了解结直肠癌(CRC)与其他癌症之间的共享基因基础，并鉴定潜在的多效位点来补偿CRC遗传可遗传性丢失。我们进行了系统性全基因组多效性扫描，评估欧洲人群癌症相关遗传变异与CRC风险之间的关联。利用英国生物库和苏格兰结直肠癌研究(10,039个CRC病例和30,277个对照组)的数据进行SNP集分析，评估CRC和其他癌症易感性的重合遗传区域。通过CRC GWAS meta分析和PLACO多效性测试，研究个体水平的CRC和其他癌症之间的多效性关联。进行基于基因、共表达和通路富集分析，探讨潜在的共享生物通路。进一步检查新遗传变异和常见环境因素之间的相互作用，以了解它们对CRC的影响。 基因组全基因组多效性分析确定了三个新SNP(rs2230469、rs9277378、rs143190905)和三个映射基因(PIP4K2A、HLA-DPB1、RTEL1)与CRC相关。这些遗传变异在结肠组织中是显著的eQTL，影响它们的映射基因的表达。观察到与吸烟和饮酒等环境因素的PIP4K2A和HLA-DPB1的显著相互作用。所有映射基因及其共表达基因都在参与癌变过程的通路中显著富集。 我们的发现提供了对CRC与其他癌症之间共享基因基础的重要见解。我们揭示了几个新的CRC易感位点，以帮助了解CRC的遗传结构。 ©作者2023年。由牛津大学出版社发表。版权所有。如需许可，请发送电子邮件至：journals.permissions@oup.com。

To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC.We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. SNP-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC GWAS meta-analysis and the PLACO pleiotropy test. Gene-based, co-expression, and pathway enrichment analyses were performed to explore potential shared biological pathways. Interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC.Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378, rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1, RTEL1) to be associated with CRC. These genetic variants were significant eQTL in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis.Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.