Genetic variants in the coding region could directly affect the structure and expression levels of genes and proteins. However, the importance of variants in the non-coding region, such as microRNAs (miRNAs), remain to be elucidated. Genetic variants in miRNA-related sequences could affect their biogenesis or functionality and ultimately affect disease risk. Yet, their implications and pleiotropic effects on many clinical conditions remain unknown. Here, we utilised genotyping and hospital records data in the UK Biobank (N = 423,419) to investigate associations between 346 genetic variants in miRNA-related sequences and a wide range of clinical diagnoses through phenome-wide association studies. Further, we tested whether changes in blood miRNA expression levels could affect disease risk through colocalisation and Mendelian randomisation analysis. We identified 122 associations for six variants in the seed region of miRNAs, nine variants in the mature region of miRNAs, and 27 variants in the precursor miRNAs. These included associations with hypertension, dyslipidaemia, immune-related disorders, and others. Nineteen miRNAs were associated with multiple diagnoses, with six of them associated with multiple disease categories. The strongest association was reported between rs4285314 in the precursor of miR-3135b and celiac disease risk (odds ratio (OR) per effect allele increase = 0.37, P = 1.8 × 10–162). Colocalisation and Mendelian randomisation analysis highlighted potential causal role of miR-6891-3p in dyslipidaemia. Our study demonstrates the pleiotropic effect of miRNAs and offers insights to their possible clinical importance.

中文翻译：

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miRNA 相关序列变异的表型组范围关联研究：英国生物银行

编码区的遗传变异可能直接影响基因和蛋白质的结构和表达水平。然而，非编码区变异的重要性，例如 microRNA (miRNA)，仍有待阐明。miRNA 相关序列的遗传变异可能会影响其生物发生或功能，并最终影响疾病风险。然而，它们对许多临床病症的影响和多效性仍然未知。在这里，我们利用英国生物库 (N = 423,419) 中的基因分型和医院记录数据，通过全表组关联研究来研究 miRNA 相关序列中的 346 个遗传变异与广泛的临床诊断之间的关联。此外，我们通过共定位和孟德尔随机分析测试了血液 miRNA 表达水平的变化是否会影响疾病风险。我们鉴定了 miRNA 种子区域中的 6 个变体、miRNA 成熟区域中的 9 个变体以及前体 miRNA 中的 27 个变体的 122 个关联。这些包括与高血压、血脂异常、免疫相关疾病等的关联。19 个 miRNA 与多种诊断相关，其中 6 个与多种疾病类别相关。据报道，miR-3135b 前体中的 rs4285314 与乳糜泻风险之间的关联最强（每个效应等位基因增加的比值比 (OR) = 0.37，P = 1.8 × 10–162）。共定位和孟德尔随机化分析强调了 miR-6891-3p 在血脂异常中的潜在因果作用。我们的研究证明了 miRNA 的多效性，并为它们可能的临床重要性提供了见解。