Integration of summary data from GWAS and eQTLs studies predicts causality of S1PR1 and breast cancer

Breast cancer is a major health threat to women, with limited effective indicators for early screening and prognosis. The role of sphingosine 1-phosphate receptor 1 (S1PR1) in breast cancer remains controversial. This study aims to explore the potential causal relationship between S1PR1 and breast cancer risk, considering estrogen receptor (ER) status. Summary-level data for genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) from European ancestry was collected. A summary-data-based Mendelian randomization (SMR), multi-SNP-based SMR, heterogeneity in dependent instruments (HEIDI) test, 2-sample MR analysis, and Bayesian colocalization method were conducted. Potential targets for S1PR1 were predicted based on DrugBank and ChEMBL databases. Elevated S1PR1 expression in blood was significantly associated with a heightened risk of overall breast cancer (odds ratio (OR): 1.15, 95% CI: 1.02-1.29; PSMR = .019) and ER+ breast cancer (OR: 1.20, 95% CI: 1.04-1.38; PSMR = .010), as demonstrated by SMR analysis. A protective association was identified between S1PR1 expression in the brain cortex and the risk of ER+ breast cancer (OR: 0.89, 95% CI: 0.84-0.99; PSMR = .032). No significant association was found regarding breast cancer survival (PSMR > .05). The MR analysis corroborated these findings, indicating an increased risk for both overall breast cancer (OR: 1.10, 95% CI: 1.02-1.20; P = .019) and ER+ breast cancer (OR: 1.16, 95% CI: 1.05-1.28; P = .003). Colocalization analysis revealed no evidence of shared genetic polymorphisms between S1PR1 expression and breast cancer risk or ER status (PP.H4 < 0.8), yet these studies were probably underpowered. Our finding revealed that the S1PR1 gene might act as a potential target for diagnosing the risk of breast cancer, especially for ER+ breast cancer.