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

Felix R Day, Katherine S Ruth, Deborah J Thompson, Kathryn L Lunetta, Natalia Pervjakova, Daniel I Chasman, Lisette Stolk, Hilary K Finucane, Patrick Sulem, Brendan Bulik-Sullivan, Tõnu Esko, Andrew D Johnson, Cathy E Elks, Nora Franceschini, Chunyan He, Elisabeth Altmaier, Jennifer A Brody, Lude L Franke, Jennifer E Huffman, Margaux F KellerPatrick F McArdle, Teresa Nutile, Eleonora Porcu, Antonietta Robino, Lynda M Rose, Ursula M Schick, Jennifer A Smith, Alexander Teumer, Michela Traglia, Dragana Vuckovic, Jie Yao, Wei Zhao, Eva Albrecht, Najaf Amin, Tanguy Corre, Jouke-Jan Hottenga, Massimo Mangino, Albert V Smith, Toshiko Tanaka, Gonçalo R Abecasis, Irene L Andrulis, Hoda Anton-Culver, Antonis C Antoniou, Volker Arndt, Alice M Arnold, Caterina Barbieri, Matthias W Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Lynne Hocking, PRACTICAL Consortium

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1294-1303
Number of pages10
JournalNature Genetics
Issue number11
Early online date28 Sept 2015
Publication statusPublished - Nov 2015

Bibliographical note

Date of Acceptance: 21/08/2015

We acknowledge the use of data from the International Consortium for Blood Pressure Genome-Wide Association Studies

various funding bodies are acknowledged by the authors


  • Breast cancer
  • Genome wide association studies
  • Menopause


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