title: Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.
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.
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Bailey
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Perry G
authors.initials: PG
authors.lastname: Ridge
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Perry
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wadsworth
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Kaitlyn L
authors.initials: KL
authors.lastname: Hoyt
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America.
authors.forename: Lyndsay A
authors.initials: LA
authors.lastname: Staley
authors.affiliation: 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.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Oscar
authors.initials: O
authors.lastname: Harari
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: The Genome Institute, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Ainscough
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Bales
authors.affiliation: Neuroscience Research Unit, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut, United States of America.
authors.forename: Eve H
authors.initials: EH
authors.lastname: Pickering
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.affiliation: 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.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: 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.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: 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.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000235:genetics*; D001798:Blood Proteins / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics; D054407:Chemokine CCL4 / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D020932:Nerve Growth Factor / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000235:genetics; D012083:Renin / Q000235:genetics*; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D001798:Blood Proteins; C111835:CCL2 protein, human; C066507:CCL4 protein, human; D018932:Chemokine CCL2; D054407:Chemokine CCL4; C508603:IL6R protein, human; D019947:Receptors, Interleukin-6; D018110:Receptors, Lipoprotein; D016875:tau Proteins; D020932:Nerve Growth Factor; D012083:Renin; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3