Day, FR, Ruth, KS, Thompson, DJ et al. (240 more authors) (2015) Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics, 47 (11). ISSN 1061-4036
Abstract
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damageresponse (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016. This is an author produced version of a paper subsequently published in Nature Genetics . Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number YORKSHIRE CANCER RESEARCH S299 CANCER RESEARCH UK (CRUK) C5410/A7315. |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 08 Dec 2016 15:05 |
Last Modified: | 23 Mar 2018 23:03 |
Published Version: | https://doi.org/10.1038/ng.3412 |
Status: | Published |
Publisher: | Nature Publishing Group |
Refereed: | Yes |
Identification Number: | 10.1038/ng.3412 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:107830 |