Mendelian Randomization Analysis of the Relationship between Neurotransmitter-Related Genes and Cancer: Insights from Multi-omics Data
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Background: Epidemiological evidence indicates a potential association between mental disorders and cancer. However, the specific role of neurotransmitter-related genes (NRG) in cancer development remains unclear. This study employs Mendelian randomization with multi-omics summary data to explore the causal effects and underlying mechanisms of NRG in cancer. Materials and Methods: The causal relationships between 10 mental disorders and 14 cancer types were investigated. NRG was retrieved from the GeneCards database. Transcriptome datasets from breast cancer were gathered from the Gene Expression Omnibus (GEO). The Summary-data-based Mendelian Randomization (SMR) method was utilized for genome-wide association study (GWAS) analysis, incorporating expression quantitative trait loci (eQTLs), DNA methylation QTLs (mQTLs), genetic variants that influence gene expression in the intestines (intestinal eQTLs) and influence the composition of the fecal microbiota (mbQTLs). Colocation analysis was performed to identify potential links between host gene expression and gut microbiota. Sensitivity analyses were conducted using two additional Mendelian randomization techniques. Results: Mendelian randomization analysis established a causal association between mental disorders and breast cancer. A meta-analysis of five breast cancer datasets identified 821 differentially expressed genes (DEGs) among 829 non-redundant genes. KRTCAP2 was identified as a potential causal gene in blood tissues, while SMR analysis highlighted cg24674445 as a significant methylation site. KRTCAP2 expression was inversely correlated with breast cancer, whereas cg24674445 methylation negatively affected KRTCAP2 expression, suggesting a positive influence of cg24674445 on breast cancer progression. Conclusion: This study using multi-omics Mendelian randomization found that DNA methylation regulates the association between NRG and breast cancer.
