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Background Microglia play a central role in Alzheimer's disease (AD) pathogenesis, yet it remains unclear whether microglia-related gene expression changes contribute causally to disease risk or reflect downstream responses to neurodegeneration. Objective This study aimed to systematically identify microglia-expressed genes with genetically regulated expression associated with AD risk and to characterize their functional relevance through integrative genomic analyses. Methods We compiled 2454 microglia-associated genes from four transcriptomic studies and five expression databases. Using brain cis-eQTL data from PsychENCODE (n = 1387), we performed summary-data-based Mendelian randomization (SMR) and HEIDI tests with AD GWAS data (111,326 cases, 677,663 controls). Significant SMR signals (FDR 0.8; e.g., BLNK , SIGLEC11 , CASS4 ). Most prioritized genes overlapped with PU.1-associated regulatory regions. Single-nucleus RNA-seq confirmed dysregulation of several candidates (e.g., USP6NL , MS4A4A ) in AD microglia. Conclusions We identify microglia-expressed genes with genetic evidence consistent with a potential causal role in AD. These genes are enriched in microglia-specific regulatory elements and exhibit transcriptional alterations in AD, highlighting microglial pathways as potential therapeutic targets.
Zhao et al. (Tue,) studied this question.