Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Nat Genet. 2021 Jun;53(6):861-868. doi: 10.1038/s41588-021-00875-2. Epub 2021 Jun 3.
Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.
小胶质细胞是中枢神经系统（CNS）的组织驻留巨噬细胞，在免疫防御、发育和稳态中发挥着关键作用。然而，从大量人群中分离小胶质细胞是具有挑战性的。在这里，我们对从 141 名接受神经外科手术的患者中分离出的原代人小胶质细胞的基因表达变化进行了分析。使用单细胞和批量 RNA 测序，我们确定了年龄、性别和临床病理如何影响小胶质细胞的基因表达，以及使用表达数量性状基因座（eQTL）图谱确定哪些遗传变异具有小胶质细胞特异性功能。我们使用基于人诱导多能干细胞的巨噬细胞模型对我们的一个发现进行了后续研究，以精细映射 BIN1 基因座中阿尔茨海默病的一个候选因果变异。我们的研究提供了一个具有重要意义的人群规模转录图谱，该图谱涉及到人类中枢神经系统发育和疾病的关键细胞。
