期刊
PLOS GENETICS
卷 10, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004758
关键词
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资金
- Pfizer
- NIH [R01 AG035053, R01 AG042611, P50 AG05681, P01 AG03991, P01 AG026276, U01AG032984]
- Alzheimer's Association [MNIRG-11-205368, ADGC-10-196728]
- Brigham Young University Gerontology Program
- BrightFocus Foundation Alzheimer's Disease Research Grant [A2013359S]
- Washington University Institute of Clinical and Translational Sciences from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) [UL1 TR000448]
- French National Foundation on Alzheimer's disease and related disorders
- LABEX (laboratory of excellence program investment for the future) DISTALZ grant
- Inserm
- Institut Pasteur de Lille
- Universite de Lille 2
- Lille University Hospital
- Medical Research Council [503480, G0300429]
- Alzheimer's Research UK [503176]
- Wellcome Trust [082604/2/07/Z, GR082604MA]
- German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01GI0102, 01GI0711, 01GI0420]
- NIH/NIA [R01 AG033193, U01 AG032984, U24 AG021886, U01 AG016976]
- NIA [AG081220]
- AGES [N01-AG-12100]
- NHLBI [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center
- Erasmus University
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Canadian Institutes of Health Research
- MRC [G0902227, MR/K013041/1, G0300429] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PG2014-1] Funding Source: researchfish
- Medical Research Council [MR/L010305/1, MR/L501517/1, G0300429, MR/K013041/1, G0902227] Funding Source: researchfish
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (A beta 42) 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 < 1.46x10(-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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