RT Journal Article
SR Electronic
T1 Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 076794
DO 10.1101/076794
A1 Felix R. Day
A1 Deborah J. Thompson
A1 Hannes Helgason
A1 Daniel I. Chasman
A1 Hilary Finucane
A1 Patrick Sulem
A1 Katherine S. Ruth
A1 Sean Whalen
A1 Abhishek K. Sarkar
A1 Eva Albrecht
A1 Elisabeth Altmaier
A1 Marzyeh Amini
A1 Caterina M. Barbieri
A1 Thibaud Boutin
A1 Archie Campbell
A1 Ellen Demerath
A1 Ayush Giri
A1 Chunyan He
A1 Jouke J. Hottenga
A1 Robert Karlsson
A1 Ivana Kolcic
A1 Po-Ru Loh
A1 Kathryn L. Lunetta
A1 Massimo Mangino
A1 Brumat Marco
A1 George McMahon
A1 Sarah E. Medland
A1 Ilja M. Nolte
A1 Raymond Noordam
A1 Teresa Nutile
A1 Lavinia Paternoster
A1 Natalia Perjakova
A1 Eleonora Porcu
A1 Lynda M. Rose
A1 Katharina E. Schraut
A1 Ayellet V. Segrè
A1 Albert V. Smith
A1 Lisette Stolk
A1 Alexander Teumer
A1 Irene L. Andrulis
A1 Stefania Bandinelli
A1 Matthias W. Beckmann
A1 Javier Benitez
A1 Sven Bergmann
A1 Murielle Bochud
A1 Eric Boerwinkle
A1 Stig E. Bojesen
A1 Manjeet K. Bolla
A1 Judith S. Brand
A1 Hiltrud Brauch
A1 Hermann Brenner
A1 Linda Broer
A1 Thomas Brüning
A1 Julie E. Buring
A1 Harry Campbell
A1 Eulalia Catamo
A1 Stephen Chanock
A1 Georgia Chenevix-Trench
A1 Tanguy Corre
A1 Fergus J. Couch
A1 Diana L. Cousminer
A1 Angela Cox
A1 Laura Crisponi
A1 Kamila Czene
A1 George Davey-Smith
A1 Eco J.C.N de Geus
A1 Renée de Mutsert
A1 Immaculata De Vivo
A1 Joe Dennis
A1 Peter Devilee
A1 Isabel dos-Santos-Silva
A1 Alison M. Dunning
A1 Johan G. Eriksson
A1 Peter A. Fasching
A1 Lindsay Fernández-Rhodes
A1 Luigi Ferrucci
A1 Dieter Flesch-Janys
A1 Lude Franke
A1 Marike Gabrielson
A1 Ilaria Gandin
A1 Graham G. Giles
A1 Harald Grallert
A1 Daniel F. Gudbjartsson
A1 Pascal Guénel
A1 Per Hall
A1 Emily Hallberg
A1 Ute Hamann
A1 Tamara B. Harris
A1 Catharina A. Hartman
A1 Gerardo Heiss
A1 Maartje J. Hooning
A1 John L. Hopper
A1 Frank Hu
A1 David Hunter
A1 M. Arfan Ikram
A1 Hae Kyung Im
A1 Marjo-Riitta Järvelin
A1 Peter K. Joshi
A1 David Karasik
A1 Zoltan Kutalik
A1 Genevieve LaChance
A1 Diether Lambrechts
A1 Claudia Langenberg
A1 Lenore J. Launer
A1 Joop S.E. Laven
A1 Stefania Lenarduzzi
A1 Jingmei Li
A1 Penelope A. Lind
A1 Sara Lindstrom
A1 YongMei Liu
A1 Jian'an Luan
A1 Reedik Mägi
A1 Arto Mannermaa
A1 Hamdi Mbarek
A1 Mark I. McCarthy
A1 Christa Meisinger
A1 Thomas Meitinger
A1 Cristina Menni
A1 Andres Metspalu
A1 Kyriaki Michailidou
A1 Lili Milani
A1 Roger L. Milne
A1 Grant W. Montgomery
A1 Anna M. Mulligan
A1 Mike A. Nalls
A1 Pau Navarro
A1 Heli Nevanlinna
A1 Dale R. Nyholt
A1 Albertine J. Oldehinkel
A1 Tracy A. O'Mara
A1 Aarno Palotie
A1 Nancy Pedersen
A1 Annette Peters
A1 Julian Peto
A1 Paul D.P. Pharoah
A1 Anneli Pouta
A1 Paolo Radice
A1 Iffat Rahman
A1 Susan M. Ring
A1 Antonietta Robino
A1 Frits R. Rosendaal
A1 Igor Rudan
A1 Rico Rueedi
A1 Daniela Ruggiero
A1 Cinzia F. Sala
A1 Marjanka K. Schmidt
A1 Robert A. Scott
A1 Mitul Shah
A1 Rossella Sorice
A1 Melissa C. Southey
A1 Ulla Sovio
A1 Meir Stampfer
A1 Maristella Steri
A1 Konstantin Strauch
A1 Toshiko Tanaka
A1 Emmi Tikkanen
A1 Nicholas J. Timpson
A1 Michela Traglia
A1 Thérèse Truong
A1 Jonathan P. Tyrer
A1 André G. Uitterlinden
A1 Digna R. Velez Edwards
A1 Veronique Vitart
A1 Uwe Völker
A1 Peter Vollenweider
A1 Qin Wang
A1 Elisabeth Widen
A1 Ko Willems van Dijk
A1 Gonneke Willemsen
A1 Robert Winqvist
A1 Bruce H.R Wolffenbuttel
A1 Jing Hua Zhao
A1 Magdalena Zoledziewska
A1 Marek Zygmunt
A1 Behrooz Z. Alizadeh
A1 Dorret I. Boomsma
A1 Marina Ciullo
A1 Francesco Cucca
A1 Tõnu Esko
A1 Nora Franceschini
A1 Christian Gieger
A1 Vilmundur Gudnason
A1 Caroline Hayward
A1 Peter Kraft
A1 Debbie A. Lawlor
A1 Patrik K.E Magnusson
A1 Nicholas G. Martin
A1 Dennis O. Mook-Kanamori
A1 Ellen A. Nohr
A1 Ozren Polasek
A1 David Porteous
A1 Alkes L. Price
A1 Paul M. Ridker
A1 Harold Snieder
A1 Tim D. Spector
A1 Doris Stöckl
A1 Daniela Toniolo
A1 Sheila Ulivi
A1 Jenny A. Visser
A1 Henry Völzke
A1 Nicholas J. Wareham
A1 James F. Wilson
A1 The LifeLines Cohort Study
A1 The InterAct Consortium
A1 kConFab/AOCS Investigators
A1 Endometrial Cancer Association Consortium
A1 Ovarian Cancer Association Consortium
A1 PRACTICAL consortium
A1 Amanda B. Spurdle
A1 Unnur Thorsteindottir
A1 Katherine S. Pollard
A1 Douglas F. Easton
A1 Joyce Y. Tung
A1 Jenny Chang-Claude
A1 David Hinds
A1 Anna Murray
A1 Joanne M. Murabito
A1 Kari Stefansson
A1 Ken K. Ong
A1 John R.B Perry
YR 2016
UL http://biorxiv.org/content/early/2016/09/23/076794.abstract
AB 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.