Naslov
Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Autori
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. et al.

Izvornik
Nature Genetics (1061-4036) 47 (2015), 11; 1294-1303

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
PREMATURE OVARIAN FAILURE ; BRCA2 MUTATION CARRIERS ; BODY-MASS INDEX ; NATURAL MENOPAUSE ; HOMOLOGOUS RECOMBINATION ; CHROMOSOMAL INSTABILITY ; WIDE ASSOCIATION ; BLOOD-PRESSURE ; CELL-TYPES ; LOCI

Sažetak
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 similar to 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 regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year ; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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