Wang Haiwei, Wang Xinrui, Lin Na, Lin Yingying, Xu Liangpu
Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, China.
Sci Rep. 2025 May 9;15(1):16171. doi: 10.1038/s41598-025-99492-w.
Lung cancer is a complex disease with varying subtypes. The genetic architectures and risk factors that are similar or distinct among these subtypes remain unclear. In this work, Genome-wide association studies (GWAS) conducted by the International Lung Cancer Consortium and transdisciplinary Research in Cancer of the Lung were utilized to illustrate the genetic landscapes of different subtypes of lung cancer. GWAS of 942 phenotypes from UK Biobank and 902 phenotypes from FinnGen Biobank were analyzed to identify the genetic risk factors specific or common to each subtype of lung cancer through two sample Mendelian randomization inverse variance weighting method. Multivariable Mendelian randomization was employed to assess the true causals of lung cancer. We found that lung cancer, small cell lung carcinoma, squamous cell lung cancer and lung adenocarcinoma shared similar, yet varied genetic architectures. Genetic risk loci at 15q25 were identified in all types of lung cancer. Yet, genetic risk loci at 5p15 were observed in squamous cell lung cancer and lung adenocarcinoma, but not in small cell lung carcinoma. Out of 942 phenotypes from UK Biobank, smoking, time spent watching television, age first had sexual intercourse, alcohol usually taken with meal and age at first live birth were common risk factors for all types of lung cancer. Moreover, out of 902 traits in FinnGen Biobank, chronic obstructive pulmonary disease (COPD) was positively associated with small cell lung carcinoma, squamous cell lung cancer and lung adenocarcinoma. Angina pectoris and myocardial infarction were negatively associated with lung cancer, squamous cell lung cancer and lung adenocarcinoma. And Alzheimer's disease was negatively associated with lung cancer, small cell lung carcinoma and squamous cell lung cancer. In further weighted median and weighted mode methods, myocardial infarction, angina pectoris and Alzheimer's disease also had genetical associations with lung cancer or its subtypes. Even, considering factors such as smoking, COPD, and other risk factors together, myocardial infarction, angina pectoris and Alzheimer's disease retained the genetical associations with lung cancer and its subtypes. Overall, in a phenome-wide Mendelian randomization analysis, our results have highlighted both similar and distinct risk factors among different subtypes of lung cancer. Additionally, our findings have provided genetic associations linking myocardial infarction, angina pectoris and Alzheimer's disease with lung cancer or its various subtypes.
肺癌是一种具有多种亚型的复杂疾病。这些亚型之间相似或不同的遗传结构和风险因素仍不清楚。在这项研究中，国际肺癌联盟进行的全基因组关联研究（GWAS）以及肺癌跨学科研究被用于阐明不同亚型肺癌的遗传图谱。通过两样本孟德尔随机化逆方差加权法，分析了英国生物银行的942种表型和芬兰生物银行的902种表型的GWAS，以确定每种肺癌亚型特有的或共有的遗传风险因素。采用多变量孟德尔随机化来评估肺癌的真正病因。我们发现肺癌、小细胞肺癌、肺鳞状细胞癌和肺腺癌具有相似但又不同的遗传结构。在所有类型的肺癌中均发现了位于15q25的遗传风险位点。然而，在肺鳞状细胞癌和肺腺癌中观察到了位于5p15的遗传风险位点，而在小细胞肺癌中未观察到。在英国生物银行的942种表型中，吸烟、看电视的时间、首次性交年龄、通常就餐时饮酒量以及首次生育年龄是所有类型肺癌的常见风险因素。此外，在芬兰生物银行的902个性状中，慢性阻塞性肺疾病（COPD）与小细胞肺癌、肺鳞状细胞癌和肺腺癌呈正相关。心绞痛和心肌梗死与肺癌、肺鳞状细胞癌和肺腺癌呈负相关。而阿尔茨海默病与肺癌、小细胞肺癌和肺鳞状细胞癌呈负相关。在进一步的加权中位数和加权模式方法中，心肌梗死、心绞痛和阿尔茨海默病也与肺癌或其亚型存在遗传关联。甚至，综合考虑吸烟、COPD和其他风险因素等因素后，心肌梗死、心绞痛和阿尔茨海默病仍与肺癌及其亚型存在遗传关联。总体而言，在全表型孟德尔随机化分析中，我们的结果突出了不同亚型肺癌之间相似和不同的风险因素。此外，我们的研究结果提供了心肌梗死、心绞痛和阿尔茨海默病与肺癌或其各种亚型之间的遗传关联。
