Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB168, Boston, MA 02115, USA.
Sci Transl Med. 2017 Dec 20;9(421). doi: 10.1126/scitranslmed.aai7635.
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 (, , , , , and ) in which the risk haplotype drives the association with both disease susceptibility and altered expression of a nearby gene (cis-eQTL). In the and 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 and , and we confirmed that the risk haplotype altered phagocytosis by the MDMi cells. We propose that increased gene expression by MDMi cells could be a functional outcome of , a single-nucleotide polymorphism in the locus that is associated with Parkinson's disease.
小胶质细胞在神经退行性疾病中作为一种关键细胞类型而出现，但人类小胶质细胞在体外研究中具有挑战性。我们开发了一种由人单核细胞来源的小胶质样（MDMi）细胞组成的体外细胞模型系统，该系统再现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对与阿尔茨海默病、帕金森病和多发性硬化症相关的 94 个基因进行了表达数量性状基因座（eQTL）研究。我们发现了六个基因座（，，，，，和），其中风险单倍型与疾病易感性和附近基因表达的改变（顺式-eQTL）相关。在和基因座中，顺式-eQTL 存在于 MDMi 细胞中，但不存在于人类外周血单核细胞中，这表明单核细胞分化为小胶质样细胞导致了细胞状态的获得，这种细胞状态可能揭示了某些遗传变异的功能后果。我们进一步在蛋白水平上验证了和基因座风险单倍型的效应，我们证实了风险单倍型改变了 MDMi 细胞的吞噬作用。我们提出，MDMi 细胞中基因表达的增加可能是帕金森病相关基因座中单核苷酸多态性的功能结果。
