associations per underlying disease status.
Methods We conducted GWAS for the AD biomarkers on subjects from the Parkinson’s Progression Markers Initiative (PPMI), the Fox Investigation for New Discovery of Biomarkers (BioFIND), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and meta-analyzed with the largest AD GWAS.[7] We tested heterogeneity of associations of interest between different disease statuses (AD, PD, and control).
Results We observed three GWAS signals: the APOE locus for Aβ, the 3q28 locus between GEMC1 and OSTN for p-tau and t-tau, and the 7p22 locus (top hit: rs60871478, an intronic variant for DNAAF5, also known as HEATR2) for p-tau. The 7p22 locus is novel and co-localized with the brain DNAAF5 expression. While no heterogeneity from underlying disease status was observed for the above GWAS signals, some disease risk loci suggested disease specific associations with these biomarkers.
Conclusions Our study identified a novel association at the intronic region of DNAAF5 associated with increased levels of p-tau across all diseases. We also observed some disease specific genetic associations with these biomarkers.
Competing Interest Statement
M.T., H.L.L., M.A.N. and H.I.′s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Character Bio Inc. and is an advisor to Neuron23 Inc.
Funding Statement
This work was supported by the Center for Alzheimers and Related Dementias, within the Intramural Research Program of the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services. Project numbers Z01-AG000957-19 and Z01-AG000534-03. This work utilized the computational resources of the NIH HPC Biowulf cluster. (http://hpc.nih.gov).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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Data collection and sharing for this project was funded by the Alzheimers Disease Neuroimaging Initiative (ADNI). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimers Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Data used in the preparation of this article were obtained from the Parkinsons Progression Markers Initiative (PPMI) database and BioFIND.
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Footnotes
Updated supplemental table 3 to correct typo.
Data Availability
All data produced in the present study are available upon reasonable request to the authors