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人类小胶质细胞转录组在大脑区域、衰老和疾病病理方面的遗传分析。

Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies.

机构信息

Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

出版信息

Nat Genet. 2022 Jan;54(1):4-17. doi: 10.1038/s41588-021-00976-y. Epub 2022 Jan 6.

DOI:10.1038/s41588-021-00976-y
PMID:34992268
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9245609/
Abstract

Microglia have emerged as important players in brain aging and pathology. To understand how genetic risk for neurological and psychiatric disorders is related to microglial function, large transcriptome studies are essential. Here we describe the transcriptome analysis of 255 primary human microglial samples isolated at autopsy from multiple brain regions of 100 individuals. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region and aging. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, finding associations with microglial expression of USP6NL for Alzheimer's disease and P2RY12 for Parkinson's disease. We have built the most comprehensive catalog to date of genetic effects on the microglial transcriptome and propose candidate functional variants in neurological and psychiatric disorders.

摘要

小胶质细胞已成为大脑衰老和病理学的重要参与者。为了了解神经和精神疾病的遗传风险与小胶质细胞功能的关系，进行大规模转录组研究至关重要。在这里，我们描述了对 255 个人的 100 个人的多个大脑区域的尸检中分离的 255 个人类原代小胶质细胞样本的转录组分析。我们进行了系统分析，以研究小胶质细胞异质性的各个方面，包括大脑区域和衰老。我们绘制了表达和剪接数量性状基因座图谱，并表明许多神经疾病易感性基因座是通过小胶质细胞中的基因表达或剪接来介导的。对这些基因座的精细定位提名了候选因果变异，这些变异位于小胶质细胞特异性增强子内，与阿尔茨海默病的 USP6NL 和帕金森病的 P2RY12 与小胶质细胞表达相关。我们构建了迄今为止最全面的遗传对小胶质细胞转录组影响的目录，并提出了神经和精神疾病的候选功能变异。

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