School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
SFI Centre for Research Training in Genomics Data Sciences, University of Galway, H91 TK33, Galway, Ireland.
Hum Genomics. 2023 Mar 30;17(1):31. doi: 10.1186/s40246-023-00478-4.
Genome-wide association studies (GWAS) have highlighted over 200 autosomal variants associated with multiple sclerosis (MS). However, variants in non-coding regions such as those encoding microRNAs have not been explored thoroughly, despite strong evidence of microRNA dysregulation in MS patients and model organisms. This study explores the effect of microRNA-associated variants in MS, through the largest publicly available GWAS, which involved 47,429 MS cases and 68,374 controls.
We identified SNPs within the coordinates of microRNAs, ± 5-kb microRNA flanking regions and predicted 3'UTR target-binding sites using miRBase v22, TargetScan 7.0 RNA22 v2.0 and dbSNP v151. We established the subset of microRNA-associated SNPs which were tested in the summary statistics of the largest MS GWAS by intersecting these datasets. Next, we prioritised those microRNA-associated SNPs which are among known MS susceptibility SNPs, are in strong linkage disequilibrium with the former or meet a microRNA-specific Bonferroni-corrected threshold. Finally, we predicted the effects of those prioritised SNPs on their microRNAs and 3'UTR target-binding sites using TargetScan v7.0, miRVaS and ADmiRE.
We have identified 30 candidate microRNA-associated variants which meet at least one of our prioritisation criteria. Among these, we highlighted one microRNA variant rs1414273 (MIR548AC) and four 3'UTR microRNA-binding site variants within SLC2A4RG (rs6742), CD27 (rs1059501), MMEL1 (rs881640) and BCL2L13 (rs2587100). We determined changes to the predicted microRNA stability and binding site recognition of these microRNA and target sites.
We have systematically examined the functional, structural and regulatory effects of candidate MS variants among microRNAs and 3'UTR targets. This analysis allowed us to identify candidate microRNA-associated MS SNPs and highlights the value of prioritising non-coding RNA variation in GWAS. These candidate SNPs could influence microRNA regulation in MS patients. Our study is the first thorough investigation of both microRNA and 3'UTR target-binding site variation in multiple sclerosis using GWAS summary statistics.
全基因组关联研究（GWAS）已经确定了 200 多个与多发性硬化症（MS）相关的常染色体变异。然而，尽管在 MS 患者和模型生物中存在强烈的 miRNA 失调证据，但对非编码区域（如 miRNA 编码）中的变异的探索并不充分。本研究通过最大的公开 GWAS 探索了 miRNA 相关变异在 MS 中的作用，该研究涉及 47429 例 MS 病例和 68374 例对照。
我们使用 miRBase v22、TargetScan 7.0 RNA22 v2.0 和 dbSNP v151，在 miRNA 的坐标内、±5kb miRNA 侧翼区域和预测的 3'UTR 靶结合位点内确定 SNPs。我们通过将这些数据集相交，建立了在最大 MS GWAS 汇总统计中测试的 miRNA 相关 SNP 的子集。接下来，我们对已知的 MS 易感性 SNP 中、与前者紧密连锁的 SNP 或满足 miRNA 特异性 Bonferroni 校正阈值的 miRNA 相关 SNP 进行优先级排序。最后，我们使用 TargetScan v7.0、miRVaS 和 ADmiRE 预测这些优先级 SNP 对其 miRNA 和 3'UTR 靶结合位点的影响。
我们已经确定了 30 个符合我们至少一个优先级标准的候选 miRNA 相关变体。其中，我们强调了一个 miRNA 变体 rs1414273（MIR548AC）和 SLC2A4RG 内的四个 3'UTR miRNA 结合位点变体(rs6742)、CD27(rs1059501)、MMEL1(rs881640)和 BCL2L13(rs2587100)。我们确定了这些 miRNA 和靶位点的预测 miRNA 稳定性和结合位点识别的变化。
我们系统地检查了候选 MS 变异在 miRNA 和 3'UTR 靶标中的功能、结构和调节作用。该分析使我们能够识别候选 miRNA 相关 MS SNPs，并强调了在 GWAS 中优先考虑非编码 RNA 变异的价值。这些候选 SNP 可能会影响 MS 患者的 miRNA 调节。我们的研究是首次使用 GWAS 汇总统计数据对多发性硬化症中的 miRNA 和 3'UTR 靶结合位点变异进行全面调查。
