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 bodu 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 = 90,115), 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).

Substantial 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 (mean age 23.9 years) reduced overall breast cancer risk (IVW odds ratio per standard deviation increase: 0.24, 95% CI: 0.12 to 0.45, P = 9.60×10^-6), as well as most subtypes except HER2-enriched breast cancer. The protective effect was strongest between menarche and <20 years, decreasing in later intervals. These effects persisted after adjusting for later-life body size but attenuated when prepubertal body size was included in multivariable MR models, suggesting that prepuberal body size primarily drives the observed protection.

Our findings suggest that while higher BMI in early adulthood is associated with reduced breast cancer risk, this effect may be largely attributable to adiposity accrued before puberty. These results refine our understanding of the timing of adiposity’s protective influence on breast cancer and highlight prepuberty as a critical window for risk modulation.

Teaser

Improving knowledge of adiposity’s genetic architecture across the lifecourse refines insights into its role in breast cancer