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Get Free AccessAbstract The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P<5×10 −8 ) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.
Felix R. Day, Deborah J. Thompson, Hannes Helgason, Daniel I. Chasman, Hilary K. Finucane, Patrick Sulem, Katherine S. Ruth, Sean Whalen, Abhishek Sarkar, Eva Albrecht, Elisabeth Altmaier, Marzyeh Amini, Caterina Barbieri, Thibaud Boutin, Archie Campbell, Ellen W. Demerath, Ayush Giri, Chunyan He, Jouke‐Jan Hottenga, Robert Karlsson, Ivana Kolčić, Po−Ru Loh, Kathryn L. Lunetta, Massimo Mangino, Marco Brumat, George McMahon, Sarah E. Medland, Ilja M. Nolte, Raymond Noordam, Teresa Nutile, Lavinia Paternoster, Natalia Perjakova, Eleonora Porcu, Lynda M. Rose, Katharina E. Schraut, Ayellet V. Segrè, Albert V. Smith, Lisette Stolk, Alexander Teumer, Irene L. Andrulis, Stefania Bandinelli, Matthias W. Beckmann, Javier Benı́tez, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E. Bojesen, Manjeet K. Bolla, Judith S. Brand, Hiltrud Brauch, Hermann Brenner, Linda Broer, Thomas Brüning, Julie E. Buring, Harry Campbell, Eulalia Catamo, Stephen J. Chanock, Georgia Chenevix‐Trench, Tanguy Corre, Fergus J. Couch, Diana L. Cousminer, Angela Cox, Laura Crisponi, Kamila Czene, George Davey Smith, Eco J. C. de Geus, Renée de Mutsert, Immaculata De Vivo, Joe Dennis, Peter Devilee, Isabel dos‐Santos‐Silva, Alison M. Dunning, Johan G. Eriksson, Peter A. Fasching, Lindsay Fernández‐Rhodes, Luigi Ferrucci, Dieter Flesch‐Janys, Lude Franke, Marike Gabrielson, Ilaria Gandin, Graham G. Giles, Harald Grallert, Daníel F. Guðbjartsson, Pascal Guénel, Per Hall, Emily Hallberg, Ute Hamann, Tamara B. Harris, Catharina A. Hartman, Gerardo Heiss, Maartje J. Hooning, John L. Hopper, Frank B. Hu, David J. Hunter, M. Arfan Ikram, Hae Kyung Im, Paul M Ridker, Peter K. Joshi, David Karasik, Zoltán Kutalik (2016). Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility. , DOI: https://doi.org/10.1101/076794.
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Type
Preprint
Year
2016
Authors
100
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1101/076794
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