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Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation
Open accessAbstract
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.
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“This dataset represents an expansion of previous CSF pQTL work10,16–19 in both sample size (n=3,506) and number of proteins (n=6,361).”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [19]
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“cerebrospinal fluid (CSF) levels of the angiotensin-converting enzyme (ACE) are associated with Aβ levels81 and LOAD risk82, and studies show ACE can inhibit Aβ toxicity and aggregation83.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [82]
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“In a previous GWAS we looked for genetic loci associated with CSF levels of CLU in an overall smaller dataset (n=574) by analyzing each study and performing a meta-analysis, and we found no genome-wide significant associations (Kauwe, et al., 2014)”
From A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin (2016) · cites this paper as Kauwe, et al., 2014
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Metadata
- Authors
- Kauwe, J. S. K., Bailey, M. H., Ridge, P. G., Perry, R., Wadsworth, M. E., Hoyt, K. L., Staley, L. A., Karch, C. M., Harari, O., Cruchaga, C., Ainscough, B. J., Bales, K., Pickering, E. H., Bertelsen, S., Initiative, T. A. D. N., Fagan, A. M., Holtzman, D. M., Morris, J. C., & Goate, A. M.
- Affiliations
- Brigham Young University (US)
- Washington University in St. Louis (US)
- Pfizer (United States) (US)
- Corresponding author
- Goate, Alison M.
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-10-23
- Volume
- 10
- Issue
- 10
- Pages
- e1004758
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4207667
- OpenAlex
- W2028156288
- Cited by
- 125
- References
- 106
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 13 · 2022: 8 · 2021: 16 · 2020: 13 · 2019: 11 · 2018: 9 · 2017: 14 · 2016: 15 · 2015: 7 · 2014: 1
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
- Foundation for the National Institutes of Health (W81XWH-12-2-0012, U01AG024904, Grant U01 AG024904, UL1TR000448, U24 AG021886, AG024904, U01 AG016976, N01-AG-12100)
- Alzheimer's Association (U01 AG016976, U01 AG032984, AG05681, U01 AG024904, ADGC-10–196728, U24AG021886, AG033193, MNIRG-11-205368, W81XWH-12-2-0012)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- University of Southern California (W81XWH-12-2-0012, U01 AG024904)
- BrightFocus Foundation (A2013359S)
- Brigham Young University
- F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Medpace (U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Synarc (U01 AG024904)
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01 AG032984, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- Institute of Clinical and Translational Sciences (UL1TR000448)
- Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
- Wellcome Trust (082604/2/07/Z, 082604, GR082604MA)
- Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease
- Institut National de la Santé et de la Recherche Médicale
- Bundesministerium für Bildung und Forschung (01GI0102, 01GI0711, 01GI0420)
- Erasmus Medisch Centrum
- Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
- Hjartavernd (N01-AG-1-2100)
- Centre hospitalier régional universitaire de Lille
- IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
- National Institutes of Health (n01ag12100-57-0-2, 3u01ag024904-10s2, MNIRG-11-205368, N01-AG-1-2100, W81XWH, UL1TR000448, W81XWH-12-2-0012, NIA AG081220, AG016976, U01-AG024904, AG05681, Grant U01 AG024904, TR000448, AG024904, AG 03991)
- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- University of California, San Diego
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
- Medical Research Council (MR/L501517/1, 503480, U01 AG024904, MR/L010305/1, MR/K013041/1, G0300429)
- National Institute on Aging (U01-AG-024904, AG 016976, R01AG042611, AG03991, W81XWH-12-2–0012, N01-AG12100, R01 AG035053, AG 024904, AG081220, U01AG016976, NIA AG081220, AG 05681, U01AG032984, AG033193, P 50 AG05681, AG026276, AG032984, P50AG005681, P01 AG0 3991, P01AG003991, R01AG033193, AG021886, P01AG026276, U24AG021886)
- National Heart, Lung, and Blood Institute (HL-105756, TR000448, R01HL105756, AG033193)
- National Cancer Institute (T32CA113275)
- National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
- National Center for Advancing Translational Sciences (TR000448)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, cerebrospinal fluid biomarkers, amyloid processing, inflammation, angiotensin-converting enzyme, IL-6 receptor, matrix metalloproteinase-3, MCP-1, carbon tetrachloride, chemokines, single nucleotide polymorphisms, genetic association, endophenotypes, therapeutic target
- MeSH terms
- Alzheimer Disease, Blood Proteins, Female, Humans, Male, Renin, Amyloid beta-Peptides, tau Proteins, Receptors, Lipoprotein, Chemokine CCL2, Matrix Metalloproteinase 3, Receptors, Interleukin-6, Polymorphism, Single Nucleotide, Nerve Growth Factor, Chemokine CCL4, Genome-Wide Association Study
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