小柯机器人

近日，瑞士罗氏公司Dheeraj Malhotra、Julien Bryois等研究人员合作发现，八种人脑细胞类型中的细胞类型特异性顺式eQTL可识别精神和神经疾病的新风险基因。这一研究成果发表在2022年8月1日出版的国际学术期刊《自然—神经科学》上。

研究人员使用单核RNA测序对192名个体进行了定量性状位点（eQTL）分析，这些个体的8种脑细胞类型来自于前额叶皮层、颞叶皮层和白质。研究人员确定了7,607个eGene，其中相当一部分（46%，3,537/7,607）显示出细胞类型的特异性影响，对小胶质细胞的影响最强。细胞类型的eQTL影响了更多的限制性基因，并且比组织层面的eQTL具有更大的效应尺寸。

将脑细胞类型eQTL与全基因组关联研究（GWAS）相结合，揭示了神经精神疾病和神经退行性疾病的表达和疾病风险之间的新关系。对于大多数GWAS位点，单一基因在单一细胞类型中共同定位，为疾病病因学提供了新的线索。这项发现显示了脑细胞类型之间基因表达的遗传调控的巨大反差，并揭示了疾病风险基因影响大脑疾病的潜在机制。

据悉，迄今为止，大多数eQTL研究，即研究遗传变异如何促进基因表达，都是在异质性脑组织而非特定细胞类型中进行的。

附：英文原文

Title: Cell-type-specific cis-eQTLs in eight human brain cell types identify novel risk genes for psychiatric and neurological disorders

Author: Bryois, Julien, Calini, Daniela, Macnair, Will, Foo, Lynette, Urich, Eduard, Ortmann, Ward, Iglesias, Victor Alejandro, Selvaraj, Suresh, Nutma, Erik, Marzin, Manuel, Amor, Sandra, Williams, Anna, Castelo-Branco, Gonalo, Menon, Vilas, De Jager, Philip, Malhotra, Dheeraj

Issue&Volume: 2022-08-01

Abstract: 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. Bryois et al. mapped genetic variants regulating gene expression in eight major brain cell types. They found a large number of cell-type-specific genetic effects and leveraged their results to identify novel putative risk genes for brain disorders.

DOI: 10.1038/s41593-022-01128-z

Source: https://www.nature.com/articles/s41593-022-01128-z

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex