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 Keller & 31 others 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, Javier Benitez, Lynne Hocking, PRACTICAL Consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1294-1303
Number of pages10
JournalNature Genetics
Volume47
Issue number11
Early online date28 Sep 2015
DOIs
Publication statusPublished - Nov 2015

Fingerprint

Menopause
DNA Repair
Breast Neoplasms
Mendelian Randomization Analysis
DNA Damage
Delayed Puberty
Gonadal Steroid Hormones
Infertility
Genes
Alleles
Proteins

Keywords

  • Breast cancer
  • Genome wide association studies
  • Menopause

Cite this

Day, F. R., Ruth, K. S., Thompson, D. J., Lunetta, K. L., Pervjakova, N., Chasman, D. I., ... PRACTICAL Consortium (2015). Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics, 47(11), 1294-1303. https://doi.org/10.1038/ng.3412

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. / Day, Felix R; Ruth, Katherine S; Thompson, Deborah J; Lunetta, Kathryn L; Pervjakova, Natalia; Chasman, Daniel I; Stolk, Lisette; Finucane, Hilary K; Sulem, Patrick; Bulik-Sullivan, Brendan; Esko, Tõnu; Johnson, Andrew D; Elks, Cathy E; Franceschini, Nora; He, Chunyan; Altmaier, Elisabeth; Brody, Jennifer A; Franke, Lude L; Huffman, Jennifer E; Keller, Margaux F; McArdle, Patrick F; Nutile, Teresa; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M; Schick, Ursula M; Smith, Jennifer A; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Zhao, Wei; Albrecht, Eva; Amin, Najaf; Corre, Tanguy; Hottenga, Jouke-Jan; Mangino, Massimo; Smith, Albert V; Tanaka, Toshiko; Abecasis, Gonçalo R; Andrulis, Irene L; Anton-Culver, Hoda; Antoniou, Antonis C; Arndt, Volker; Arnold, Alice M; Barbieri, Caterina; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Hocking, Lynne; PRACTICAL Consortium.

In: Nature Genetics, Vol. 47, No. 11, 11.2015, p. 1294-1303.

Research output: Contribution to journalArticle

Day, FR, Ruth, KS, Thompson, DJ, Lunetta, KL, Pervjakova, N, Chasman, DI, Stolk, L, Finucane, HK, Sulem, P, Bulik-Sullivan, B, Esko, T, Johnson, AD, Elks, CE, Franceschini, N, He, C, Altmaier, E, Brody, JA, Franke, LL, Huffman, JE, Keller, MF, McArdle, PF, Nutile, T, Porcu, E, Robino, A, Rose, LM, Schick, UM, Smith, JA, Teumer, A, Traglia, M, Vuckovic, D, Yao, J, Zhao, W, Albrecht, E, Amin, N, Corre, T, Hottenga, J-J, Mangino, M, Smith, AV, Tanaka, T, Abecasis, GR, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Arnold, AM, Barbieri, C, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Hocking, L & PRACTICAL Consortium 2015, 'Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair', Nature Genetics, vol. 47, no. 11, pp. 1294-1303. https://doi.org/10.1038/ng.3412
Day, Felix R ; Ruth, Katherine S ; Thompson, Deborah J ; Lunetta, Kathryn L ; Pervjakova, Natalia ; Chasman, Daniel I ; Stolk, Lisette ; Finucane, Hilary K ; Sulem, Patrick ; Bulik-Sullivan, Brendan ; Esko, Tõnu ; Johnson, Andrew D ; Elks, Cathy E ; Franceschini, Nora ; He, Chunyan ; Altmaier, Elisabeth ; Brody, Jennifer A ; Franke, Lude L ; Huffman, Jennifer E ; Keller, Margaux F ; McArdle, Patrick F ; Nutile, Teresa ; Porcu, Eleonora ; Robino, Antonietta ; Rose, Lynda M ; Schick, Ursula M ; Smith, Jennifer A ; Teumer, Alexander ; Traglia, Michela ; Vuckovic, Dragana ; Yao, Jie ; Zhao, Wei ; Albrecht, Eva ; Amin, Najaf ; Corre, Tanguy ; Hottenga, Jouke-Jan ; Mangino, Massimo ; Smith, Albert V ; Tanaka, Toshiko ; Abecasis, Gonçalo R ; Andrulis, Irene L ; Anton-Culver, Hoda ; Antoniou, Antonis C ; Arndt, Volker ; Arnold, Alice M ; Barbieri, Caterina ; Beckmann, Matthias W ; Beeghly-Fadiel, Alicia ; Benitez, Javier ; Hocking, Lynne ; PRACTICAL Consortium. / Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. In: Nature Genetics. 2015 ; Vol. 47, No. 11. pp. 1294-1303.
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AU - Pervjakova, Natalia

AU - Chasman, Daniel I

AU - Stolk, Lisette

AU - Finucane, Hilary K

AU - Sulem, Patrick

AU - Bulik-Sullivan, Brendan

AU - Esko, Tõnu

AU - Johnson, Andrew D

AU - Elks, Cathy E

AU - Franceschini, Nora

AU - He, Chunyan

AU - Altmaier, Elisabeth

AU - Brody, Jennifer A

AU - Franke, Lude L

AU - Huffman, Jennifer E

AU - Keller, Margaux F

AU - McArdle, Patrick F

AU - Nutile, Teresa

AU - Porcu, Eleonora

AU - Robino, Antonietta

AU - Rose, Lynda M

AU - Schick, Ursula M

AU - Smith, Jennifer A

AU - Teumer, Alexander

AU - Traglia, Michela

AU - Vuckovic, Dragana

AU - Yao, Jie

AU - Zhao, Wei

AU - Albrecht, Eva

AU - Amin, Najaf

AU - Corre, Tanguy

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AU - Smith, Albert V

AU - Tanaka, Toshiko

AU - Abecasis, Gonçalo R

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