Lifecourse Genome-Wide Association Study Meta-Analysis Refines the Critical Life Stages for the Influence of Adiposity on Breast Cancer

Previous evidence suggests that higher prepubertal adiposity may protect against breast cancer risk; however, this protective effect does not appear to persist into later life. The specific age at which this effect diminishes remains unclear and has yet to be explored using causal inference methods. This study examined the effect of body mass index (BMI) in nulliparous women during the early reproductive years on breast cancer risk. Using data from five large cohorts, we conducted genome-wide association studies (GWAS) on BMI from menarche to <40 years (N = 56,628), including three age sub-intervals: menarche to <20 years, 20 to <30 years, and 30 to <40 years. Results were meta-analysed, and consistency in genetic effects across age intervals was assessed. Two-sample Mendelian randomization (MR) within a lifecourse framework was applied to estimate the causal effect of genetically proxied BMI on overall breast cancer risk and seven subtypes using data from the Breast Cancer Association Consortium (N=up to 247,173). Heterogeneity in genetic effects on BMI across early adulthood was observed, with 9 of the 45 discovery variants showing significant variation (Qhet < 0.05). Genome-wide genetic correlations suggested that BMI in early adulthood may be influenced by partially distinct genetic factors compared to other life stages (rG = 0.76 with prepubertal body size; rG = 0.85 with later-life body size). Univariable MR analyses provided strong evidence that higher genetically predicted BMI between menarche and <40 years reduced overall breast cancer risk as well as most subtypes except HER2-enriched breast cancer. These effects persisted after adjusting for later-life body size but attenuated when prepubertal body size was included in multivariable MR models. Our findings suggest that while higher BMI in early adulthood is associated with reduced breast cancer risk, this effect may in part be attributable to adiposity accrued before puberty. These results refine our understanding of the timing of adipositys protective influence on breast cancer and highlight earlier life stages as critical windows for risk modulation. TeaserImproving knowledge of adipositys genetic architecture across the lifecourse refines insights into its role in breast cancer