小柯机器人

荷兰格罗宁根大学Harm-Jan Westra，Lude Franke和美国Biogen公司Heiko Runz共同合作，近期取得重要工作进展。他们通过研究大脑表达数量性状位点和网络分析揭示大脑相关疾病的下游效应和假定驱动因素。相关论文2023年2月23日在线发表于《自然—遗传学》杂志上。

据介绍，从全基因组关联研究（GWAS）中识别治疗靶点需要深入了解下游功能性结果。

研究人员统一了来自14个大脑数据集的8613个RNA测序样本，以创建MetaBrain资源，并在多个大脑区域和祖先特定数据集（n≤2759) 中进行了顺式和反式表达定量性状位点（eQTL）元分析。与血液顺式eQTL相比，16169个皮质顺式eQTL中的许多是组织依赖性的。研究人员通过相互作用分析推断了3549个顺式eQTL的脑细胞类型。他们使用孟德尔随机化和共定位对31个大脑相关性状的186个顺式eQTL进行了优先排序，包括40个具有推断细胞类型的顺式eQTL，例如多发性硬化症的神经元特异性顺式eQTL（CYP24A1）。研究人员进一步描述了737个反式eQTL的526个独特变体和108个独特基因，他们使用大脑特异性基因共调节网络来连接GWAS基因座，并对五种中枢神经系统疾病的额外基因进行优先排序。

总之，这项研究为后GWAS研究中枢神经系统疾病提供了宝贵的资源。

附：英文原文

Title: Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases

Author: de Klein, Niek, Tsai, Ellen A., Vochteloo, Martijn, Baird, Denis, Huang, Yunfeng, Chen, Chia-Yen, van Dam, Sipko, Oelen, Roy, Deelen, Patrick, Bakker, Olivier B., El Garwany, Omar, Ouyang, Zhengyu, Marshall, Eric E., Zavodszky, Maria I., van Rheenen, Wouter, Bakker, Mark K., Veldink, Jan, Gaunt, Tom R., Runz, Heiko, Franke, Lude, Westra, Harm-Jan

Issue&Volume: 2023-02-23

Abstract: Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples from 14 brain datasets to create the MetaBrain resource and performed cis- and trans-expression quantitative trait locus (eQTL) meta-analyses in multiple brain region- and ancestry-specific datasets (n≤2,759). Many of the 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs. We inferred brain cell types for 3,549 cis-eQTLs by interaction analysis. We prioritized 186 cis-eQTLs for 31 brain-related traits using Mendelian randomization and co-localization including 40 cis-eQTLs with an inferred cell type, such as a neuron-specific cis-eQTL (CYP24A1) for multiple sclerosis. We further describe 737 trans-eQTLs for 526 unique variants and 108 unique genes. We used brain-specific gene-co-regulation networks to link GWAS loci and prioritize additional genes for five central nervous system diseases. This study represents a valuable resource for post-GWAS research on central nervous system diseases.

DOI: 10.1038/s41588-023-01300-6

Source: https://www.nature.com/articles/s41588-023-01300-6

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex