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

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  • Kathryn L Lunetta
  • Felix R Day
  • Patrick Sulem
  • Katherine S Ruth
  • Joyce Y Tung
  • David A Hinds
  • Tõnu 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 Mägi
  • Alanna C Morrison
  • Ailith Pirie
  • Ozren Polasek
  • David Porteous
  • Igor Rudan
  • Caroline Hayward
  • EPIC-InterAct Consortium
  • Archibald Campbell (Member of Consortium)

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Original languageEnglish
Pages (from-to)7756
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 4 Aug 2015

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; P<5 × 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.

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