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

In this new study, researchers from 177 institutions worldwide analyzed the DNA of about 70,000 women of European ancestry. They found more than 50 genetic variations, including 18 previously discovered ones, that seem to be linked to the age a woman reaches menopause.

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 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 (~6% increase in risk per year; P = 3 × 10−14), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Reference

Pery, JR et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet. 2015 Sep 28. doi: 10.1038/ng.3412. [Epub ahead of print] 

Content updated 16 October 2015

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