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、发育和体内平衡中发挥着关键作用。然而，从大量人类中分离出小胶质细胞具有挑战性。在这里，我们分析了从 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异。使用单细胞和大量 RNA 测序，我们确定年龄、性别和临床病理学如何影响小胶质细胞基因表达，以及使用表达数量性状位点 (eQTL) 映射的遗传变异具有小胶质细胞特异性功能。我们使用基于人类诱导多能干细胞的巨噬细胞模型跟进我们的一项发现，以在BIN1处精细定位阿尔茨海默氏病的候选因果变异轨迹。我们的研究提供了一个对人类中枢神经系统发育和疾病至关重要的细胞的群体规模转录图谱。