Deciphering how early life adiposity influences breast cancer risk using Mendelian randomization

Abstract

Studies suggest that adiposity in childhood may reduce the risk of breast cancer in later life. The biological mechanism underlying this effect is unclear but is likely to be independent of body size in adulthood. Using a Mendelian randomization framework, we investigated 18 hypothesised mediators of the protective effect of childhood adiposity on later-life breast cancer, including hormonal, reproductive, physical, and glycaemic traits. Our results indicate that, while most of the hypothesised mediators are affected by childhood body size, only IGF-1, testosterone, age at menarche and age at menopause influenced breast cancer risk. However, accounting for those traits in multivariable Mendelian randomization showed that the protective effect of childhood body size still remained. This suggests either a direct effect of childhood body size on breast cancer risk or mediation via other pathways not considered. Our work presents a framework for the systematic exploration of potential biological mediators of disease in Mendelian randomization analysis.

A structural mean modelling Mendelian randomization approach to investigate the lifecourse effect of adiposity: applied and methodological considerations

“…This helps us to further unpick pathways associated with disease risk. For example, there are long run effects of childhood adiposity on physical development shown though mammographic density being a strong mediator for the protective effects of childhood adiposity on breast cancer (47).…”