Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease. Genetic studies involving genome-wide association studies (GWAS) and meta-analysis have discovered numerous genomic loci associated with AD; however, the causal genes and variants remain unidentified in most loci. Integration of GWAS signals with epigenomic annotations has demonstrated that AD risk variants are enriched in myeloid-specific enhancers, implicating myeloid cells in AD etiology. AD risk variants in these regulatory elements modify disease susceptibility by regulating the expression of genes that play crucial roles in microglial phagocytosis. Several of these AD risk genes are specifically expressed in myeloid cells, whereas others are ubiquitously expressed but are regulated by AD risk variants within myeloid enhancers in a cell type-specific manner. We discuss the impact of established AD risk variants on microglial phagocytosis and debris processing via the endolysosomal system.

中文翻译：

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小胶质细胞吞噬作用：阿尔茨海默病遗传学中出现的疾病相关过程

阿尔茨海默病 (AD) 是一种使人衰弱的慢性神经退行性疾病。涉及全基因组关联研究 (GWAS) 和荟萃分析的遗传学研究发现了许多与 AD 相关的基因组位点；然而，在大多数基因座中，致病基因和变异仍然无法识别。GWAS 信号与表观基因组注释的整合表明，AD 风险变异富含骨髓特异性增强子，表明骨髓细胞与 AD 病因有关。这些调节元件中的 AD 风险变异通过调节在小胶质细胞吞噬作用中起关键作用的基因的表达来改变疾病易感性。这些 AD 风险基因中有几个在骨髓细胞中特异性表达，而另一些则普遍表达，但受骨髓增强子内的 AD 风险变异体以细胞类型特异性方式调节。