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

Day, F. R. et al. (2015) Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics, 47(11), pp. 1294-1303. (doi: 10.1038/ng.3412) (PMID:26414677)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Padmanabhan, Professor Sandosh
• Authors: 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. I., 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.'a., 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. P., 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. H. R., 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. R., 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., Price, A. L., Stefansson, K., Visser, J. A., Ong, K. K., Chang-Claude, J., Murabito, J. M., Perry, J. R. B., and Murray, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Genetics
• Publisher: Nature Publishing Group
• ISSN: 1061-4036
• ISSN (Online): 1546-1718