Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort

Neurology. 2011 Jan 4;76(1):69-79. doi: 10.1212/WNL.0b013e318204a397. Epub 2010 Dec 1.


Objectives: CSF levels of Aβ1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42).

Methods: A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p<0.01 (uncorrected p<3.10×10(-8)) and secondarily examined SNPs with uncorrected p values less than 10(-5) to identify potential candidates.

Results: Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates.

Conclusions: In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.

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
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Amyloid beta-Peptides / genetics*
  • Antigens, Neoplasm / cerebrospinal fluid
  • Antigens, Neoplasm / genetics
  • Apolipoproteins E / genetics
  • Cognition Disorders / cerebrospinal fluid
  • Cognition Disorders / genetics
  • Cognition Disorders / pathology
  • Cohort Studies
  • Diagnostic Imaging
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Male
  • Membrane Transport Proteins / cerebrospinal fluid
  • Membrane Transport Proteins / genetics
  • Peptide Fragments / cerebrospinal fluid*
  • Peptide Fragments / genetics*
  • Phosphorylation
  • Polymorphism, Single Nucleotide / genetics
  • Threonine / metabolism*
  • tau Proteins / cerebrospinal fluid*
  • tau Proteins / genetics*


  • Amyloid beta-Peptides
  • Antigens, Neoplasm
  • Apolipoproteins E
  • Membrane Transport Proteins
  • Peptide Fragments
  • TOMM40 protein, human
  • amyloid beta-protein (1-42)
  • early prostate cancer antigen-2, human
  • tau Proteins
  • Threonine