Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for lung cancer

Abstract Background Drug repurposing provides a cost-effective approach to address the need for lung cancer prevention and therapeutics. We aimed to identify actionable druggable targets using Mendelian randomization (MR). Methods Summary-level data of gene expression quantitative trait loci (eQTLs) were sourced from the eQTLGen resource. We procured genetic associations with lung cancer and its subtypes from the TRICL, ILCCO studies (discovery) and the FinnGen study (replication). We implemented Summary-data-based Mendelian Randomization analysis to identify potential therapeutic targets for lung cancer. Colocalization analysis was further conducted to assess whether the identified signal pairs shared a causal genetic variant. Findings In the main analysis dataset, we identified 55 genes that demonstrate a causal relationship with lung cancer and its subtypes. However, in the replication cohort, only three genes were found to have such a causal association with lung cancer and its subtypes, and of these, HYKK (also known as AGPHD1) was consistently present in both the primary analysis dataset and the replication cohort. Following HEIDI tests and colocalization analyses, it was revealed that HYKK (AGPHD1) is associated with an increased risk of squamous cell carcinoma of the lung, with an odds ratio and confidence interval of OR = 1.28,95%CI = 1.24 to 1.33. Interpretation We have found that the HYKK (AGPHD1) gene is associated with an increased risk of squamous cell carcinoma of the lung, suggesting that this gene may represent a potential therapeutic target for both the prevention and treatment of lung squamous cell carcinoma.