Lifecourse genome-wide association study meta-analysis refines the critical life stages for adiposity’s influence on breast cancer risk

Power, Grace 1 ; Hughes, Amanda1 ; Bhatta, Laxmi2 ; Medina-Gomez, Carolina3 ; Richmond, Anne4 ; Leyden, Genevieve1 ; Lloyd-Lewis, Bethan 1 ; Sanderson, Eleanor1 ; Richmond, Rebecca1 ; Corfield, Elizabeth 1 ; McCartney, Daniel4 ; Hayward, Caroline4 ; Fontes Marques, Irene5 ; Rivadeneira, Fernando 3 ; Åsvold, Bjørn Olav 2 ; Hemani, Gibran 1 ; Felix, Janine F.5 ; Brumpton, Ben 2 ; Havdahl, Alexandra6 ; Davey Smith, George 1

Published Dec 18, 2025 on Dryad. https://doi.org/10.5061/dryad.0gb5mkmcn

Data files

Dec 18, 2025 version files 3.38 GB

Abstract

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.

Dataset DOI: 10.5061/dryad.0gb5mkmcn

Description of the data and file structure

Four files:

gwas_metaanalysis_bmi_f_1019
gwas_metaanalysis_bmi_f_2029
gwas_metaanalysis_bmi_f_3039
gwas_metaanalysis_bmi_f_total

The data consist of meta-analysed genome-wide association study (GWAS) summary statistics for BMI in nulliparous females between menarche and age <40 years. Summary statistics were generated separately for three age groups (<20 years, 20–<30 years, and 30–<40 years) using data from five population-based cohorts (ALSPAC, HUNT, MoBa, Generation R, and Generation Scotland), and combined using fixed-effect meta-analysis.

Code/software

The standard operating procedure (SOP) and analysis scripts used to conduct the genome-wide association study (GWAS) of BMI between menarche and first birth are available in a GitHub repository:
https://github.com/gracemarionpower/Collaboration_MA_BMI_M2FB.
A citable snapshot of the repository is archived on Zenodo:
https://doi.org/10.5281/zenodo.17178557

Access information

Data access for the Avon Longitudinal Study of Parents and Children (ALSPAC) operates via a managed open access system. Approved proposals are reviewed by the ALSPAC Executive Committee. Full details are provided in the ALSPAC Data Management Plan (www.bristol.ac.uk/alspac/researchers/data-access/documents/alspac-data-management-plan.pdf). Data from the Norwegian Mother, Father and Child (MoBa) Cohort Study is managed by the Norwegian Institute of Public Health. Access is provided upon approval from the Regional Committees for Medical and Health Research Ethics (REC), compliance with GDPR, and data owner approval. Participant consent does not allow individual-level data storage in repositories or journals. Researchers seeking access for replication must apply via www.helsedata.no. To request access to data from the Trøndelag Health Study (HUNT), researchers affiliated with Norwegian research institutes can apply for the use of HUNT data and biological samples, subject to approval by the Regional Committee for Medical and Health Research Ethics. Researchers from other countries may also apply if collaborating with a Norwegian Principal Investigator. All applications are reviewed by the HUNT Data Access Committee, and successful applicants are required to enter into data access and/or material transfer agreements. Detailed information on the application process, ethical requirements, and available datasets can be found on the HUNT website (www.ntnu.edu/hunt/data). Data from Generation Scotland are available on application to an independent access committee. More information can be found on the Generation Scotland website (www.generationscotland.org). Data from the Generation R Study are available upon reasonable request to the director of the Generation R Study (generationr@erasmusmc.nl), subject to local, national, and European rules and regulations.

Human subjects data

All participants provided informed consent for cohort participation and for the use of their de-identified data in research. Only summary-level genome-wide association study (GWAS) statistics, which contain no individual-level information, are shared in this repository. No directly identifying variables are included. All data were aggregated across large participant groups, and all cohort-level governance policies regarding the sharing of de-identified data were strictly followed prior to public release.