Rare coding variants and X-linked loci associated with age at menarche.

Nat Commun
Authors
Kathryn Lunetta
Felix Day
Patrick Sulem
Katherine Ruth
Joyce Tung
David Hinds
Tõnu Esko
Cathy Elks
Elisabeth Altmaier
Chunyan He
Jennifer Huffman
Evelin Mihailov
Eleonora Porcu
Antonietta Robino
Lynda Rose
Ursula Schick
Lisette Stolk
Alexander Teumer
Deborah Thompson
Michela Traglia
Carol Wang
Laura Yerges-Armstrong
Antonis Antoniou
Caterina Barbieri
Andrea Coviello
Francesco Cucca
Ellen Demerath
Alison Dunning
Ilaria Gandin
Megan Grove
Daniel Gudbjartsson
Lynne Hocking
Albert Hofman
Jinyan Huang
Rebecca Jackson
David Karasik
Jennifer Kriebel
Ethan Lange
Leslie Lange
Claudia Langenberg
Xin Li
Jian'an Luan
Reedik Mägi
Alanna Morrison
Sandosh Padmanabhan
Ailith Pirie
Ozren Polasek
David Porteous
Alex Reiner
Fernando Rivadeneira
Igor Rudan
Cinzia Sala
David Schlessinger
Robert Scott
Doris Stöckl
Jenny Visser
Uwe Volker
Diego Vozzi
James Wilson
Marek Zygmunt
EPIC-InterAct Consortium
Generation Scotland
Eric Boerwinkle
Julie Buring
Laura Crisponi
Douglas Easton
Caroline Hayward
Frank Hu
Simin Liu
Andres Metspalu
Craig Pennell
Paul Ridker
Konstantin Strauch
Elizabeth Streeten
Daniela Toniolo
André Uitterlinden
Sheila Ulivi
Henry Völzke
Nicholas Wareham
Melissa Wellons
Nora Franceschini
Daniel Chasman
Unnur Thorsteinsdottir
Anna Murray
Kari Stefansson
Joanne Murabito
Ken Ong
John Perry
Keywords
Female
Humans
Adult
Aged
Phenotype
RNA Interference
Genotype
Middle Aged
Signal Transduction
Adolescent
Gene Frequency
Genetic Variation
Young Adult
European Continental Ancestry Group
Proteins
Membrane Proteins
Penetrance
RNA-Binding Proteins
Age Factors
Fatty Acids
Mutation, Missense
Codon, Nonsense
Immunoglobulins
Amides
Energy Metabolism
Autoantigens
Chromosomes, Human, X
AMP-Activated Protein Kinases
Menarche
Genes, X-Linked
Hypogonadism
Laminin
Receptors, Neurokinin-3
Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
Year of Publication
2015
Journal
Nat Commun
Volume
6
Pages
7756
Date Published
2015 Aug 04
ISSN
2041-1723
URL
http://dx.doi.org/10.1038/ncomms8756
DOI
10.1038/ncomms8756
PubMed ID
26239645
PubMed Central ID
PMC4538850
Links
Grant list
MC_UP_A100_1003 / Medical Research Council / United Kingdom
11174 / Cancer Research UK / United Kingdom
P30 CA015704 / CA / NCI NIH HHS / United States
MR/K026992/1 / Medical Research Council / United Kingdom
UL1 TR001108 / TR / NCATS NIH HHS / United States
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_U106179472 / Medical Research Council / United Kingdom
R01 AG029451 / AG / NIA NIH HHS / United States
CZD/16/6/4 / Chief Scientist Office / United Kingdom
MC_PC_U127561128 / Medical Research Council / United Kingdom
UM1 CA182913 / CA / NCI NIH HHS / United States
R21 AG032598 / AG / NIA NIH HHS / United States
MC_UU_12015/5 / Medical Research Council / United Kingdom

Recent Broad Publications