A phenome-wide Mendelian randomization analysis reveals the genetical associations of myocardial infarction, angina pectoris and Alzheimer’s disease with lung cancer

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.