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; 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; Thibaud S Boutin; Archie Campbell; Harry Campbell; Jonine Figueroa; Nicola Pirastu; Ailith Pirie; Ozren Polasek; David Porteous; Igor Rudan; James F Wilson; Alan F Wright; Caroline Hayward; PRACTICAL Consortium; Ian Tomlinson

doi:10.1038/ng.3412

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, Thibaud S Boutin, Archie Campbell, Harry Campbell, Jonine Figueroa, Nicola Pirastu, Ailith Pirie, Ozren Polasek, David Porteous, Igor Rudan, James F Wilson, Alan F Wright, Caroline Hayward, PRACTICAL Consortium, Ian Tomlinson

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Abstract / Description of output

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 language	English
Pages (from-to)	1294-303
Number of pages	10
Journal	Nature Genetics
Volume	47
Issue number	11
DOIs	https://doi.org/10.1038/ng.3412
Publication status	Published - Nov 2015

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Day, F. R., Ruth, K. S., Thompson, D. J., Lunetta, K. L., Pervjakova, N., Chasman, D. I., Stolk, L., Finucane, H. K., Sulem, P., Bulik-Sullivan, B., Esko, T., Johnson, A. D., Elks, C. E., Franceschini, N., He, C., Altmaier, E., Brody, J. A., Franke, L. L., Huffman, J. E., ... Tomlinson, I. (2015). Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics, 47(11), 1294-303. https://doi.org/10.1038/ng.3412

@article{9a88d39324644349a0812ef1d0e94346,

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

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.",

author = "Day, {Felix R} and Ruth, {Katherine S} and Thompson, {Deborah J} and Lunetta, {Kathryn L} and Natalia Pervjakova and Chasman, {Daniel I} and Lisette Stolk and Finucane, {Hilary K} and Patrick Sulem and Brendan Bulik-Sullivan and T{\~o}nu Esko and Johnson, {Andrew D} and Elks, {Cathy E} and Nora Franceschini and Chunyan He and Elisabeth Altmaier and Brody, {Jennifer A} and Franke, {Lude L} and Huffman, {Jennifer E} and Keller, {Margaux F} and McArdle, {Patrick F} and Teresa Nutile and Eleonora Porcu and Antonietta Robino and Rose, {Lynda M} and Schick, {Ursula M} and Smith, {Jennifer A} and Alexander Teumer and Michela Traglia and Dragana Vuckovic and Jie Yao and Wei Zhao and Eva Albrecht and Najaf Amin and Tanguy Corre and Jouke-Jan Hottenga and Massimo Mangino and Smith, {Albert V} and Boutin, {Thibaud S} and Archie Campbell and Harry Campbell and Jonine Figueroa and Nicola Pirastu and Ailith Pirie and Ozren Polasek and David Porteous and Igor Rudan and Wilson, {James F} and Wright, {Alan F} and Caroline Hayward and {PRACTICAL Consortium} and Ian Tomlinson",

year = "2015",

month = nov,

doi = "10.1038/ng.3412",

language = "English",

volume = "47",

pages = "1294--303",

journal = "Nature Genetics",

issn = "1061-4036",

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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, Boutin, TS , Campbell, A , Campbell, H , Figueroa, J , Pirastu, N , Pirie, A, Polasek, O, Porteous, D, Rudan, I , Wilson, JF, Wright, AF, Hayward, C, PRACTICAL Consortium & Tomlinson, I 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. 1294-303. https://doi.org/10.1038/ng.3412

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T1 - Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

AU - Day, Felix R

AU - Ruth, Katherine S

AU - Thompson, Deborah J

AU - Lunetta, Kathryn L

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

AU - Hottenga, Jouke-Jan

AU - Mangino, Massimo

AU - Smith, Albert V

AU - Boutin, Thibaud S

AU - Campbell, Archie

AU - Campbell, Harry

AU - Figueroa, Jonine

AU - Pirastu, Nicola

AU - Pirie, Ailith

AU - Polasek, Ozren

AU - Porteous, David

AU - Rudan, Igor

AU - Wilson, James F

AU - Wright, Alan F

AU - Hayward, Caroline

AU - PRACTICAL Consortium

AU - Tomlinson, Ian

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

U2 - 10.1038/ng.3412

DO - 10.1038/ng.3412

M3 - Article

C2 - 26414677

SN - 1061-4036

VL - 47

SP - 1294

EP - 1303

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

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