Exploring the association between birthweight and breast cancer using summary statistics from a perspective of genetic correlation, mediation, and causality

Abstract Background Previous studies demonstrated a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations also emerged, and the nature of such relationship remains unknown. Methods Using summary statistics of birthweight (n=264,498 for own birthweight and 179,360 for offspring birthweight) and breast cancer (n=266,081), we assessed the fetal/maternal-specific genetic correlation between them via LDSC and prioritized fetal/maternal-specific pleiotropic genes through MAIUP. Relying on summary statistics we conducted Mendelian randomization (MR) analyses to evaluate the fetal/maternal-specific origin of causal relationship between birthweight, age of menarche, age at menopause and breast cancer. Results With summary statistics we identified a positive genetic correlation between fetal-specific birthweight and breast cancer (rg=0.123 and P=0.013) as well as a negative but insignificant correlation between maternal-specific birthweight and breast cancer (rg=-0.068, P=0.206); and detected 84 pleiotropic genes shared by fetal-specific birthweight and breast cancer, 49 shared by maternal-specific birthweight and breast cancer. We also revealed fetal-specific birthweight indirectly influenced breast cancer risk in adulthood via the path of age of menarche or age at menopause in terms of MR-based mediation analysis. Conclusion This study reveals that shared genetic foundation and causal mediation commonly drive the connection between the two traits, and that fetal/maternal-specific birthweight plays substantially distinct roles in such relationship. However, our work offers little supportive evidence for the fetal origins hypothesis of breast cancer originating in utero.