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

Research output: Contribution to journalArticle

Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding 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; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 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 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

Details

Authors
  • Kathryn L. Lunetta
  • Felix R. Day
  • Patrick Sulem
  • Katherine S. Ruth
  • Joyce Y. Tung
  • David A. Hinds
  • Tonu Esko
  • Cathy E. Elks
  • Elisabeth Altmaier
  • Chunyan He
  • Jennifer E. Huffman
  • Evelin Mihailov
  • Eleonora Porcu
  • Antonietta Robino
  • Lynda M. Rose
  • Ursula M. Schick
  • Lisette Stolk
  • Alexander Teumer
  • Deborah J. Thompson
  • Michela Traglia
  • Carol A. Wang
  • Laura M. Yerges-Armstrong
  • Antonis C. Antoniou
  • Caterina Barbieri
  • Andrea D. Coviello
  • Francesco Cucca
  • Ellen W. Demerath
  • Alison M. Dunning
  • Ilaria Gandin
  • Megan L. Grove
  • Daniel F. Gudbjartsson
  • Lynne J. Hocking
  • Albert Hofman
  • Jinyan Huang
  • Rebecca D. Jackson
  • David Karasik
  • Jennifer Kriebel
  • Ethan M. Lange
  • Leslie A. Lange
  • Claudia Langenberg
  • Xin Li
  • Jian'an Luan
  • Reedik Maegi
  • Alanna C. Morrison
  • Sandosh Padmanabhan
  • Ailith Pirie
  • Ozren Polasek
  • David Porteous
  • Alex P. Reiner
  • Fernando Rivadeneira
  • Igor Rudan
  • Cinzia F. Sala
  • David Schlessinger
  • Robert A. Scott
  • Doris Stoeckl
  • Jenny A. Visser
  • Uwe Voelker
  • Diego Vozzi
  • James G. Wilson
  • Marek Zygmunt
  • Eric Boerwinkle
  • Julie E. Buring
  • Laura Crisponi
  • Douglas F. Easton
  • Caroline Hayward
  • Frank B. Hu
  • Simin Liu
  • Andres Metspalu
  • Craig E. Pennell
  • Paul M. Ridker
  • Konstantin Strauch
  • Elizabeth A. Streeten
  • Daniela Toniolo
  • Andre G. Uitterlinden
  • Sheila Ulivi
  • Henry Voelzke
  • Nicholas J. Wareham
  • Melissa Wellons
  • Nora Franceschini
  • Daniel I. Chasman
  • Unnur Thorsteinsdottir
  • Anna Murray
  • Kari Stefansson
  • Joanne M. Murabito
  • Ken K. Ong
  • John R. B. Perry
  • Nita G. Forouhi
  • Nicola D. Kerrison
  • Stephen J. Sharp
  • Matt Sims
  • Ines Barroso
  • Panos Deloukas
  • Mark I. McCarthy
  • Larraitz Arriola
  • Beverley Balkau
  • Aurelio Barricarte
  • Heiner Boeing
  • Carlos Gonzalez
  • Sara Grioni
  • Rudolf Kaaks
  • Timothy J. Key
  • Carmen Navarro
  • Kim Overvad
  • Domenico Palli
  • Salvatore Panico
  • J. Ramon Quiros
  • Olov Rolandsson
  • Carlotta Sacerdote
  • Maria-Jose Sanchez
  • Nadia Slimani
  • Anne Tjonneland
  • Rosario Tumino
  • Daphne L. van der A
  • Yvonne T. van der Schouw
  • Elio Riboli
  • Blair H. Smith
  • Archie Campbell
  • Ian J. Deary
  • Andrew M. McIntosh
Organisations
External organisations
  • Umeå University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Article number7756
JournalNature Communications
Volume6
Publication statusPublished - 2015
Publication categoryResearch
Peer-reviewedYes