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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • 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 Keller
  • Patrick 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
  • Bojesen, Stig Egil
  • Nordestgaard, Børge
  • PRACTICAL Consortium

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.

TidsskriftNature Genetics
Udgave nummer11
Sider (fra-til)1294-303 + 2 unpag.
Antal sider12
StatusUdgivet - nov. 2015

ID: 160865949