Tehran University of Medical Sciences Iranian Journal of Public Health 2251-6085 53 1 2024 01 01 187 197 EN Meng Zhang Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China Jiahao Qiao Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China Ping Zeng 1. Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China 2. Center for Medical Statistics and Data Analysis, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China 3. Key Laboratory of Human Genetics and Environmental Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China 4. Key Laboratory of Environment and Health, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China 5. Engineering Research Innovation Center of Biological Data Mining and Healthcare Transformation, Xuzhou Medical Uni-versity, Xuzhou, Jiangsu, 221004, China Zhuanzhuan Liu Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China 2022 08 13 2023 02 02 Background: Epidemiological studies have shown a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations emerged. We re-explored the association between them in the UK Biobank cohort. Methods: Relying on the UK Biobank cohort data of white British volunteers recruited between 2006 and 2010 (5,760 cases and 162,778 controls), we evaluated the causal mediation between birthweight and breast cancer, with age of menarche and age at menopause as two potential mediators under the traditional mediation analysis framework. The non-linear relationship between birthweight and breast cancer was also investigated by including the square of birthweight or discretized birthweight categories (<2.5, 2.5~4.0, or >4.0). Furthermore, we performed a stratification analysis in terms of the menopause status. Results: Birthweight can indirectly influence breast cancer risk in adulthood via the path of age of menarche or age at menopause, and found statistical evidence supporting the existence of suggestive non-linear association between birthweight and breast cancer (β=0.062 and P=0.004 for the square of birthweight) although failing to discover a linear relationship (P=0.230). We also demonstrated such non-linear association seemed more pronounced and robust for premenopausal women compared with postmenopausal ones (27.5% vs. 19.5% increase in breast cancer risk). Conclusion: This study provided an in-depth insight into the observed relationship between birthweight and breast cancer and revealed that non-linear impact and causal mediation commonly drive the connection between the two traits. https://ijph.tums.ac.ir/index.php/ijph/article/view/29549 https://ijph.tums.ac.ir/index.php/ijph/article/download/29549/8143