Mendelian randomization reveals pleiotropic genes between major depression and bowel cancer

Abstract

Abstract Background: In recent years, researchers have been increasingly focused on the association between mental disorders and the gut-brain axis. The gut-brain axis refers to a bidirectional communication system between the gastrointestinal tract and the central nervous system, involving interactions among the gut, microbiota, nervous system, and immune system. However, the precise relationship between mental illnesses and Bowel cancer necessitates further investigation for clarification. Elucidating these associations could offer crucial insights for the development of more effective treatment strategies and preventive measures in the future. Methods: We employed the Two-Sample Mendelian Randomization (TSMR) approach to investigate the genetic relationships between three common mental disorders (AD, MDD, and SC) and Bowel cancer. Leveraging Genome-Wide Association Study (GWAS) and summary data for Mendelian Randomization (SMR), along with expression Quantitative Trait Locus (eQTL) data, we sought to identify significantly associated genes shared between MDD and Bowel cancer. This approach aimed to explore the potential association between the two conditions. Employing the mediation MR technique, utilizing the jointly significant genes as mediators, we examined whether there exists a MDD-gene-Bowel cancer directional relationship. Furthermore, the TSMR methodology was utilized to validate the previously identified shared genes' relevance to both MDD and Bowel cancer. Results: The study findings reveal significant causal effects, wherein increased risk of AD is associated with a lowered risk of Bowel cancer, while heightened risk of MDD shows a significant positive causal influence on Bowel cancer risk. The gene OTUD4 emerges as a mediator variable with a certain level of correlation between MDD and Bowel cancer. Genes PPP6C, THUMPD3, and EML3 simultaneously exert positive causal effects on both MDD and Bowel cancer. Conversely, the gene RP3-395C13.1 exhibits negative causal effects on both MDD and Bowel cancer. HPCAL4 demonstrates a positive causal effect on MDD and a negative causal effect on Bowel cancer.MDD and Bowel Cancer show significant enrichment in pathways related to organellar localization and establishment, innate immune response, mitotic cell cycle, and defense response against other organisms. Conclusion: This study has identified five genes (PPP6C, THUMPD3, EML3, RP3-395C13.1, HPCAL4) that concurrently influence both MDD and Bowel cancer.