Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Day, F. R. et al. (2017) Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nature Genetics, 49(6), pp. 834-841. (doi: 10.1038/ng.3841) (PMID:28436984)

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Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh
Authors: Day, F. R., Thompson, D. J., Helgason, H., Chasman, D. I., Finucane, H., Sulem, P., Ruth, K. S., Whalen, S., Sarkar, A. K., Albrecht, E., Altmaier, E., Amini, M., Barbieri, C. M., Boutin, T., Campbell, A., Demerath, E., Giri, A., He, C., Hottenga, J. J., Karlsson, R., Kolcic, I., Loh, P.-R., Lunetta, K. L., Mangino, M., Marco, B., McMahon, G., Medland, S. E., Nolte, I. M., Noordam, R., Nutile, T., Paternoster, L., Perjakova, N., Porcu, E., Rose, L. M., Schraut, K. E., Segrè, A. V., Smith, A. V., Stolk, L., Teumer, A., Andrulis, I. L., Bandinelli, S., Beckmann, M. W., Benitez, J., Bergmann, S., Bochud, M., Boerwinkle, E., Bojesen, S. E., Bolla, M. K., Brand, J. S., Brauch, H., Brenner, H., Broer, L., Brüning, T., Buring, J. E., Campbell, H., Catamo, E., Chanock, S., Chenevix-Trench, G., Corre, T., Couch, F. J., Cousminer, D. L., Cox, A., Crisponi, L., Czene, K., Davey Smith, G., de Geus, E. J. C. N., de Mutsert, R., De Vivo, I., Dennis, J., Devilee, P., Dos-Santos-Silva, I., Dunning, A. M., Eriksson, J. G., Fasching, P. A., Fernández-Rhodes, L., Ferrucci, L., Flesch-Janys, D., Franke, L., Gabrielson, M., Gandin, I., Giles, G. G., Grallert, H., Gudbjartsson, D. F., Guénel, P., Hall, P., Hallberg, E., Hamann, U., Harris, T. B., Hartman, C. A., Heiss, G., Hooning, M. J., Hopper, J. L., Hu, F., Hunter, D. J., Ikram, M. A., Im, H. K., Järvelin, M.-R., Joshi, P. K., Karasik, D., Kellis, M., Kutalik, Z., LaChance, G., Lambrechts, D., Langenberg, C., Launer, L. J., Laven, J. S. E., Lenarduzzi, S., Li, J., Lind, P. A., Lindstrom, S., Liu, Y., Luan, J.'a., Mägi, R., Mannermaa, A., Mbarek, H., McCarthy, M. I., Meisinger, C., Meitinger, T., Menni, C., Metspalu, A., Michailidou, K., Milani, L., Milne, R. L., Montgomery, G. W., Mulligan, A. M., Nalls, M. A., Navarro, P., Nevanlinna, H., Nyholt, D. R., Oldehinkel, A. J., O'Mara, T. A., Padmanabhan, S., Palotie, A., Pedersen, N., Peters, A., Peto, J., Pharoah, P. D. P., Pouta, A., Radice, P., Rahman, I., Ring, S. M., Robino, A., Rosendaal, F. R., Rudan, I., Rueedi, R., Ruggiero, D., Sala, C. F., Schmidt, M. K., Scott, R. A., Shah, M., Sorice, R., Southey, M. C., Sovio, U., Stampfer, M., Steri, M., Strauch, K., Tanaka, T., Tikkanen, E., Timpson, N. J., Traglia, M., Truong, T., Tyrer, J. P., Uitterlinden, A. G., Edwards, D. R. V., Vitart, V., Völker, U., Vollenweider, P., Wang, Q., Widen, E., van Dijk, K. W., Willemsen, G., Winqvist, R., Wolffenbuttel, B. H. R., Zhao, J. H., Zoledziewska, M., Zygmunt, M., Alizadeh, B. Z., Boomsma, D. I., Ciullo, M., Cucca, F., Esko, T., Franceschini, N., Gieger, C., Gudnason, V., Hayward, C., Kraft, P., Lawlor, D. A., Magnusson, P. K. E., Martin, N. G., Mook-Kanamori, D. O., Nohr, E. A., Polasek, O., Porteous, D., Price, A. L., Ridker, P. M., Snieder, H., Spector, T. D., Stöckl, D., Toniolo, D., Ulivi, S., Visser, J. A., Völzke, H., Wareham, N. J., Wilson, J. F., Spurdle, A. B., Thorsteindottir, U., Pollard, K. S., Easton, D. F., Tung, J. Y., Chang-Claude, J., Hinds, D., Murray, A., Murabito, J. M., Stefansson, K., Ong, K. K., and Perry, J. R. B.
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
Published Online:24 April 2017
Copyright Holders:Copyright © 2017 Nature America, Inc., part of Springer Nature
First Published:First published in Nature Genetics 49(6): 834-841
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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