利用人群层面数据对血浆循环微RNA的遗传调控和疾病相关性进行全面研究
A comprehensive study of genetic regulation and disease associations of plasma circulatory microRNAs using population-level data
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影响因子:9.4
分区:生物学1区 Top / 生物工程与应用微生物1区 遗传学1区
发表日期:2024 Oct 21
作者:
Rima Mustafa, Michelle M J Mens, Arno van Hilten, Jian Huang, Gennady Roshchupkin, Tianxiao Huan, Linda Broer, Joyce B J van Meurs, Paul Elliott, Daniel Levy, M Arfan Ikram, Marina Evangelou, Abbas Dehghan, Mohsen Ghanbari
DOI:
10.1186/s13059-024-03420-6
摘要
微RNA（miRNAs）是一类调控基因表达的小非编码RNA，在转录后水平调节基因表达。血浆中miRNA水平的扰动已知会影响疾病风险，具有潜在的疾病生物标志物价值。探索miRNA的遗传调控可能为理解其在调控基因表达和疾病机制中的重要作用提供新见解。我们基于Rotterdam研究的2178名参与者，进行了2083个血浆循环miRNA的全基因组关联研究（GWAS），以鉴定miRNA表达数量性状基因座（miR-eQTLs）。共识别出3292个与1289个SNPs和63个miRNAs相关的关联，其中65%的关联在两个独立队列中得到复制。研究显示，血浆miR-eQTLs与基因表达、蛋白质和代谢物的QTLs共定位，有助于识别miRNA调控的通路。通过表型全关联研究和孟德尔随机化分析（利用UK Biobank，N = 423,419），探讨血浆miRNA水平变化对各种临床疾病的影响，揭示了多种miRNAs的多效性和因果效应。在孟德尔随机化分析中，我们发现miR-1908-5p对良性结肠肿瘤风险具有保护性因果作用，并显示这一作用与其宿主基因（FADS1）无关。本研究丰富了我们对血浆miRNAs遗传结构的理解，并探索了miRNAs在广泛临床状态中的特征。结合群体基础的基因组学、其他组学层面和临床数据，为揭示miRNAs的潜在临床意义和提供新型miRNA靶向治疗工具提供了可能。
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Perturbations in plasma miRNA levels are known to impact disease risk and have potential as disease biomarkers. Exploring the genetic regulation of miRNAs may yield new insights into their important role in governing gene expression and disease mechanisms.We present genome-wide association studies of 2083 plasma circulating miRNAs in 2178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We identify 3292 associations between 1289 SNPs and 63 miRNAs, of which 65% are replicated in two independent cohorts. We demonstrate that plasma miR-eQTLs co-localise with gene expression, protein, and metabolite-QTLs, which help in identifying miRNA-regulated pathways. We investigate consequences of alteration in circulating miRNA levels on a wide range of clinical conditions in phenome-wide association studies and Mendelian randomisation using the UK Biobank data (N = 423,419), revealing the pleiotropic and causal effects of several miRNAs on various clinical conditions. In the Mendelian randomisation analysis, we find a protective causal effect of miR-1908-5p on the risk of benign colon neoplasm and show that this effect is independent of its host gene (FADS1).This study enriches our understanding of the genetic architecture of plasma miRNAs and explores the signatures of miRNAs across a wide range of clinical conditions. The integration of population-based genomics, other omics layers, and clinical data presents opportunities to unravel potential clinical significance of miRNAs and provides tools for novel miRNA-based therapeutic target discovery.