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

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 TragliaCarol 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)

Research output: Contribution to journalArticlepeer-review


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.

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


Dive into the research topics of 'Rare coding variants and X-linked loci associated with age at menarche'. Together they form a unique fingerprint.

Cite this