Cell-type-specific expression quantitative trait loci associated with Alzheimer disease in blood and brain tissue

Abstract

Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1 Mb of genes was evaluated using linear regression models for unrelated subjects and linear-mixed models for related subjects. Cell-type-specific eQTL (ct-eQTL) models included an interaction term for the expression of "proxy" genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell types is supported by the observation that a large portion of GWS ct-eQTLs map within 1 Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type-specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type-specific analysis.

Fig. 1. Significant gene-SNP eQTLs and ct-eQTLs in blood and brain tissue genome-wide.

A Venn diagram shows the number of overlapping eQTLs and ct-eQTLs in blood and brain. Gold color indicates significant eQTLs that are cell-type-specific. Orange color indicates significant eQTLs that are shared between blood and brain. B Cell-type distributions of significant genome-wide ct-eQTL results in blood and brain.

Fig. 2. Intersection of significant gene-SNP eQTL pairs between cell types in blood and brain tissue.

A Venn diagram showing overlap of ct-eQTL pairs in myeloid cell types (microglia and monocytes/macrophages). B Number of significant eQTLs unique to and that overlap cell types in blood and brain. The bar chart on the left side indicates the number of significant eQTLs involving each cell type and the bar chart above the matrix indicates the number of significant eQTLs that are unique to each cell type and set of cell types. Pink colored bar indicates the number of eQTLs pairs that are unique to microglia and monocytes/macrophages.