Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.
;
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;
Daniel F Gudbjartsson;
Pascal Guénel;
Per Hall;
Emily Hallberg;
Ute Hamann;
Tamara B Harris;
Catharina A Hartman;
Gerardo Heiss;
Maartje J Hooning;
John L Hopper;
Frank Hu;
David J Hunter;
M Arfan Ikram;
Hae Kyung Im;
Marjo-Riitta Järvelin;
Peter K Joshi;
David Karasik;
Manolis Kellis;
Zoltan Kutalik;
Genevieve LaChance;
Diether Lambrechts;
Claudia Langenberg;
Lenore J Launer;
Joop SE Laven;
Stefania Lenarduzzi;
Jingmei Li;
Penelope A Lind;
Sara Lindstrom;
YongMei Liu;
Jian'an Luan;
Reedik Mägi;
Arto Mannermaa;
Hamdi Mbarek;
Mark I McCarthy;
Christa Meisinger;
Thomas Meitinger;
Cristina Menni;
Andres Metspalu;
Kyriaki Michailidou;
Lili Milani;
Roger L Milne;
Grant W Montgomery;
Anna M Mulligan;
Mike A Nalls;
Pau Navarro;
Heli Nevanlinna;
Dale R Nyholt;
Albertine J Oldehinkel;
Tracy A O'Mara;
Sandosh Padmanabhan;
Aarno Palotie;
Nancy Pedersen;
Annette Peters;
Julian Peto ;
Paul DP Pharoah;
Anneli Pouta;
Paolo Radice;
Iffat Rahman;
Susan M Ring;
Antonietta Robino;
Frits R Rosendaal;
Igor Rudan;
Rico Rueedi;
Daniela Ruggiero;
Cinzia F Sala;
Marjanka K Schmidt;
Robert A Scott;
Mitul Shah;
Rossella Sorice;
Melissa C Southey;
Ulla Sovio;
Meir Stampfer;
Maristella Steri;
Konstantin Strauch;
Toshiko Tanaka;
Emmi Tikkanen;
Nicholas J Timpson;
Michela Traglia;
Thérèse Truong;
Jonathan P Tyrer;
André G Uitterlinden;
Digna R Velez Edwards;
Veronique Vitart;
Uwe Völker;
Peter Vollenweider;
Qin Wang;
Elisabeth Widen;
Ko Willems van Dijk;
Gonneke Willemsen;
Robert Winqvist;
Bruce HR Wolffenbuttel;
Jing Hua Zhao;
Magdalena Zoledziewska;
Marek Zygmunt;
Behrooz Z Alizadeh;
Dorret I Boomsma;
Marina Ciullo;
Francesco Cucca;
Tõnu Esko;
Nora Franceschini;
Christian Gieger;
Vilmundur Gudnason;
Caroline Hayward;
Peter Kraft;
Debbie A Lawlor;
Patrik KE Magnusson;
Nicholas G Martin;
Dennis O Mook-Kanamori;
Ellen A Nohr;
Ozren Polasek;
David Porteous;
Alkes L Price;
Paul M Ridker;
Harold Snieder;
Tim D Spector;
Doris Stöckl;
Daniela Toniolo;
Sheila Ulivi;
Jenny A Visser;
Henry Völzke;
Nicholas J Wareham;
James F Wilson;
LifeLines Cohort Study;
InterAct Consortium;
kConFab/AOCS Investigators;
Endometrial Cancer Association Consortium;
Ovarian Cancer Association Consortium;
PRACTICAL consortium;
Amanda B Spurdle;
Unnur Thorsteindottir;
Katherine S Pollard;
Douglas F Easton;
Joyce Y Tung;
Jenny Chang-Claude;
David Hinds;
Anna Murray;
Joanne M Murabito;
Kari Stefansson;
Ken K Ong;
John RB Perry;
(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.
ISSN 1061-4036
DOI: 10.1038/ng.3841
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.
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subject - Accepted Version
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- Available under Creative Commons: NC-ND 3.0