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.

中文翻译：

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使用人群水平数据对血浆循环 microRNA 的遗传调控和疾病关联进行全面研究


MicroRNA （miRNA） 是转录后调节基因表达的小非编码 RNA。已知血浆 miRNA 水平的扰动会影响疾病风险，并有可能成为疾病生物标志物。探索 miRNAs 的遗传调控可能会对它们在控制基因表达和疾病机制中的重要作用产生新的见解。我们提出了鹿特丹研究的 2083 名参与者中 2178 个血浆循环 miRNA 的全基因组关联研究，以鉴定 miRNA 表达数量性状位点 （miR-eQTL）。我们确定了 1289 个 SNP 和 63 个 miRNAs 之间的 3292 个关联，其中 65% 在两个独立的队列中复制。我们证明血浆 miR-eQTLs 与基因表达、蛋白质和代谢物 QTL 共定位，这有助于识别 miRNA 调节的通路。我们使用英国生物样本库数据 （N = 423,419） 在全表型组关联研究和孟德尔随机化中调查了循环 miRNA 水平改变对各种临床条件的影响，揭示了几种 miRNA 对各种临床状况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的保护性因果效应，并表明这种效应与其宿主基因 （FADS1） 无关。这项研究丰富了我们对血浆 miRNA 遗传结构的理解，并探索了 miRNA 在各种临床条件下的特征。基于群体的基因组学、其他组学层和临床数据的整合为揭示 miRNA 的潜在临床意义提供了机会，并为基于 miRNA 的新型治疗靶点发现提供了工具。