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 sub-intervals
of this life stage. Results were meta-analysed, and two-sample univariable
and multivariable Mendelian randomisation was applied within a life-course
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 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.