@article{8662e0c62b3242c889e012d10fcbdf09,
title = "Rare coding variants and X-linked loci associated with age at menarche",
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 {\textquoteleft}missing heritability{\textquoteright} of this complex trait.",
keywords = "biological sciences, genetics",
author = "Lunetta, {Kathryn L.} and Day, {Felix R.} and Patrick Sulem and Ruth, {Katherine S.} and Tung, {Joyce Y.} and Hinds, {David A.} and Tonu Esko and Elks, {Cathy E.} and Elisabeth Altmaier and Chunyan He and Huffman, {Jennifer E} and Evelin Mihailov and Eleanora Porcu and Antoinetta Robino and Rose, {Lynda M.} and Ursula Schick and Lisette Stolk and Alexander Tuemer and Thompson, {Deborah J.} and Michela Traglia and Wang, {Carol A.} and Yerges-Armstrong, {Laura M.} and Antoniou, {Antonis C} and Caterina Barbieri and Coviello, {Andrea D.} and Francesco Cucca and Demerath, {Ellen W.} and Dunning, {Alison M.} and Ilaria Gandin and Grove, {Megan L.} and Gudbjartsson, {Daniel F.} and Hocking, {Lynne J.} and Albert Hofman and Jinyan Huang and Jackson, {Rebecca D.} and David Karasik and Jennifer Kriebel and Lange, {Ethan M.} and Lange, {Leslie A} and Claudia Langenberg and Li Xin and Jian'an Luan and Reedik M{\"a}gi and Morrison, {Alana C.} and Sandosh Padmanabhan and Ailith Pirie and Ozren Polasek and David Porteous and Reiner, {David P.} and Fernando Rivadeneira and {Generation Scotland, InterAct Consortium}",
note = "This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. ",
year = "2015",
month = aug,
day = "4",
doi = "10.1038/ncomms8756",
language = "English",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}