特发性肺纤维化（IPF）是一种进行性间质性肺疾病，伴有局部和全身合并症。遗传因素在 IPF 和某些相关合并症的发生中发挥着重要作用。然而，尚不确定 IPF 和这些合并症是否存在共同的遗传因素。为了弥补这一知识差距，我们对 IPF 与十种常见遗传性合并症（即体重指数 [BMI]、冠状动脉疾病 [CAD]、慢性阻塞性肺疾病 [COPD]、胃食管反流）之间的共享遗传结构进行了系统调查疾病、肺癌、重度抑郁症 [MDD]、阻塞性睡眠呼吸暂停、肺动脉高压 [PH]、中风和 2 型糖尿病），利用来自各自全基因组关联研究和多组学研究的大规模汇总数据。我们发现 IPF 与七种合并症（不包括肺癌、MDD 和 PH）之间存在显着（错误发现率 [FDR] < 0.05）和中度遗传相关性。有证据表明 IPF 对 CAD 具有部分假定的因果效应。值得注意的是，我们在肺中观察到 IPF 和 CAD 之间交叉特征的 FDR 显着遗传富集，在肝脏中观察到 IPF 和 COPD 之间交叉特征的 FDR 显着遗传富集。此外，我们还发现了 65 个 FDR 显着基因，它们在与 IPF、BMI 和 COPD 病因学相关的 20 条生物途径中过度表达，包括与炎症相关的粘蛋白基因簇。其中一些基因与治疗 IPF、CAD 和/或 COPD 的临床相关药物相关。我们的结果强调了 IPF 及其常见合并症之间普遍存在的共同遗传基础，并对 IPF 相关合并症的早期诊断、药物再利用以及 IPF 新疗法的开发具有未来影响。© 2024。作者。

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease accompanied by both local and systemic comorbidities. Genetic factors play a role in the development of IPF and certain associated comorbidities. Nevertheless, it is uncertain whether there are shared genetic factors underlying IPF and these comorbidities. To bridge this knowledge gap, we conducted a systematic investigation into the shared genetic architecture between IPF and ten prevalent heritable comorbidities (i.e., body mass index [BMI], coronary artery disease [CAD], chronic obstructive pulmonary disease [COPD], gastroesophageal reflux disease, lung cancer, major depressive disorder [MDD], obstructive sleep apnoea, pulmonary hypertension [PH], stroke, and type 2 diabetes), by utilizing large-scale summary data from their respective genome-wide association studies and multi-omics studies. We revealed significant (false discovery rate [FDR] < 0.05) and moderate genetic correlations between IPF and seven comorbidities, excluding lung cancer, MDD and PH. Evidence suggested a partially putative causal effect of IPF on CAD. Notably, we observed FDR-significant genetic enrichments in lung for the cross-trait between IPF and CAD and in liver for the cross-trait between IPF and COPD. Additionally, we identified 65 FDR-significant genes over-represented in 20 biological pathways related to the etiology of IPF, BMI, and COPD, including inflammation-related mucin gene clusters. Several of these genes were associated with clinically relevant drugs for the treatment of IPF, CAD, and/or COPD. Our results underscore the pervasive shared genetic basis between IPF and its common comorbidities and hold future implications for early diagnosis of IPF-related comorbidities, drug repurposing, and the development of novel therapies for IPF.© 2024. The Author(s).