Mendelian Randomization Analysis of the Relationship between Neurotransmitter-related Genes and Cancer: Insights from Multi-omics Data.

INTRODUCTION

Epidemiological studies indicate a potential link between mental disorders and cancer; however, the role of neurotransmitter-related genes (NRGs) in carcinogenesis remains unclear. In this study, we employed Mendelian randomization utilizing multi-omics data to investigate the causal effects and mechanisms of NRGs in cancer.

METHODS

We assessed the causal relationships between ten mental disorders and fourteen cancer types. NRGs were sourced from GeneCards, and transcriptome data for breast cancer (BC) were obtained from the Gene Expression Omnibus (GEO). Summary-data-based Mendelian Randomization (SMR) integrated genome-wide association study (GWAS) data with expression quantitative trait loci (eQTLs), DNA methylation QTLs (mQTLs), intestinal eQTLs, and fecal microbiota QTLs (mbQTLs). Colocalization analyses were conducted to explore the relationships between host genes and gut microbiota, with sensitivity assessments performed using two additional Mendelian randomization methods.

RESULTS

Mendelian randomization confirmed a causal association between mental disorders and BC. A meta-analysis of five BC datasets identified 821 differentially expressed genes (DEGs) among 829 non-redundant genes. SMR highlighted KRTCAP2 as a potential causal gene in blood, and cg24674445 as a significant methylation site. The expression of KRTCAP2 was found to be inversely correlated with BC, while methylation at cg24674445 downregulated KRTCAP2, suggesting that cg24674445 may promote BC progression.

DISCUSSION: This study advances beyond established epidemiological correlations by providing genetically validated evidence for a causal link between mental disorders and breast cancer. Its primary significance lies in delineating a plausible biological pathway-epigenetic regulation of neurotransmitter-related genes-that may mechanistically elucidate this connection. By integrating multi-omics data, we transition from mere association to a testable model of disease etiology, where genetic predispositions to mental illness and cancer converge upon shared regulatory mechanisms within the genome.

CONCLUSION

Multi-omics Mendelian randomization demonstrates that DNA methylation modulates the association between neurotransmitter-related genes and breast cancer.