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

Abstract

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.

Figure 1. Manhattan plot (A) and quantile-quantile plot (B) of total tau

Genomic inflation factor (based on median χ²) is 1.01. In the Manhattan plot, the blue and red lines represent the −log₁₀(10⁻⁶) and −log₁₀(3.10 × 10⁻⁸) threshold levels.

Figure 2. Linkage disequilibrium (LD) among single nucleotide polymorphisms (SNPs) in the region of EPC2 at chromosome 2q23.1

LD plot, showing D′, was created by Haploview v4.2 on chromosome 2 (149095–149295 kb, HapMap v3.0 release 27 panel CEU). SNPs, highlighted by blue, pink, and cyan rectangles, were at uncorrected p values less than 3.1 × 10⁻⁸, 10⁻⁶, 10⁻⁵.

Figure 3. Mean CSF biomarker levels as a function of baseline diagnosis and genotype

Mean and standard errors of amyloid-β 1-42 peptide (Aβ_1-42) and total tau (t-tau) are shown for groups defined by baseline diagnosis and associated single nucleotide polymorphisms reaching genome-wide significance. Baseline Aβ_1-42 CSF level by diagnosis group and genotype: (A) TOMM40 (rs2075650), (B) APOE (rs429358), (C) LOC100129500 (rs439401), (D) EPC2 (rs4499362). AD = Alzheimer disease; HC = healthy controls; MCI = mild cognitive impairment.