Allele-specific analysis reveals exon- and cell-type-specific regulatory effects of Alzheimer’s disease-associated genetic variants

Elucidating regulatory effects of Alzheimer’s disease (AD)-associated genetic variants is critical for unraveling their causal pathways and understanding the pathology. However, their cell-type-specific regulatory mechanisms in the brain remain largely unclear. Here, we conducted an analysis of allele-specific expression quantitative trait loci (aseQTLs) for 33 AD-associated variants in four brain regions and seven cell types using ~3000 bulk RNA-seq samples and >0.25 million single nuclei. We first develop a flexible hierarchical Poisson mixed model (HPMM) and demonstrate its superior statistical power to a beta-binomial model achieved by unifying samples in both allelic and genotype-level expression data. Using the HPMM, we identified 24 (~73%) aseQTLs in at least one brain region, including three new eQTLs associated with CA12 , CHRNE , and CASS4 . Notably, the APOE ε4 variant reduces APOE expression across all regions, even in AD-unaffected controls. Our results reveal region-dependent and exon-specific effects of multiple aseQTLs, such as rs2093760 with CR1 , rs7982 with CLU , and rs3865444 with CD33 . In an attempt to pinpoint the cell types responsible for the observed tissue-level aseQTLs using the snRNA-seq data, we detected many aseQTLs in microglia or monocytes associated with immune-related genes, including HLA-DQB1 , HLA-DQA2 , CD33 , FCER1G , MS4A6A , SPI1 , and BIN1 , highlighting the regulatory role of AD-associated variants in the immune response. These findings provide further insights into potential causal pathways and cell types mediating the effects of the AD-associated variants.