Genome-wide association reveals genetic effects on human Aβ42 and τ protein levels in cerebrospinal fluids: a case control study

Abstract

Background: Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI) and AD in terms of changes in cerebrospinal fluid (CSF) levels of Aβ1-42, T-tau, and P-tau181P, have not been clearly delineated. We carried out a genome-wide association study (GWAS) in order to better define the genetic backgrounds to these three states in relation to CSF levels.

Methods: Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The GWAS dataset consisted of 818 participants (mainly Caucasian) genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD) with measurements of CSF Aβ1-42, T-tau, and P-tau181P Levels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software.

Results: We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Aβ1-42 levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. CYP19A1 'aromatase' (rs2899472), NCAM2, and multiple SNPs located on chromosome 10 near the ARL5B gene demonstrated the strongest associations with Aβ1-42 in normal subjects. Two genes found to be near the top SNPs, CYP19A1 (rs2899472, p = 1.90 × 10(-7)) and NCAM2 (rs1022442, p = 2.75 × 10(-7)) have been reported as genetic factors related to the progression of AD from previous studies. In AD subjects, APOE ε2/ε3 and ε2/ε4 genotypes were associated with elevated T-tau levels and ε4/ε4 genotype was associated with elevated T-tau and P-tau181P levels. Pathway analysis detected several biological pathways implicated in Normal with CSF β-amyloid peptide (Aβ1-42).

Conclusions: Our genome-wide association analysis identified several SNPs as important factors for CSF biomarker. We also provide new evidence for additional candidate genetic risk factors from pathway analysis that can be tested in further studies.

Figure 1

Manhattan plots of the quantitative trait (CSF biomarkers: T-tau, P-tau_181P and Aβ_1-42) genome wide association analysis in normal subjects. Colors on x-axis indicate an autosomal chromosome (from chromosome 1 to chromosome 22). The y-axis indicates p-values (-log₁₀(observed p-values)). Red arrows indicate rs2899472 on chromosome 15 and blue arrow indicates rs1022442 on chromosome 21.

Figure 2

Manhattan plots of the quantitative trait (CSF biomarkers: T-tau, P-tau_181P and Aβ_1-42) genome wide association analysis in MCI subjects. Colors on x-axis indicate an autosomal chromosome (from chromosome 1 to chromosome 22). The y-axis indicates p-values (-log₁₀(observed p-values)).

Figure 3

Manhattan plots of the quantitative trait (CSF biomarkers: T-tau, P-tau_181P and Aβ_1-42) genome wide association analysis in AD subjects. Colors on x-axis indicate an autosomal chromosome (from chromosome 1 to chromosome 22). The y-axis indicates p-values (-log₁₀(observed p-values)).

Figure 4

Upper image shows genes in linkage disequilibrium with the SNP rs1022442 and lower plot shows the distribution of SNP rs1022442 and nearby SNPs. In lower plot, the x-axis indicates loci on chromosome 21 and y-axis indicates p-values (-log₁₀(observed GENO_2DF p-values)). Green arrow indicates rs1022442 (p = 2.75 × 10^-7) on loci 21277717 and pink arrow indicates rs2826629 (p = 8.40 × 10^-5) on loci 21265887.

Figure 5

Boxplots of Aβ_1-42 levels in normal, MCI and AD subjects stratified by rs1022442 genotype. The x-axis indicates AA, AB and BB respectively.

Figure 6

Boxplots of the APOE ε4 copy number with CSF biomarkers in normal, MCI and AD subjects. The x-axis indicates number of APOE ε4 alleles and y-axis indicates CSF biomarkers. P-values are produced by the Kruskal-Wallis test.

Figure 7

Boxplots of the APOE genotype with CSF biomarkers in normal, MCI and AD subjects. The x-axis indicates five different APOE genotypes and y-axis indicates CSF biomarkers. P-values are produced by the Kruskal-Wallis test.