Relationship Between Chronic Pain and Breast Cancer: Insight From Genetic Correlation Analyses and 2-Sample Mendelian Randomization

Previous observational studies have discussed the relationship between chronic pain and breast cancer, and Mendelian randomization was used to demonstrate a causal relationship between migraine and breast cancer. However, the potential genetic factors or common pathogenic genes of the 2 diseases remained unknown. This study utilized 2-sample Mendelian randomization to uncover the causal relationship between chronic pain and breast cancer. In addition, LD score regression (LDSC) was used for genetic correlation analysis, and Bayesian colocalization analysis was employed to explore the biological mechanisms underlying the comorbidity of chronic pain and breast cancer. The results showed a significant genetic correlation between migraine and ER-(estrogen receptor-negative) breast cancer. The rs2183271 locus was identified as a shared mutation in multisite chronic pain (MCP) and ER + (estrogen receptor-positive) breast cancer, suggesting that the MLLT10 gene, where rs2183271 located, might be involved in regulating both multisite pain and ER + breast cancer. These findings are of great significance for further understanding the genetic mechanisms of pain and breast cancer. Objective: To evaluate potential genetic causal relationships between chronic pain subtypes like migraine and multi-site chronic pain (MCP) and their impact on breast cancer occurrence and survival rates. Background: The association between chronic pain and breast cancer was reported before, yet the causal nature between them remained uncertain. Methods: Data on chronic pain and breast cancer were sourced from publicly available European genome-wide association study (GWAS) datasets. Genetic association between chronic pain and breast cancer phenotypes was assessed using linkage disequilibrium genetic correlation (LDSC). Colocalization analysis further identified potential shared causal variation. Based on Inverse variance weighted method, 2-sample Mendelian Randomization (MR) was conducted to investigate causal associations between migraine, MCP, and breast cancer or breast cancer survival. Sensitive analysis was conducted to ensure the absence of heterogeneity and horizontal pleiotropy. Results: LDSC demonstrated significant genetic correlations between migraine and both estrogen receptor-negative (ER-) and overall breast cancer, while also revealing a notable genetic association between MCP and ER-and ER + breast cancer, as well as overall breast cancer. Through colocalization analysis, potential involvement of rs2183271, located in MLLT10 gene, in regulating MCP and ER + breast cancer was identified. MR analysis revealed the association between migraine and elevated risk of ER-breast cancer (IVW, P = 4.95 x 10-3 ). Cochran's Q test ensured the absence of heterogeneity and MR-PRESSO global test, MR-Egger intercept test ensured the absence of horizontal pleiotropy. Conclusion: Our results provided new insights into the role of migraine and MCP in breast cancer, paving the way for targeted preventive strategies and future investigations.