Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility
Authors: Day Felix R. , Thompson Deborah J. , Helgason Hannes , Chasman Daniel I. , Finucane Hilary , Sulem Patrick , Ruth Katherine S. , Whalen Sean , Sarkar Abhishek K. , Albrecht Eva , Altmaier Elisabeth , Amini Marzyeh , Barbieri Caterina M. , Boutin Thibaud , Campbell Archie , Demerath Ellen , Giri Ayush , He Chunyan , Hottenga Jouke J. , Karlsson Robert , Kolcic Ivana , Loh Po-Ru , Lunetta Kathryn L. , Mangino Massimo , Marco Brumat , McMahon George , Medland Sarah E. , Nolte Ilja M. , Noordam Raymond , Nutile Teresa , Paternoster Lavinia , Perjakova Natalia , Porcu Eleonora , Rose Lynda M. , Schraut Katharina E. , Segrè Ayellet V. , Smith Albert V. , Stolk Lisette , Teumer Alexander , Andrulis Irene L. , Bandinelli Stefania , Beckmann Matthias W. , Benitez Javier , Bergmann Sven , Bochud Murielle , Boerwinkle Eric , Bojesen Stig E. , Bolla Manjeet K. , Brand Judith S. , Brauch Hiltrud , Brenner Hermann , Broer Linda , Brüning Thomas , Buring Julie E. , Campbell Harry , Catamo Eulalia , Chanock Stephen , Chenevix-Trench Georgia , Corre Tanguy , Couch Fergus J. , Cousminer Diana L. , Cox Angela , Crisponi Laura , Czene Kamila , Davey-Smith George , de Geus Eco J.C.N , de Mutsert Renée , De Vivo Immaculata , Dennis Joe , Devilee Peter , dos-Santos-Silva Isabel , Dunning Alison M. , Eriksson Johan G. , Fasching Peter A. , Fernández-Rhodes Lindsay , Ferrucci Luigi , Flesch-Janys Dieter , Franke Lude , Gabrielson Marike , Gandin Ilaria , Giles Graham G. , Grallert Harald , Gudbjartsson Daniel F. , Guénel Pascal , Hall Per , Hallberg Emily , Hamann Ute , Harris Tamara B. , Hartman Catharina A. , Heiss Gerardo , Hooning Maartje J. , Hopper John L. , Hu Frank , Hunter David , Ikram M. Arfan , Im Hae Kyung , Järvelin Marjo-Riitta , Joshi Peter K. , Karasik David , Kutalik Zoltan , LaChance Genevieve , Lambrechts Diether , Langenberg Claudia , Launer Lenore J. , Laven Joop S.E. , Lenarduzzi Stefania , Li Jingmei , Lind Penelope A. , Lindstrom Sara , Liu YongMei , Luan Jian'an , Mägi Reedik , Mannermaa Arto , Mbarek Hamdi , McCarthy Mark I. , Meisinger Christa , Meitinger Thomas , Menni Cristina , Metspalu Andres , Michailidou Kyriaki , Milani Lili , Milne Roger L. , Montgomery Grant W. , Mulligan Anna M. , Nalls Mike A. , Navarro Pau , Nevanlinna Heli , Nyholt Dale R. , Oldehinkel Albertine J. , O'Mara Tracy A. , Palotie Aarno , Pedersen Nancy , Peters Annette , Peto Julian , Pharoah Paul D.P. , Pouta Anneli , Radice Paolo , Rahman Iffat , Ring Susan M. , Robino Antonietta , Rosendaal Frits R. , Rudan Igor , Rueedi Rico , Ruggiero Daniela , Sala Cinzia F. , Schmidt Marjanka K. , Scott Robert A. , Shah Mitul , Sorice Rossella , Southey Melissa C. , Sovio Ulla , Stampfer Meir , Steri Maristella , Strauch Konstantin , Tanaka Toshiko , Tikkanen Emmi , Timpson Nicholas J. , Traglia Michela , Truong Thérèse , Tyrer Jonathan P. , Uitterlinden André G. , Velez Edwards Digna R. , Vitart Veronique , Völker Uwe , Vollenweider Peter , Wang Qin , Widen Elisabeth , van Dijk Ko Willems , Willemsen Gonneke , Winqvist Robert , Wolffenbuttel Bruce H.R , Zhao Jing Hua , Zoledziewska Magdalena , Zygmunt Marek , Alizadeh Behrooz Z. , Boomsma Dorret I. , Ciullo Marina , Cucca Francesco , Esko Tõnu , Franceschini Nora , Gieger Christian , Gudnason Vilmundur , Hayward Caroline , Kraft Peter , Lawlor Debbie A. , Magnusson Patrik K.E , Martin Nicholas G. , Mook-Kanamori Dennis O. , Nohr Ellen A. , Polasek Ozren , Porteous David , Price Alkes L. , Ridker Paul M. , Snieder Harold , Spector Tim D. , Stöckl Doris , Toniolo Daniela , Ulivi Sheila , Visser Jenny A. , Völzke Henry , Wareham Nicholas J. , Wilson James F. ,   The LifeLines Cohort Study,   The InterAct Consortium,   kConFab/AOCS Investigators,   Endometrial Cancer Association Consortium,   Ovarian Cancer Association Consortium,   PRACTICAL consortium, Spurdle Amanda B. , Thorsteindottir Unnur , Pollard Katherine S. , Easton Douglas F. , Tung Joyce Y. , Chang-Claude Jenny , Hinds David , Murray Anna , Murabito Joanne M. , Stefansson Kari , Ong Ken K. , Perry John R.B 
Published: September 2016

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 genesMKRN3andDLK1that 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.