Neuroticism, a personality trait characterized by emotional instability, has been linked to an increased risk of lung cancer (LC). However, the genetic underpinnings of this association remain poorly understood. This study aimed to comprehensively dissect the genetic link underlying neuroticism and LC.We used genome-wide association study (GWAS) data to investigate the intricate genetic relationship between neuroticism and LC, along with specific histological subtypes: lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small-cell LC (SCLC). Our analytical framework encompassed global and local genetic correlation, cross-trait meta-analysis, transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) analysis.Notable genetic correlations were found between neuroticism and overall LC (rg=0.15, P=2.24×10-5), with stronger associations observed for LUSC (rg=0.21, P=3.39×10-6) and SCLC (rg=0.16, P=2.50×10-3). Partitioning the genome revealed additional genetic correlations in specific local genomic regions (including chr6q27 and chr6q16.2-q16.3) and functional categories (such as H3K27ac and H3K9ac). The cross-trait meta-analysis revealed 24 genetic loci that influenced both traits, including four novel ones. Looking into the gene-tissue level, TWAS identified 35 genes associated with both neuroticism and LC across multiple tissues, particularly in the nervous, respiratory, cardiovascular, and endocrine systems. MR analysis indicated a potential causal effect of neuroticism on overall LC [odds ratio (OR) =1.48, P=5.53×10-4] and LUSC (OR =1.52, P=8.00×10-3), but not on LUAD or SCLC. No reverse causality was observed.This study reveals a genetic link between neuroticism and LC, offering new insights into LC risk assessment and potential prevention strategies for individuals with high neuroticism levels.Copyright © 2025 AME Publishing Company. All rights reserved.