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

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.; Keller, M.F.; McArdle, P.F.; Nutile, T.; Porcu, E.; Robino, A.; Rose, L.M.; Schick, U.M.; Smith, J.A.; Teumer, A.; Traglia, M.; Vuckovic, D.; Yao, J.; Zhao, W.; Albrecht, E.; Amin, N.; Corre, T.; Hottenga, J.J.; Mangino, M.; Smith, A.V.; Tanaka, T.; Abecasis, G.R.; Andrulis, I.L.; Anton-Culver, H.; Antoniou, A.C.; Arndt, V.; Arnold, A.M.; Barbieri, C.; Beckmann, M.W.; Beeghly-Fadiel, A.; Benitez, J.; Bernstein, L.; Bielinski, S.J.; Blomqvist, C.; Boerwinkle, E.; Bogdanova, N.V.; Bojesen, S.E.; Bolla, M.K.; Borresen-Dale, A.L.; Boutin, T.S.; Brauch, H.; Brenner, H.; Brüning, T.; Burwinkel, B.; Campbell, A.; Campbell, H.; Chanock, S.J.; Chapman, J.R.; Chen, Y.D.; Chenevix-Trench, G.; Couch, F.J.; Coviello, A.D.; Cox, A.; Czene, K.; Darabi, H.; De Vivo, I.; Demerath, E.W.; Dennis, J.; Devilee, P.; Dörk, T.; Dos-Santos-Silva, I.; Dunning, A.M.; Eicher, J.D.; Fasching, P.A.; Faul, J.D.; Figueroa, J.; Flesch-Janys, D.; Gandin, I.; Garcia, M.E.; García-Closas, M.; Giles, G.G.; Girotto, G.G.; Goldberg, M.S.; González-Neira, A.; Goodarzi, M.O.; Grove, M.L.; Gudbjartsson, D.F.; Guénel, P.; Guo, X.; Haiman, C.A.; Hall, P.; Hamann, U.; Henderson, B.E.; Hocking, L.J.; Hofman, A.; Homuth, G.; Hooning, M.J.; Hopper, J.L.; Hu, F.B.; Huang, J.; Humphreys, K.; Hunter, D.J.; Jakubowska, A.; Jones, S.E.; Kabisch, M.; Karasik, D.; Knight, J.A.; Kolcic, I.; Kooperberg, C.; Kosma, V.M.; Kriebel, J.; Kristensen, V.; Lambrechts, D.; Langenberg, C.; Li, J.; Li, X.; Lindström, S.; Liu, Y.; Luan, J.; Lubinski, J.; Mägi, R.; Mannermaa, A.; Manz, J.; Margolin, S.; Marten, J.; Martin, N.G.; Masciullo, C.; Meindl, A.; Michailidou, K.; Mihailov, E.; Milani, L.; Milne, R.L.; Müller-Nurasyid, M.; Nalls, M.; Neale, B.M.; Nevanlinna, H.; Neven, P.; Newman, A.B.; Nordestgaard, B.G.; Olson, J.E.; Padmanabhan, S.; Peterlongo, P.; Peters, U.; Petersmann, A.; Peto, J.; Pharoah, P.D.; Pirastu, N.N.; Pirie, A.; Pistis, G.; Polasek, O.; Porteous, D.; Psaty, B.M.; Pylkäs, K.; Radice, P.; Raffel, L.J.; Rivadeneira, F.; Rudan, I.; Rudolph, A.; Ruggiero, D.; Sala, C.F.; Sanna, S.; Sawyer, E.J.; Schlessinger, D.; Schmidt, M.K.; Schmidt, F.; Schmutzler, R.K.; Schoemaker, M.J.; Scott, R.A.; Seynaeve, C.M.; Simard, J.; Sorice, R.; Southey, M.C.; Stöckl, D.; Strauch, K.; Swerdlow, A.; Taylor, K.D.; Thorsteinsdottir, U.; Toland, A.E.; Tomlinson, I.; Truong, T.; Tryggvadottir, L.; Turner, S.T.; Vozzi, D.; Wang, Q.; Wellons, M.; Willemsen, G.; Wilson, J.F.; Winqvist, R.; Wolffenbuttel, B.B.; Wright, A.F.; Yannoukakos, D.; Zemunik, T.; Zheng, W.; Zygmunt, M.; Bergmann, S.; Boomsma, D.I.; Buring, J.E.; Ferrucci, L.; Montgomery, G.W.; Gudnason, V.; Spector, T.D.; van Duijn, C.M.; Alizadeh, B.Z.; Ciullo, M.; Crisponi, L.; Easton, D.F.; Gasparini, P.P.; Gieger, C.; Harris, T.B.; Hayward, C.; Kardia, S.L.; Kraft, P.; McKnight, B.; Metspalu, A.; Morrison, A.C.; Reiner, A.P.; Ridker, P.M.; Rotter, J.I.; Toniolo, D.; Uitterlinden, A.G.; Ulivi, S.; Völzke, H.; Wareham, N.J.; Weir, D.R.; Yerges-Armstrong, L.M.; Generation, Scotland; Price, A.L.; Price, A.L.; Stefansson, K.; Visser, J.A.; Ong, K.K.; Chang-Claude, J.; Murabito, J.M.; Perry, J.R.; Murray, A.

doi:10.1038/ng.3412

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

Details

Download: 26414677_BIB_95D27766A246.pdf (1137.12 [Ko])
State: Public
Version: Author's accepted manuscript
License: Not specified

Serval ID

serval:BIB_95D27766A246

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

Nature Genetics

Author(s)

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., Keller M.F., McArdle P.F., Nutile T., Porcu E., Robino A., Rose L.M., Schick U.M., Smith J.A., Teumer A., Traglia M., Vuckovic D., Yao J., Zhao W., Albrecht E., Amin N., Corre T., Hottenga J.J., Mangino M., Smith A.V., Tanaka T., Abecasis G.R., Andrulis I.L., Anton-Culver H., Antoniou A.C., Arndt V., Arnold A.M., Barbieri C., Beckmann M.W., Beeghly-Fadiel A., Benitez J., Bernstein L., Bielinski S.J., Blomqvist C., Boerwinkle E., Bogdanova N.V., Bojesen S.E., Bolla M.K., Borresen-Dale A.L., Boutin T.S., Brauch H., Brenner H., Brüning T., Burwinkel B., Campbell A., Campbell H., Chanock S.J., Chapman J.R., Chen Y.D., Chenevix-Trench G., Couch F.J., Coviello A.D., Cox A., Czene K., Darabi H., De Vivo I., Demerath E.W., Dennis J., Devilee P., Dörk T., Dos-Santos-Silva I., Dunning A.M., Eicher J.D., Fasching P.A., Faul J.D., Figueroa J., Flesch-Janys D., Gandin I., Garcia M.E., García-Closas M., Giles G.G., Girotto G.G., Goldberg M.S., González-Neira A., Goodarzi M.O., Grove M.L., Gudbjartsson D.F., Guénel P., Guo X., Haiman C.A., Hall P., Hamann U., Henderson B.E., Hocking L.J., Hofman A., Homuth G., Hooning M.J., Hopper J.L., Hu F.B., Huang J., Humphreys K., Hunter D.J., Jakubowska A., Jones S.E., Kabisch M., Karasik D., Knight J.A., Kolcic I., Kooperberg C., Kosma V.M., Kriebel J., Kristensen V., Lambrechts D., Langenberg C., Li J., Li X., Lindström S., Liu Y., Luan J., Lubinski J., Mägi R., Mannermaa A., Manz J., Margolin S., Marten J., Martin N.G., Masciullo C., Meindl A., Michailidou K., Mihailov E., Milani L., Milne R.L., Müller-Nurasyid M., Nalls M., Neale B.M., Nevanlinna H., Neven P., Newman A.B., Nordestgaard B.G., Olson J.E., Padmanabhan S., Peterlongo P., Peters U., Petersmann A., Peto J., Pharoah P.D., Pirastu N.N., Pirie A., Pistis G., Polasek O., Porteous D., Psaty B.M., Pylkäs K., Radice P., Raffel L.J., Rivadeneira F., Rudan I., Rudolph A., Ruggiero D., Sala C.F., Sanna S., Sawyer E.J., Schlessinger D., Schmidt M.K., Schmidt F., Schmutzler R.K., Schoemaker M.J., Scott R.A., Seynaeve C.M., Simard J., Sorice R., Southey M.C., Stöckl D., Strauch K., Swerdlow A., Taylor K.D., Thorsteinsdottir U., Toland A.E., Tomlinson I., Truong T., Tryggvadottir L., Turner S.T., Vozzi D., Wang Q., Wellons M., Willemsen G., Wilson J.F., Winqvist R., Wolffenbuttel B.B., Wright A.F., Yannoukakos D., Zemunik T., Zheng W., Zygmunt M., Bergmann S., Boomsma D.I., Buring J.E., Ferrucci L., Montgomery G.W., Gudnason V., Spector T.D., van Duijn C.M., Alizadeh B.Z., Ciullo M., Crisponi L., Easton D.F., Gasparini P.P., Gieger C., Harris T.B., Hayward C., Kardia S.L., Kraft P., McKnight B., Metspalu A., Morrison A.C., Reiner A.P., Ridker P.M., Rotter J.I., Toniolo D., Uitterlinden A.G., Ulivi S., Völzke H., Wareham N.J., Weir D.R., Yerges-Armstrong L.M., Generation Scotland, Price A.L., Price A.L., Stefansson K., Visser J.A., Ong K.K., Chang-Claude J., Murabito J.M., Perry J.R., Murray A.

Working group(s)

PRACTICAL Consortium, kConFab Investigators, AOCS Investigators, EPIC-InterAct Consortium, LifeLines Cohort Study

Contributor(s)

Generation Scotland

ISSN

1546-1718 (Electronic)

ISSN-L

1061-4036

Publication state

Published

Issued date

2015

Peer-reviewed

Oui

Volume

Number

Pages

1294-1303

Language

english

Notes

Publication types: Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: ppublish

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

URN

urn:nbn:ch:serval-BIB_95D27766A2465

OAI-PMH

oai:serval.unil.ch:BIB_95D27766A246

DOI

10.1038/ng.3412

Pubmed

26414677

Web of science

000363988200013

Create date

01/12/2015 18:44