title: Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease.
abstract: Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants in BIN1, CLU, CR1 and PICALM that show replicable association with risk for disease. We have thoroughly sampled common variation in these genes, genotyping 355 variants in over 600 individuals for whom measurements of two AD biomarkers, cerebrospinal fluid (CSF) 42 amino acid amyloid beta fragments (Aβ(42)) and tau phosphorylated at threonine 181 (ptau(181)), have been obtained. Association analyses were performed to determine whether variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of these biomarkers. Despite adequate power to detect effects as small as a 1.05 fold difference, we have failed to detect evidence for association between SNPs in these genes and CSF Aβ(42) or ptau(181) levels in our sample. Our results suggest that these variants do not affect risk via a mechanism that results in a strong additive effect on CSF levels of Aβ(42) or ptau(181).
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America. kauwe@byu.edu
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.forename: Brooke
authors.initials: B
authors.lastname: Sadler
authors.forename: Mo
authors.initials: M
authors.lastname: Lee
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: Wayne
authors.initials: W
authors.lastname: Latu
authors.forename: Manti
authors.initials: M
authors.lastname: Su'a
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D051152:Clusterin / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017463:Receptors, Complement 3b / Q000235:genetics*; D012694:Serine / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C101410:BIN1 protein, human; D015415:Biomarkers; C495242:CLU protein, human; C509991:CR1 protein, human; D051152:Clusterin; D034041:Monomeric Clathrin Assembly Proteins; D009687:Nuclear Proteins; C439003:PICALM protein, human; D010446:Peptide Fragments; D017463:Receptors, Complement 3b; D025521:Tumor Suppressor Proteins; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D012694:Serine