GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.

TitleGWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2013
AuthorsCruchaga, C, Kauwe, JSK, Harari, O, Jin, SChih, Cai, Y, Karch, CM, Benitez, BA, Jeng, AT, Skorupa, T, Carrell, D, Bertelsen, S, Bailey, M, McKean, D, Shulman, JM, De Jager, PL, Chibnik, L, Bennett, DA, Arnold, SE, Harold, D, Sims, R, Gerrish, A, Williams, J, Van Deerlin, VM, Lee, VM-Y, Shaw, LM, Trojanowski, JQ, Haines, JL, Mayeux, R, Pericak-Vance, MA, Farrer, LA, Schellenberg, GD, Peskind, ER, Galasko, D, Fagan, AM, Holtzman, DM, Morris, JC, Goate, AM
Corporate AuthorsGERAD Consortium, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Alzheimer Disease Genetic Consortium (ADGC)
JournalNeuron
Volume78
Issue2
Pagination256-68
Date Published2013 Apr 24
ISSN1097-4199
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Apolipoproteins E, Case-Control Studies, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 6, Female, Genome-Wide Association Study, Genotype, Humans, Male, Membrane Glycoproteins, Middle Aged, Muscle Proteins, Peptide Fragments, Phenotype, Phosphorylation, Polymorphism, Single Nucleotide, Receptors, Immunologic, Risk Factors, Serine, tau Proteins, Transcription Factors
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.

DOI10.1016/j.neuron.2013.02.026
Alternate JournalNeuron
PubMed ID23562540
PubMed Central IDPMC3664945
Grant ListP01 AG05131 / AG / NIA NIH HHS / United States
K01 AG030514 / AG / NIA NIH HHS / United States
MR/K013041/1 / / Medical Research Council / United Kingdom
P50 AG05681 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
K08 AG034290 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 AG042611 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
U19 AG010483 / AG / NIA NIH HHS / United States
G0300429 / / Medical Research Council / United Kingdom
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
P30 NS069329-01 / NS / NINDS NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
G0902227 / / Medical Research Council / United Kingdom
P50 AG005136 / AG / NIA NIH HHS / United States
AG010124 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
AG05136 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R25 DA027995 / DA / NIDA NIH HHS / United States
P30 NS069329 / NS / NINDS NIH HHS / United States
R01 AG16208 / AG / NIA NIH HHS / United States
R01 AG016208 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
R01 AG035083 / AG / NIA NIH HHS / United States