Cell‐type specific eQTLs (ct‐eQTLs) associated with Alzheimer disease in blood and brain tissue

Abstract

AbstractBackgroundExpression quantitative trait locus(eQTL) analysis has demonstrated that changes in gene expression play a role in Alzheimer disease(AD) pathogenesis. Regulation of gene expression is dependent on context such as tissue and cell‐type. Previous studies found monocyte‐specific eQTLs among AD variants.MethodCis‐eQTL mapping was performed for 723 genes located within 1 Mb of 79 AD‐associated loci in RNA‐seq data in blood from Framingham Heart Study (FHS) participants and in brain tissue from Religious Orders Study/Memory & Aging Project(ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within these genes was evaluated using linear regression models for ROSMAP and linear mixed models adjusting for family structure in FHS. Models testing associations with cell type‐specific eQTLs (ct‐eQTLs) included an interaction term for expression of “proxy” genes that discriminate the particular cell type.ResultA total of 10,970 eQTLs and 1,324 ct‐eQTLs in brain, and 29,508 eQTLs and 2,313 ct‐eQTLs in blood were nominally significant after Bonferroni correction. Ct‐eQTL analysis identified 964 and 44 significant gene‐SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 760 gene‐SNP eQTL pairs were shared between blood and brain and are enriched in AD‐related immune pathways. Among the significant ct‐eQTLs, the most frequent cell types were interferon response/antibacterial cells in blood(70.6%) and endothelial cells in brain(35.5%). Established AD genes CD2AP and NCR2 had a large number of significant eQTLs in NK/ CD8+T cells in blood and brain endothelial cells respectively. In addition, several significant eSNPs were observed for novel genes under linkage analysis peaks spanning multiple genes. The eGene target for one of these AD peak eSNPs, rs2985987, is COG3 is involved in ER‐Golgi transport, a key AD‐related pathway. Furthermore, many novel variants and genes were identified among the significant eQTLs that target previously associated AD genes or associate with AD peak SNPs. Target eGenes associated with AD peak eSNPs include TAS2R60, PILRB, CNN2‐ previously implicated in AD in a targeted gene sequencing study in African Americans, HLA‐DQA2, and MS4A5.ConclusionWe identified novel AD‐related ct‐eQTLs that highlight the importance of cell‐type specific analysis and cell‐type dependent context.