To date, most expression quantitative trait loci (eQTL) studies, which investigate how genetic variants contribute to gene expression, have been performed in heterogeneous brain tissues rather than specific cell types. In this study, we performed an eQTL analysis using single-nuclei RNA sequencing from 192 individuals in eight brain cell types derived from the prefrontal cortex, temporal cortex and white matter. We identified 7,607 eGenes, a substantial fraction (46%, 3,537/7,607) of which show cell-type-specific effects, with strongest effects in microglia. Cell-type-level eQTLs affected more constrained genes and had larger effect sizes than tissue-level eQTLs. Integration of brain cell type eQTLs with genome-wide association studies (GWAS) revealed novel relationships between expression and disease risk for neuropsychiatric and neurodegenerative diseases. For most GWAS loci, a single gene co-localized in a single cell type, providing new clues into disease etiology. Our findings demonstrate substantial contrast in genetic regulation of gene expression among brain cell types and reveal potential mechanisms by which disease risk genes influence brain disorders.

迄今为止，大多数研究遗传变异如何影响基因表达的表达数量性状位点 (eQTL) 研究都是在异质性脑组织而非特定细胞类型中进行的。在这项研究中，我们使用来自前额皮质、颞叶皮质和白质的八种脑细胞类型的 192 个人的单核 RNA 测序进行了 eQTL 分析。我们确定了 7,607 个 eGenes，其中很大一部分 (46%, 3,537/7,607) 显示出细胞类型特异性效应，在小胶质细胞中的效应最强。与组织水平的 eQTL 相比，细胞类型水平的 eQTL 影响更多的受限基因并且具有更大的效应量。脑细胞类型 eQTL 与全基因组关联研究 (GWAS) 的整合揭示了神经精神疾病和神经退行性疾病的表达与疾病风险之间的新关系。对于大多数 GWAS 基因座，单个基因共定位于单个细胞类型，为疾病病因学提供了新线索。我们的研究结果证明了脑细胞类型之间基因表达的遗传调控存在显着差异，并揭示了疾病风险基因影响脑部疾病的潜在机制。