Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Nature
Authors
John Perry
Felix Day
Cathy Elks
Patrick Sulem
Deborah Thompson
Teresa Ferreira
Chunyan He
Daniel Chasman
Tõnu Esko
Gudmar Thorleifsson
Eva Albrecht
Wei Ang
Tanguy Corre
Diana Cousminer
Bjarke Feenstra
Nora Franceschini
Andrea Ganna
Andrew Johnson
Sanela Kjellqvist
Kathryn Lunetta
George McMahon
Ilja Nolte
Lavinia Paternoster
Eleonora Porcu
Albert Smith
Lisette Stolk
Alexander Teumer
Natalia Tšernikova
Emmi Tikkanen
Sheila Ulivi
Erin Wagner
Najaf Amin
Laura Bierut
Enda Byrne
Jouke-Jan Hottenga
Daniel Koller
Massimo Mangino
Tune Pers
Laura Yerges-Armstrong
Jing Zhao
Irene Andrulis
Hoda Anton-Culver
Femke Atsma
Stefania Bandinelli
Matthias Beckmann
Javier Benitez
Carl Blomqvist
Stig Bojesen
Manjeet Bolla
Bernardo Bonanni
Hiltrud Brauch
Hermann Brenner
Julie Buring
Jenny Chang-Claude
Stephen Chanock
Jinhui Chen
Georgia Chenevix-Trench
J Margriet Collée
Fergus Couch
David Couper
Andrea Coviello
Angela Cox
Kamila Czene
Adamo D'adamo
George Smith
Immaculata De Vivo
Ellen Demerath
Joe Dennis
Peter Devilee
Aida Dieffenbach
Alison Dunning
Gudny Eiriksdottir
Johan Eriksson
Peter Fasching
Luigi Ferrucci
Dieter Flesch-Janys
Henrik Flyger
Tatiana Foroud
Lude Franke
Melissa Garcia
Montserrat García-Closas
Frank Geller
Eco de Geus
Graham Giles
Daniel Gudbjartsson
Vilmundur Gudnason
Pascal Guénel
Suiqun Guo
Per Hall
Ute Hamann
Robin Haring
Catharina Hartman
Andrew Heath
Albert Hofman
Maartje Hooning
John Hopper
Frank Hu
David Hunter
David Karasik
Douglas Kiel
Julia Knight
Veli-Matti Kosma
Zoltán Kutalik
Sandra Lai
Diether Lambrechts
Annika Lindblom
Reedik Mägi
Patrik Magnusson
Arto Mannermaa
Nicholas Martin
Gisli Masson
Patrick McArdle
Wendy McArdle
Mads Melbye
Kyriaki Michailidou
Evelin Mihailov
Lili Milani
Roger Milne
Heli Nevanlinna
Patrick Neven
Ellen Nohr
Albertine Oldehinkel
Ben Oostra
Aarno Palotie
Munro Peacock
Nancy Pedersen
Paolo Peterlongo
Julian Peto
Paul Pharoah
Dirkje Postma
Anneli Pouta
Katri Pylkäs
Paolo Radice
Susan Ring
Fernando Rivadeneira
Antonietta Robino
Lynda Rose
Anja Rudolph
Veikko Salomaa
Serena Sanna
David Schlessinger
Marjanka Schmidt
Mellissa Southey
Ulla Sovio
Meir Stampfer
Doris Stöckl
Anna Storniolo
Nicholas Timpson
Jonathan Tyrer
Jenny Visser
Peter Vollenweider
Henry Völzke
Gérard Waeber
Melanie Waldenberger
Henri Wallaschofski
Qin Wang
Gonneke Willemsen
Robert Winqvist
Bruce Wolffenbuttel
Margaret Wright
Australian Ovarian Cancer Study
GENICA Network
kConFab
LifeLines Cohort Study
InterAct Consortium
Early Growth Genetics (EGG) Consortium
Dorret Boomsma
Michael Econs
Kay-Tee Khaw
Ruth Loos
Mark McCarthy
Grant Montgomery
John Rice
Elizabeth Streeten
Unnur Thorsteinsdottir
Cornelia van Duijn
Behrooz Alizadeh
Sven Bergmann
Eric Boerwinkle
Heather Boyd
Laura Crisponi
Paolo Gasparini
Christian Gieger
Tamara Harris
Erik Ingelsson
Marjo-Riitta Jarvelin
Peter Kraft
Debbie Lawlor
Andres Metspalu
Craig Pennell
Paul Ridker
Harold Snieder
Thorkild Sørensen
Tim Spector
David Strachan
André Uitterlinden
Nicholas Wareham
Elisabeth Widén
Marek Zygmunt
Anna Murray
Douglas Easton
Kari Stefansson
Joanne Murabito
Ken Ong
Keywords
Female
Humans
Male
Breast Neoplasms
Alleles
Adolescent
Child
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Proteins
Membrane Proteins
Genetic Loci
Diabetes Mellitus, Type 2
Obesity
Age Factors
Body Mass Index
Genomic Imprinting
Europe
Receptors, Retinoic Acid
Intercellular Signaling Peptides and Proteins
Ribonucleoproteins
Cardiovascular Diseases
Potassium Channels, Tandem Pore Domain
Hypothalamo-Hypophyseal System
Menarche
Ovary
Parents
Receptors, GABA-B
Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P  5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
Year of Publication
2014
Journal
Nature
Volume
514
Issue
7520
Pages
92-7
Date Published
2014 Oct 02
ISSN
1476-4687
URL
http://dx.doi.org/10.1038/nature13545
DOI
10.1038/nature13545
PubMed ID
25231870
PubMed Central ID
PMC4185210
Links
Grant list
R01 NS017950 / NS / NINDS NIH HHS / United States
MC_UU_12013/3 / Medical Research Council / United Kingdom
G1000143 / Medical Research Council / United Kingdom
MR/J012165/1 / Medical Research Council / United Kingdom
R01 AG041517 / AG / NIA NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
102215 / Wellcome Trust / United Kingdom
MC_UU_12015/1 / Medical Research Council / United Kingdom
MC_U106179471 / Medical Research Council / United Kingdom
MC_UU_12015/2 / Medical Research Council / United Kingdom
MC_PC_15018 / Medical Research Council / United Kingdom
MC_U106179472 / Medical Research Council / United Kingdom
P50 CA116201 / CA / NCI NIH HHS / United States
G0401527 / Medical Research Council / United Kingdom
MC_UU_12013/1 / Medical Research Council / United Kingdom
G0701863 / Medical Research Council / United Kingdom
098381 / Wellcome Trust / United Kingdom
10118 / Cancer Research UK / United Kingdom
G9815508 / Medical Research Council / United Kingdom
10124 / Cancer Research UK / United Kingdom
U01 AG049505 / AG / NIA NIH HHS / United States

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