title: GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.
abstract: Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ₄₂ are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10⁻⁹ for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10⁻⁸ and p = 3.22 × 10⁻⁹ for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10⁻⁸ for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10⁻⁴, 0.039, 4.86 × 10⁻⁵, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Oscar
authors.initials: O
authors.lastname: Harari
authors.forename: Sheng Chih
authors.initials: SC
authors.lastname: Jin
authors.forename: Yefei
authors.initials: Y
authors.lastname: Cai
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.forename: Amanda T
authors.initials: AT
authors.lastname: Jeng
authors.forename: Tara
authors.initials: T
authors.lastname: Skorupa
authors.forename: David
authors.initials: D
authors.lastname: Carrell
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Matthew
authors.initials: M
authors.lastname: Bailey
authors.forename: David
authors.initials: D
authors.lastname: McKean
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Lori
authors.initials: L
authors.lastname: Chibnik
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Steve E
authors.initials: SE
authors.lastname: Arnold
authors.forename: Denise
authors.initials: D
authors.lastname: Harold
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sims
authors.forename: Amy
authors.initials: A
authors.lastname: Gerrish
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.forename: Douglas
authors.initials: D
authors.lastname: Galasko
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: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010641:Phenotype; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics; D012097:Repressor Proteins; D012307:Risk Factors; D012694:Serine / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; C512851:GLIS3 protein, human; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; C480236:OSTN protein, human; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D012097:Repressor Proteins; C498715:TREM2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D012694:Serine
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