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

Institut for Klinisk Medicin

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	47
Udgave nummer	11
Sider (fra-til)	1294-303 + 2 unpag.
Antal sider	12
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3412
Status	Udgivet - 1 dec. 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., ... 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, bind 47, nr. 11, s. 1294-303 + 2 unpag. https://doi.org/10.1038/ng.3412

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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.",

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",

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 Toshiko Tanaka and Abecasis, {Gon{\c c}alo R} and Andrulis, {Irene L} and Hoda Anton-Culver and Antoniou, {Antonis C} and Volker Arndt and Arnold, {Alice M} and Caterina Barbieri and Beckmann, {Matthias W} and Alicia Beeghly-Fadiel and Bojesen, {Stig E} and Nordestgaard, {B{\o}rge G} and {PRACTICAL Consortium}",

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doi = "10.1038/ng.3412",

language = "English",

volume = "47",

pages = "1294--303 + 2 unpag.",

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TY - JOUR

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 - 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

PY - 2015/12/1

Y1 - 2015/12/1

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

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