Lifecourse genome-wide association study meta-analysis refines the critical life stages for adiposity's influence on breast cancer risk.

Previous evidence suggests that higher prepubertal adiposity protects against breast cancer risk. Whether this protection extends into early adulthood remains uncertain. We conducted genome-wide association studies on body mass index (BMI) in nulliparous women from menarche to <40 years across five cohorts, with additional analyses in three subintervals of this life stage. Results were meta-analyzed, and two-sample univariable and multivariable Mendelian randomization was applied within a lifecourse framework to assess the effect of BMI on breast cancer risk. Between menarche and <40 years, we observed heterogeneity in genetic effects. Genome-wide correlations further suggest that BMI during this early adult period may be partly influenced by distinct genetic factors compared with adiposity at other life stages. Higher genetically proxied BMI between menarche and 40 years reduced breast cancer risk. This protective effect attenuated after adjusting for prepubertal adiposity. These findings refine our understanding of adiposity's role in breast cancer and highlight earlier life stages as critical windows for risk modulation.