Abstract
Background
Ovarian cancer is a major female reproductive health issue with heterogeneous biological features on its subtypes, which may require different therapeutic strategies. Glucagon-like peptide-1 receptor (GLP-1R) agonists were reported to be beneficial for ovarian cancer, but the causal effects and mechanisms on its heterogeneous subtypes remain unclear.
Methods
We used genetic variants robustly associated with gene expression, protein level, splicing event, and DNA methylation of GLP-1R in six endocrine-related tissues (N ≤ 35,431) as genetic instruments to proxy the effect of GLP-1R agonism. To increase power, we conducted a meta-analysis of genome-wide association studies of ovarian cancer (29,066 cases, 461,542 controls), and identified 12 genome-wide associated variants, including two previously unreported variants: rs77247401 (MIR1208) and rs56159231 (PLEKHM1).
Results
Here we show that gene expression of GLP-1R in pancreas is associated with a reduced risk of overall ovarian cancer risk odds ratio ([OR] = 0.94, 95% confidence interval [CI] 0.89-1.00) and endometrioid ovarian cancer (ENOC; OR = 0.83, 95% CI = 0.72-0.95), which the finding is validated using splicing event of GLP-1R in pancreas (OR = 0.13, 95% CI = 0.02-0.86). However, null association is found for GLP-1R expression in pancreas with other ovarian cancer subtypes. The phenome-wide MR followed by mediation MR identifies six body composition and metabolic factors as mediators, including 18:2 linoleic acid.
Conclusions
The protective effect of GLP-1R agonists on ovarian cancer, especially ENOC, needs further validation in large-scale and well-conducted clinical trials.
Plain language summary
The class of drugs known as GLP-1 receptor (GLP-1R) agonists are known to have a range of health benefits. However, their effect on ovarian cancer, which is a significant health concern for women worldwide, has been unclear. GLP-1R agonists act on a protein expressed in the outside of cells, called the GLP-1 receptor. In our study, we used human genetic data to predict activity of the GLP-1 receptor in over 490,000 individuals. We found that GLP-1R activity in the pancreas was associated with a lower risk of a specific subtype of ovarian cancer called endometrioid ovarian cancer. This protective effect appeared to be partly influenced by changes in body composition and molecules in the blood, such as linoleic acid. Our results suggest that GLP-1R agonists could help prevent certain forms of ovarian cancer. Further clinical studies are needed to confirm this possibility.
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Data availability
The data of molecular traits used to proxy GLP-1R expression were available via deCODE genetics website (https://www.decode.com/summarydata/), the eQTL Gen website (https://www.eqtlgen.org), the GoDMC website (http://mqtldb.godmc.org.uk), the MetaBrain website (https://metabrain.nl/) and the Genotype-Tissue Expression (GTEx) Portal website (https://www.gtexportal.org). The summary statistics of ovarian cancer for GWAS meta-analyses used in this study are deposited in the IEU OpenGWAS database (GWAS IDs ieu-a-1120 and ieu-b-4963) and FinnGen r12 defined as II Neoplasms, from cancer register (ICD-O-3) (https://r12.finngen.fi/pheno/C3_OVARY_EXALLC). The GWAS summary statistics for the ovarian cancer subtypes are available at https://gwas.mrcieu.ac.uk with their GWAS IDs listed in the Supplementary Data. The GWAS summary statistics for positive control outcomes are downloaded from the GWAS Catalog (https://www.ebi.ac.uk/gwas/) and the accession codes are as follows: body mass index (GCST90029007) and type 2 diabetes (GCST90018926). The GWAS summary statistics for mediators were derived from EpiGraphDB database (https://www.epigraphdb.org/). No additional permissions or applications are required to access these datasets. The drug information utilized in this study was obtained from the Citeline database (https://clinicalintelligence.citeline.com/). Full access to the Citeline platform is commercially licensed and not freely available to all researchers. The source data for Figs. 1, 2 and 3 are available in Supplementary Data.
Code availability
The MR pipeline assessing the effect of GLP-1R expression on ovarian cancer is publicly available on the Omics Harbor GitHub repository (https://github.com/geneinmylife/GLP1R-OC-project) and has been permanently archived on Zenodo (https://doi.org/10.5281/zenodo.17994065).
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Acknowledgements
This work was supported by grants from the Noncommunicable Chronic Diseases–National Science and Technology Major Project (2024ZD0531500, 2024ZD0531502) and the National Key Research and Development Program of China (2022YFC2505203). J.L.L., M.X., W.Q.W., Y.F.B. and G.N. are supported by the National Natural Science Foundation of China (82088102, 81970728 and 81941017) and the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support (20161307 and 20152508 Round 2). J.L.L., M.X., W.Q.W., Y.F.B. and G.N. are members of the Innovative Research Team of High-level Local Universities in Shanghai.
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Conceptualization: J.Z.; Formal analysis: J.J.L. and Z.H.C.; Methodology: J.Z.; Investigation: J.J.L., Z.H.C., Q.Y., H.L., S.Y.W., M.L., T.G.W., Z.Y.Z., M.X., Y.H.C., Y.X., J.L.L., and Q.H.G.; Visualization: J.J.L. and Z.H.C.; Funding acquisition: L.M.W., M.X., J.Z., J.L.L., W.Q.W., Y.F.B., and G.N.; Project administration: G.N. and W.Q.W.; Supervision: L.M.W., W.Q.W., Y.F.B., and J.Z.; Writing—original draft: J.J.L.; Writing—review and editing: Q.Y. and J.Z.; L.M.W., W.Q.W., Y.F.B., and J.Z. are the guarantors of this work and shall take responsibility for the full access and integrity of the data. All authors have approved the final version of the manuscript.
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Liu, J., Chen, Z., Yang, Q. et al. Mendelian randomization study of GLP-1R effects on ovarian cancer subtypes mediated by metabolic factors. Commun Med (2026). https://doi.org/10.1038/s43856-026-01379-y
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DOI: https://doi.org/10.1038/s43856-026-01379-y
