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; 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; Stig E Bojesen; Børge G Nordestgaard; PRACTICAL Consortium

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, 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, Stig E Bojesen, Børge G Nordestgaard, PRACTICAL Consortium

Department of Clinical Medicine

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 language	English
Journal	Nature Genetics
Volume	47
Issue number	11
Pages (from-to)	1294-303 + 2 unpag.
Number of pages	12
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3412
Publication status	Published - 1 Dec 2015

Keywords

Adult
Age Factors
Aging
BRCA1 Protein
Breast Neoplasms
DNA Repair
Female
Gene Regulatory Networks
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Genomics
Genotype
Humans
Hypothalamus
Menopause
Middle Aged
Models, Genetic
Phenotype
Reproduction
Signal Transduction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.3412

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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., ... 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), 1294-303 + 2 unpag. https://doi.org/10.1038/ng.3412

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, Bojesen, SE , Nordestgaard, BG & 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. 1294-303 + 2 unpag. https://doi.org/10.1038/ng.3412

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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.",

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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 - Tanaka, Toshiko

AU - Abecasis, Gonçalo R

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Antoniou, Antonis C

AU - Arndt, Volker

AU - Arnold, Alice M

AU - Barbieri, Caterina

AU - Beckmann, Matthias W

AU - Beeghly-Fadiel, Alicia

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - PRACTICAL Consortium

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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.

KW - Adult

KW - Age Factors

KW - Aging

KW - BRCA1 Protein

KW - Breast Neoplasms

KW - DNA Repair

KW - Female

KW - Gene Regulatory Networks

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genomics

KW - Genotype

KW - Humans

KW - Hypothalamus

KW - Menopause

KW - Middle Aged

KW - Models, Genetic

KW - Phenotype

KW - Reproduction

KW - Signal Transduction

U2 - 10.1038/ng.3412

DO - 10.1038/ng.3412

M3 - Journal article

C2 - 26414677

SN - 1061-4036

VL - 47

SP - 1294-303 + 2 unpag.

JO - Nature: New biology

JF - Nature: New biology

IS - 11

ER -

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

Abstract

Keywords

UN SDGs

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