英国威康桑格研究所Dirk S. Paul团队近日取得一项新成果。他们研制了血液基因表达和剪接的遗传决定因素对分子表型和健康结果的贡献。这一研究成果发表在2025年3月4日出版的国际学术期刊《自然—遗传学》上。

为了研究基因调控机制，该课题组通过对4732名参与者进行大量RNA测序，并整合来自同一个体的蛋白质、代谢物和脂质数据，绘制了血液基因表达和剪接数量性状位点（QTLs）。该课题组鉴定了17233个基因的顺式QTL表达和29514个剪接事件（在6853个基因中）。共定位分析揭示了3430个蛋白质组学和代谢组学特征与基因表达或剪接有共同的关联信号。小组量化了具有共同病因的位点上遗传效应的相对贡献，观察到222种分子表型被基因表达或剪接显著介导。

该课题组研究人员发现了具有治疗意义的疾病位点的基因调控机制，如高血压中的WARS1，皮炎中的IL7R和COVID-19中的IFNAR2。他们的研究为人类转录表型、分子特征和健康结果的共同遗传病因提供了一个开放的途径（https://IntervalRNA.org.uk）。

据了解，大多数非蛋白质编码基因变异影响疾病风险的生物学机制尚不清楚。

附：英文原文

Title: The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes

Author: Tokolyi, Alex, Persyn, Elodie, Nath, Artika P., Burnham, Katie L., Marten, Jonathan, Vanderstichele, Thomas, Tardaguila, Manuel, Stacey, David, Farr, Ben, Iyer, Vivek, Jiang, Xilin, Lambert, Samuel A., Noell, Guillaume, Quail, Michael A., Rajan, Diana, Ritchie, Scott C., Sun, Benjamin B., Thurston, Scott A. J., Xu, Yu, Whelan, Christopher D., Runz, Heiko, Petrovski, Slav, Gaffney, Daniel J., Roberts, David J., Di Angelantonio, Emanuele, Peters, James E., Soranzo, Nicole, Danesh, John, Butterworth, Adam S., Inouye, Michael, Davenport, Emma E., Paul, Dirk S.

Issue&Volume: 2025-03-04

Abstract: The biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Colocalization analyses revealed 3,430 proteomic and metabolomic traits with a shared association signal with either gene expression or splicing. We quantified the relative contribution of the genetic effects at loci with shared etiology, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access resource on the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans (https://IntervalRNA.org.uk).

DOI: 10.1038/s41588-025-02096-3

Source: https://www.nature.com/articles/s41588-025-02096-3