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

Neuron. 2013 Apr 24;78(2):256-68. doi: 10.1016/j.neuron.2013.02.026. Epub 2013 Apr 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Apolipoproteins E / genetics
  • Case-Control Studies
  • Chromosomes, Human, Pair 3 / genetics
  • Chromosomes, Human, Pair 6 / genetics
  • DNA-Binding Proteins
  • Female
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Male
  • Membrane Glycoproteins / genetics
  • Middle Aged
  • Muscle Proteins / genetics
  • Peptide Fragments / cerebrospinal fluid
  • Phenotype
  • Phosphorylation
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Immunologic / genetics
  • Repressor Proteins
  • Risk Factors
  • Serine / metabolism
  • Trans-Activators
  • Transcription Factors / genetics
  • tau Proteins / cerebrospinal fluid*

Substances

  • Amyloid beta-Peptides
  • Apolipoproteins E
  • DNA-Binding Proteins
  • GLIS3 protein, human
  • Membrane Glycoproteins
  • Muscle Proteins
  • OSTN protein, human
  • Peptide Fragments
  • Receptors, Immunologic
  • Repressor Proteins
  • TREM2 protein, human
  • Trans-Activators
  • Transcription Factors
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Serine

Grant support