全转录组关联研究 (TWAS) 已经确定了许多结直肠癌 (CRC) 风险的假定易感基因。然而，易感性 miRNA（基因表达的关键失调因子）仍未得到探索。我们对 313 名 CRC 东亚患者的 DNA 样本进行了基因分型，并在远离肿瘤的正常结肠组织中进行了小 RNA 测序，以建立预测 miRNA 表达的遗传模型。我们应用这些模型和全基因组关联研究 (GWAS) 的数据（包括 23 942 例东亚血统病例和 217 267 例对照）来研究预测的 miRNA 表达与 CRC 风险的关联。分别通过促进和抑制 miRNA 表达进行扰动实验，并在 SW480 和 HCT116 细胞中进行进一步的体外测定。在 Bonferroni 校正阈值 P < 4.5 × 10-4 下，我们鉴定了两个假定的易感性 miRNA，miR-1307-5p 和 miR-192-3p，位于距 GWAS 识别的任何风险变异超过 500 kb 的区域。 CRC。我们观察到，miR-1307-5p 的高预测表达与 CRC 风险增加相关，而 miR-192-3p 的低预测表达与 CRC 风险增加相关。我们的实验结果进一步提供了强有力的证据，表明 miR-1307-5p 和 miR-192-3p 分别在促进和抑制 CRC 细胞增殖、迁移和侵袭方面发挥调节作用，这在SW480 和 HCT116 细胞。我们的研究为 CRC 发展的生物学机制提供了更多见解。© 作者 2023。由牛津大学出版社出版。版权所有。如需权限，请发送电子邮件至：journals.permissions@oup.com。

Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.