Mammographic density mediates the protective effect of early-life body size on breast cancer risk

Marina Vabistsevits*, George Davey Smith, Tom G Richardson, Rebecca Richmond, Weiva Sieh, Joseph Rothstein, Laurel Habel, Stacey Alexeeff, Bethan Lloyd-Lewis, Eleanor C M Sanderson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review


The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%-79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.
Original languageEnglish
Article number4021
JournalNature Communications
Publication statusPublished - 13 May 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Structured keywords

  • ICEP
  • Bristol Population Health Science Institute


  • Mendelian randomization
  • Childhood adiposity
  • Breast cancer
  • mediation analysis


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