Microglia are emerging as a key cell type in neurodegenerative diseases, yet human microglia are challenging to study in vitro. We developed an in vitro cell model system composed of human monocyte-derived microglia-like (MDMi) cells that recapitulated key aspects of microglia phenotype and function. We then used this model system to perform an expression quantitative trait locus (eQTL) study examining 94 genes from loci associated with Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. We found six loci (CD33, PILRB, NUP160, LRRK2, RGS1, and METTL21B) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL). In the PILRB and LRRK2 loci, the cis-eQTL was found in the MDMi cells but not in human peripheral blood monocytes, suggesting that differentiation of monocytes into microglia-like cells led to the acquisition of a cellular state that could reveal the functional consequences of certain genetic variants. We further validated the effect of risk haplotypes at the protein level for PILRB and CD33, and we confirmed that the CD33 risk haplotype altered phagocytosis by the MDMi cells. We propose that increased LRRK2 gene expression by MDMi cells could be a functional outcome of rs76904798, a single-nucleotide polymorphism in the LRKK2 locus that is associated with Parkinson’s disease.

小胶质细胞正在成为神经退行性疾病中的关键细胞类型，但是人类小胶质细胞在体外研究方面具有挑战性。我们开发了由人类单核细胞衍生的小胶质细胞样（MDMi）细胞组成的体外细胞模型系统，该系统概括了小胶质细胞表型和功能的关键方面。然后，我们使用该模型系统进行表达定量性状基因座（eQTL）研究，检查来自与阿尔茨海默氏病，帕金森氏病和多发性硬化症相关的基因座的94个基因。我们发现6个位点（CD33，PILRB，NUP160，LRRK2，RGS1和METTL21B），其中风险单倍型既与疾病易感性相关，又与附近基因（cis-eQTL）的表达改变相关。在PILRB和LRRK2基因座中，在MDMi细胞中发现了cis-eQTL，而在人类外周血单核细胞中却没有，这表明单核细胞分化为小胶质细胞后会导致细胞状态的获得，从而揭示了功能性后果。某些遗传变异。我们进一步验证了PILRB和CD33在蛋白质水平上的风险单倍型的作用，并且我们确认CD33风险单倍型改变了MDMi细胞的吞噬作用。我们建议增加LRRK2通过MDMI细胞中基因表达可能是的功能结果rs76904798，在一个单核苷酸多态性LRKK2基因座，其与帕金森病相关。