Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair EDITORIAL COMMENT (CROSBI ID 261853)
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Podaci o odgovornosti
Day, Felix R. ; Ruth, Katherine S. ; Thompson, Deborah J. ; Knight, Julia A. ; Kolcic, Ivana ; Polasek, Ozren ; Rudan, Igor ; Zemunik, Tatijana ; Hayward, Caroline ; Kardia, Sharon L. R. ; Kraft, Peter ; McKnight, Barbara ; Metspalu, Andres ; Morrison, Alanna C. ; Reiner, Alex P. ; Ridker, Paul M. ; Rotter, Jerome I. ; Toniolo, Daniela ; Uitterlinden, André G. ; Ulivi, Sheila ; Völzke, Henry ; Wareham, Nicholas J. ; Weir, David R. ; Yerges- Armstrong, Laura M. ; Price, Alkes L. ; Stefansson, Kari ; Visser, Jenny A. ; Ong, Ken K. ; Chang-Claude, Jenny ; Murabito, Joanne M. ; Perry, John R. B. ; Murray, Anna et al.
engleski
Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair EDITORIAL COMMENT
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 damage response (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.
GWAS ; meta-analysis ; menopause
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Podaci o izdanju
70 (12)
2015.
758-762
objavljeno
0029-7828
10.1097/01.ogx.0000473766.71624.99
Povezanost rada
Temeljne medicinske znanosti