Causal associations of psychological phenotypes with gastric cancer risk and candidate gene prioritization: a Mendelian randomization study

Abstract:

Background and Aims Psychological phenotypes may influence tumorigenesis through behavioral changes, neuroendocrine dysregulation, and immune modulation. However, their causal relationships with gastric cancer remain unclear. This study aimed to investigate the potential causal associations of anxiety, depression, neuroticism, and mood swings with gastric cancer risk using Mendelian randomization (MR), and to prioritize candidate genes potentially involved in this process.Methods A two-sample MR framework was applied. European gastric cancer genome-wide association study (GWAS) data were used as the primary outcome dataset. Univariable MR analyses were performed for four psychological phenotypes, including mood swings, anxiety, depression, and neuroticism. Positive findings were further evaluated using an East Asian gastric cancer GWAS dataset and subsequently assessed by multivariable MR and Bayesian model averaging MR (MR-BMA). Candidate genes were prioritized using the Polygenic Priority Score (PoPS) method and further evaluated through differential expression and survival analyses using the GEPIA2 platform.Results Univariable MR analysis demonstrated that only mood swings were significantly associated with an increased risk of gastric cancer, with an IVW estimate of OR=1.708 (95% CI=1.075-2.713, P=0.023). External validation in the East Asian dataset showed a consistent effect direction with borderline statistical significance (OR=1.747, 95% CI=0.999-3.056, P=0.050). MVMR analysis indicated that mood swings remained independently associated with gastric cancer risk after adjustment for anxiety, depression, and neuroticism (OR=3.296, 95% CI=1.089-9.982, P=0.035). MR-BMA analysis identified mood swings as the most important exposure (MIP=0.935, adjusted P=0.012). Sensitivity analyses revealed no substantial evidence of heterogeneity, horizontal pleiotropy, or reverse causality. PoPS analysis prioritized 32 candidate genes, among which ADAM12 and KYNU exhibited differential expression in gastric cancer tissues and were significantly associated with overall survival.Conclusion Genetic evidence suggests that mood swings may represent an important psychological phenotype associated with increased gastric cancer risk and retain an independent association among multiple psychological traits. ADAM12 and KYNU may serve as prioritized candidate genes for future mechanistic studies. These findings provide novel genetic insights into the relationship between psychological factors and gastric carcinogenesis, although the underlying biological mechanisms require further validation.