Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), has been associated with several cancer risks in observational studies, but the observed associations have been inconsistent and may face the bias of confounding and reverse causality. The potential causal relationships between IBD and the risk of cancers remain largely unclear. We performed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analyses using summary genome-wide association study (GWAS) data across East Asian and European populations to evaluate the causal relationships between IBD and cancers. Sensitivity analyses for the MR approach were additionally performed to explore the stability of the results. There were no significant genetic correlations between IBD, CD, or UC and cancers (all P values > 0.05) in East Asian or European populations. According to the main MR analysis, no significant causal relationship was observed between IBD and cancers in the East Asian population. There were significant associations between CD and ovarian cancer (odds ratio [OR] = 0.898, 95% CI = 0.844–0.955) and between UC and nonmelanoma skin cancer (OR = 1.002, 95% CI = 1.000–1.004, P = 0.019) in the European population. The multivariable MR analysis did not find any of the above significant associations. There was no shared causal variant to prove the associations of IBD, CD, or UC with cancers in East Asian or European populations using colocalization analysis. We did not provide robust genetic evidence of causal associations between IBD and cancer risk. Exposure to IBD might not independently contribute to the risk of cancers, and the increased risk of cancers observed in observational studies might be attributed to factors accompanying the diagnosis of IBD.

中文翻译：

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炎症性肠病与癌症风险之间的关联：来自东亚和欧洲人群的遗传相关性、孟德尔随机化和共定位分析的证据三角测量

炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），在观察性研究中已与多种癌症风险相关，但观察到的关联并不一致，可能面临混杂和反向因果关系的偏差。 IBD 与癌症风险之间的潜在因果关系在很大程度上仍不清楚。我们使用东亚和欧洲人群的全基因组关联研究 (GWAS) 数据进行全基因组连锁不平衡评分回归 (LDSC)、标准两样本孟德尔随机化 (MR) 和共定位分析，以评估 IBD 之间的因果关系和癌症。另外还进行了 MR 方法的敏感性分析，以探讨结果的稳定性。在东亚或欧洲人群中，IBD、CD 或 UC 与癌症之间没有显着的遗传相关性（所有 P 值 > 0.05）。根据主要的 MR 分析，在东亚人群中未观察到 IBD 与癌症之间存在显着的因果关系。 CD 和卵巢癌之间（比值比 [OR] = 0.898，95% CI = 0.844–0.955）以及 UC 和非黑色素瘤皮肤癌之间存在显着相关性（OR = 1.002，95% CI = 1.000–1.004，P = 0.019）在欧洲人口中。多变量 MR 分析未发现上述任何显着关联。使用共定位分析，没有共同的因果变异来证明 IBD、CD 或 UC 与东亚或欧洲人群中的癌症之间的关联。我们没有提供 IBD 与癌症风险之间因果关系的强有力的遗传证据。接触 IBD 可能并不独立地增加患癌症的风险，观察性研究中观察到的癌症风险增加可能归因于伴随 IBD 诊断的因素。