美国宾夕法尼亚大学Susztak Katalin团队的最新研究通过描绘人肾脏细胞的遗传结构特征确定了疾病的发生机制和潜在治疗方法。这一研究成果发表在2021年8月12日出版的国际学术期刊《自然-遗传学》上。
研究人员揭示了659个人类肾脏显微解剖样本表达数量性状基因座(eQTL)的综合图谱，通过绘制细胞类型丰度和基因型之间的相互作用来识别细胞类型特异性-eQTL。通过使用分层连锁不平衡评分回归来区分遗传性，研究将全基因组关联研究(GWAS)与单细胞RNA测序和单核分析用于转座酶染色质可及性和高通量测序数据分析。
研究人员首先分析了肾功能和内皮细胞近端小管和远端小管段的血压病理。贝叶斯共定位分析确定了200多个与肾功能和高血压相关的基因。该研究阐明了常用抗高血压和肾脏保护药物的作用机制，并揭示了肾脏疾病药物再利用的可能。
研究人员表示，由于遗传变异具有细胞类型依赖性，因此利用GWAS来解析细胞功能具有一定的挑战性。
附：英文原文
Title: Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments
Author: Sheng, Xin, Guan, Yuting, Ma, Ziyuan, Wu, Junnan, Liu, Hongbo, Qiu, Chengxiang, Vitale, Steven, Miao, Zhen, Seasock, Matthew J., Palmer, Matthew, Shin, Myung K., Duffin, Kevin L., Pullen, Steven S., Edwards, Todd L., Hellwege, Jacklyn N., Hung, Adriana M., Li, Mingyao, Voight, Benjamin F., Coffman, Thomas M., Brown, Christopher D., Susztak, Katalin
Issue&Volume: 2021-08-12
Abstract: The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability using stratified linkage disequilibrium score regression to integrate GWAS with single-cell RNA sequencing and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing data, we prioritized proximal tubules for kidney function and endothelial cells and distal tubule segments for blood pressure pathogenesis. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of commonly used antihypertensive and renal-protective drugs and identifies drug repurposing opportunities for kidney disease. Cell-type-specific eQTL maps in the human kidney generated from the analysis of over 600 microdissected kidney samples, together with single-cell RNA sequencing and single-nucleus ATAC-seq, prioritize cell types influencing kidney function, hypertension and other traits.
DOI: 10.1038/s41588-021-00909-9
Source: https://www.nature.com/articles/s41588-021-00909-9
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
本期文章：《自然—遗传学》：Online/在线发表
