Genetic evidence supporting obesity as a risk factor for lung squamous cell carcinoma and the identification of MFAP1 as a shared genetic target

Observational studies have suggested that obesity may protect against lung cancer, particularly lung squamous cell carcinoma (LUSC). However, these findings are likely influenced by confounding factors such as smoking. We aimed to clarify the genetic relationship between body mass index (BMI) and LUSC and to identify potential shared therapeutic targets. We combined several genome-wide approaches to investigate shared genetic architecture between BMI and LUSC, including genetic correlation analyses and bidirectional Mendelian randomization (MR). We then examined tissue- and cell-level heritability enrichment and used gene-level integrative analyses to prioritize functional candidates. Finally, phenome-wide MR was applied to explore potential clinical consequences of targeting key genes. BMI and LUSC showed a significant positive genetic correlation. MR analyses provided genetic evidence consistent with acausal effect of higher BMI on increased LUSC risk. Genetic signals were enriched in selected tissues and cell types, including epithelial and neuronal populations. Genetic signals were enriched in selected tissues and cell types, including epithelial and neuronal populations. Across SMR and colocalization analyses, MFAP1 emerged as a shared functional gene linking BMI and LUSC. Phenome-wide MR identified limited but notable associations between higher MFAP1 levels and connective tissue–related and other clinical phenotypes, suggesting that potential on-target effects would need to be considered carefully. This study supports obesity as a genetic risk factor for LUSC and highlights MFAP1 as a potential shared target at the interface of adiposity and squamous lung carcinogenesis. These findings provide a genetic framework for understanding obesity-related LUSC risk and offer hypotheses for future mechanistic and translational research.