Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.

TitleGenome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.
Publication TypeJournal Article
Year of Publication2014
AuthorsKauwe, JSK, Bailey, MH, Ridge, PG, Perry, R, Wadsworth, ME, Hoyt, KL, Staley, LA, Karch, CM, Harari, O, Cruchaga, C, Ainscough, BJ, Bales, K, Pickering, EH, Bertelsen, S, Fagan, AM, Holtzman, DM, Morris, JC, Goate, AM
Corporate AuthorsAlzheimer's Disease Neuroimaging Initiative
JournalPLoS Genet
Volume10
Issue10
Paginatione1004758
Date Published2014 Oct
ISSN1553-7404
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Blood Proteins, Chemokine CCL2, Chemokine CCL4, Female, Genome-Wide Association Study, Humans, Male, Matrix Metalloproteinase 3, Nerve Growth Factor, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Receptors, Lipoprotein, Renin, tau Proteins
Abstract

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.

DOI10.1371/journal.pgen.1004758
Alternate JournalPLoS Genet.
PubMed ID25340798
PubMed Central IDPMC4207667
Grant ListMR/K013041/1 / / Medical Research Council / United Kingdom
T32 CA113275 / CA / NCI NIH HHS / United States
P50 AG05681 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG035053 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 AG042611 / AG / NIA NIH HHS / United States
G0300429 / / Medical Research Council / United Kingdom
U01 AG016976 / AG / NIA NIH HHS / United States
GR082604MA / / Wellcome Trust / United Kingdom
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
G0902227 / / Medical Research Council / United Kingdom
MR/L501517/1 / / Medical Research Council / United Kingdom
U01AG032984 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
AG081220 / AG / NIA NIH HHS / United States
N01-AG-12100 / AG / NIA NIH HHS / United States
MR/L010305/1 / / Medical Research Council / United Kingdom