对血浆循环微洋纳斯的遗传调节和疾病关联的全面研究，使用种群数据
A comprehensive study of genetic regulation and disease associations of plasma circulatory microRNAs using population-level data
影响因子:9.40000
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
摘要
microRNA（miRNA）是转录后调节基因表达的小型非编码RNA。已知血浆miRNA水平的扰动会影响疾病的风险，并具有作为疾病生物标志物的潜力。探索miRNA的遗传调节可能会产生其在控制基因表达和疾病机制中的重要作用的新见解。在鹿特丹研究的2178名参与者中，对全基因组循环的MiRNA进行了全基因组循环的研究，以识别miRNA-Expression量子表达性状特征（miR-eqtls）。我们确定了1289 SNP和63个miRNA之间的3292个关联，其中65％在两个独立的队列中被复制。我们证明了血浆miR-EQTL与基因表达，蛋白质和代谢物-QTL共定位，这有助于鉴定miRNA调节的途径。我们使用英国生物库数据（n = 423,419）研究了循环miRNA水平变化对广泛的临床条件的变化和孟德尔随机化的后果，揭示了几种miRNA对各种临床条件的多效和因果关系的影响。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的保护性因果关系，表明这种效应与其宿主基因无关（FADS1）。这项研究丰富了我们对血浆miRNAS遗传结构的理解，并探索了跨跨型范围的miRNAS范围的范围。基于人群的基因组学，其他OMICS和临床数据的整合为揭示了miRNA的潜在临床意义，并为基于miRNA的新型治疗靶靶发现提供了工具。
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.