APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study.

Quantile-quantile (Q-Q) plot of observed −log10 p-values from the GWAS of cortical Aβ load versus those expected under the null hypothesisThe Q-Q plot exhibits no evidence of genomic inflation (PLINK-calculated λ = 1.00) or population stratification in the GWAS. An additive genetic model was used and age, gender, and diagnosis were applied as covariates. Analyses were restricted to subjects with non-Hispanic Caucasian (CEU or TSI) ancestry as determined by genetic clustering. Observed −log10 p-values > 8 are represented along the top of the plot as red triangles, while all other values are represented as red dots.

Manhattan plot of observed −log10 p-values from the GWAS of cortical Aβ loadMore than six million SNPs were tested for association to global cortical Aβ burden under an additive genetic model and applying age, gender, and diagnosis as covariates. Genome-wide significant associations (exceeding the threshold represented by the red line) were identified on chromosome 19 within APOE and its neighboring genes and on chromosome 3 at the BCHE locus. Suggestive associations (exceeding the threshold represented by the blue line) were identified on five additional chromosomes. Annotations are provided for genome-wide significant associations and for the top three suggestive associations.

Regional association plots for the loci exhibiting genome-wide significant association to cortical Aβ burdenMagnified association plots are displayed for the regions around A) rs429358 within APOE and B) rs509208 at the BCHE locus. SNPs are plotted based on their GWAS −log10 p-values (left vertical axis) and their genomic position (NCBI build 36). Genes in these regions are labeled with arrows denoting their 5′-to-3′ orientation, and the red color scale of r2 values is used to label SNPs based on their degree of linkage disequilibrium with the annotated peak SNP. Recombination rates calculated from 1000 Genomes Project reference data are also displayed in a blue line corresponding to the right vertical axis.

APOE ε4 and rs509208 (BCHE) appear to exhibit independent, additive effects on cortical Aβ levelsMean cortical Aβ levels (adjusted for age, gender, and diagnosis) ± standard errors are displayed based on A) the number of APOE ε4 allele copies and B) rs509208 genotype. Presence of at least one copy of the ε4 allele was significantly associated with increased Aβ burden (Cohen’s d = 0.71), as was presence of at least one copy of the minor allele (G) of rs509208 (Cohen’s d = 0.52). These loci appeared to exert additive effects on Aβ levels (panel C): subjects having both risk factors exhibited significantly greater Aβ burden than subjects having either factor in isolation, and no significant epistasis modeled as an interaction was identified.