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.
Authors
- Genevieve M Leyden (ORCID: https://orcid.org/0000-0002-6024-4950)
- Laxmi Bhatta (ORCID: https://orcid.org/0000-0002-8166-1470)
- Amanda Hughes (ORCID: https://orcid.org/0000-0001-5896-7650)
- Grace Marion Power (ORCID: https://orcid.org/0000-0002-5702-7728)
- Bethan Lloyd‐Lewis (ORCID: https://orcid.org/0000-0001-6511-1818)
- J. Felix
- A. Havdahl
- Gibran Hemani
- Caroline Hayward
- Elizabeth C Corfield
- Carolina Medina-Gomez
- Rebecca Richmond
- George Davey Smith
- Anne Richmond
- Ben Brumpton
- Daniel McCartney
- Eleanor Sanderson
- Irene Fontes Marques
- Bjørn Olav Åsvold
Institutions
- Norwegian Institute of Public Health (NO)
- The University of Queensland (AU)
- University of Oslo (NO)
- Norwegian University of Science and Technology (NO)
- Western General Hospital (GB)
- University Hospitals Bristol NHS Foundation Trust (GB)
- Erasmus MC (NL)
- Edinburgh Cancer Research (GB)
- University of Bristol (GB)
- Lovisenberg Diakonale Høgskole (NO)
- St Olav's University Hospital (NO)
- NIHR Bristol Biomedical Research Centre (GB)
- MRC Epidemiology Unit (GB)
- Institute of Genetics and Cancer (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2026-01-21
- DOI
- https://doi.org/10.1126/sciadv.ady0374
- Primary Topic
- Cancer Risks and Factors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Scottish Government
- Cancer Research UK
- National Institute for Health and Care Research
- British Heart Foundation
- Scottish Funding Council
- European Commission
- University of Bristol
- ZonMw
- Erasmus Universiteit Rotterdam
- Norges Forskningsråd
- St. Olavs Hospital Universitetssykehuset i Trondheim
- National Institutes of Health
- HORIZON EUROPE Framework Programme
- Elizabeth Blackwell Institute for Health Research, University of Bristol
- Medical Research Council
- Helse Sør-Øst RHF
- Faculty of Medicine and Health, University of Sydney