PMID- 25340798 OWN - NLM STAT- MEDLINE DCOM- 20150630 LR - 20220309 IS - 1553-7404 (Electronic) IS - 1553-7390 (Print) IS - 1553-7390 (Linking) VI - 10 IP - 10 DP - 2014 Oct TI - Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PG - e1004758 LID - 10.1371/journal.pgen.1004758 [doi] LID - e1004758 AB - Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Abeta42) 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. FAU - Kauwe, John S K AU - Kauwe JS AD - Department of Biology, Brigham Young University, Provo, Utah, United States of America. FAU - Bailey, Matthew H AU - Bailey MH AD - Department of Biology, Brigham Young University, Provo, Utah, United States of America. FAU - Ridge, Perry G AU - Ridge PG AD - Department of Biology, Brigham Young University, Provo, Utah, United States of America. FAU - Perry, Rachel AU - Perry R AD - Department of Biology, Brigham Young University, Provo, Utah, United States of America. FAU - Wadsworth, Mark E AU - Wadsworth ME AD - Department of Biology, Brigham Young University, Provo, Utah, United States of America. FAU - Hoyt, Kaitlyn L AU - Hoyt KL AD - Department of Biology, Brigham Young University, Provo, Utah, United States of America. FAU - Staley, Lyndsay A AU - Staley LA AD - Department of Biology, Brigham Young University, Provo, Utah, United States of America. FAU - Karch, Celeste M AU - Karch CM AD - Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America; Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, United States of America. FAU - Harari, Oscar AU - Harari O AD - Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America. FAU - Cruchaga, Carlos AU - Cruchaga C AD - Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America; Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, United States of America. FAU - Ainscough, Benjamin J AU - Ainscough BJ AD - The Genome Institute, Washington University School of Medicine, St Louis, Missouri, United States of America. FAU - Bales, Kelly AU - Bales K AD - Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut, United States of America. FAU - Pickering, Eve H AU - Pickering EH AD - Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut, United States of America. FAU - Bertelsen, Sarah AU - Bertelsen S AD - Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America. CN - Alzheimer's Disease Neuroimaging Initiative FAU - Fagan, Anne M AU - Fagan AM AD - Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, United States of America; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Neurology, Washington University School of Medicine, St Louis, Missouri, United States of America. FAU - Holtzman, David M AU - Holtzman DM AD - Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, United States of America; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Neurology, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri, United States of America. FAU - Morris, John C AU - Morris JC AD - Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, United States of America; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Neurology, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America. FAU - Goate, Alison M AU - Goate AM AD - Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America; Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, United States of America; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Neurology, Washington University School of Medicine, St Louis, Missouri, United States of America; Department of Genetics, Washington University School of Medicine, St Louis, Missouri, United States of America. LA - eng GR - GR082604MA/WT_/Wellcome Trust/United Kingdom GR - G0902227/MRC_/Medical Research Council/United Kingdom GR - U01 AG024904/AG/NIA NIH HHS/United States GR - MR/L010305/1/MRC_/Medical Research Council/United Kingdom GR - P01 AG026276/AG/NIA NIH HHS/United States GR - P01 AG03991/AG/NIA NIH HHS/United States GR - R01 AG033193/AG/NIA NIH HHS/United States GR - U01AG032984/AG/NIA NIH HHS/United States GR - Wellcome Trust/United Kingdom GR - MR/L501517/1/MRC_/Medical Research Council/United Kingdom GR - T32 CA113275/CA/NCI NIH HHS/United States GR - P50 AG05681/AG/NIA NIH HHS/United States GR - U24 AG021886/AG/NIA NIH HHS/United States GR - R01 AG035053/AG/NIA NIH HHS/United States GR - U01 AG032984/AG/NIA NIH HHS/United States GR - R01 AG042611/AG/NIA NIH HHS/United States GR - U01 AG016976/AG/NIA NIH HHS/United States GR - P01 AG003991/AG/NIA NIH HHS/United States GR - P50 AG005681/AG/NIA NIH HHS/United States GR - R01 HL105756/HL/NHLBI NIH HHS/United States GR - MR/K013041/1/MRC_/Medical Research Council/United Kingdom GR - G0300429/MRC_/Medical Research Council/United Kingdom GR - UL1 TR000448/TR/NCATS NIH HHS/United States GR - AG081220/AG/NIA NIH HHS/United States GR - N01-AG-12100/AG/NIA NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141023 PL - United States TA - PLoS Genet JT - PLoS genetics JID - 101239074 RN - 0 (Amyloid beta-Peptides) RN - 0 (Blood Proteins) RN - 0 (CCL2 protein, human) RN - 0 (CCL4 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Chemokine CCL4) RN - 0 (IL6R protein, human) RN - 0 (Receptors, Interleukin-6) RN - 0 (Receptors, Lipoprotein) RN - 0 (tau Proteins) RN - 9061-61-4 (Nerve Growth Factor) RN - EC 3.4.23.15 (Renin) RN - EC 3.4.24.17 (MMP3 protein, human) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM MH - Alzheimer Disease/blood/cerebrospinal fluid/*genetics/pathology MH - Amyloid beta-Peptides/cerebrospinal fluid/*genetics MH - Blood Proteins/genetics MH - Chemokine CCL2/genetics MH - Chemokine CCL4/genetics MH - Female MH - Genome-Wide Association Study MH - Humans MH - Male MH - Matrix Metalloproteinase 3/*genetics MH - Nerve Growth Factor/genetics MH - Polymorphism, Single Nucleotide MH - Receptors, Interleukin-6/genetics MH - Receptors, Lipoprotein/genetics MH - Renin/*genetics MH - tau Proteins/cerebrospinal fluid/genetics PMC - PMC4207667 COIS- EHP and KB are employed by Pfizer Global Research and Development, Groton, CT, and St. Louis, MO and therefore, Pfizer Global played a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript. EDAT- 2014/10/24 06:00 MHDA- 2015/07/01 06:00 PMCR- 2014/10/23 CRDT- 2014/10/24 06:00 PHST- 2014/04/28 00:00 [received] PHST- 2014/09/16 00:00 [accepted] PHST- 2014/10/24 06:00 [entrez] PHST- 2014/10/24 06:00 [pubmed] PHST- 2015/07/01 06:00 [medline] PHST- 2014/10/23 00:00 [pmc-release] AID - PGENETICS-D-14-01136 [pii] AID - 10.1371/journal.pgen.1004758 [doi] PST - epublish SO - PLoS Genet. 2014 Oct 23;10(10):e1004758. doi: 10.1371/journal.pgen.1004758. eCollection 2014 Oct.