Lunetta, Kathryn L.Day, Felix R.Sulem, PatrickRuth, Katherine S.Tung, Joyce Y.Hinds, David A.Esko, TõnuElks, Cathy E.Altmaier, ElisabethHe, ChunyanHuffman, Jennifer E.Mihailov, EvelinPorcu, EleonoraRobino, AntoniettaRose, Lynda M.Schick, Ursula M.Stolk, LisetteTeumer, AlexanderThompson, Deborah J.Traglia, MichelaWang, Carol A.Yerges-Armstrong, Laura M.Antoniou, Antonis C.Barbieri, CaterinaCoviello, Andrea D.Cucca, FrancescoDemerath, Ellen W.Dunning, Alison M.Gandin, IlariaGrove, Megan L.Gudbjartsson, Daniel F.Hocking, Lynne J.Hofman, AlbertHuang, JinyanJackson, Rebecca D.Karasik, DavidKriebel, JenniferLange, Ethan M.Lange, Leslie A.Langenberg, ClaudiaLi, XinLuan, Jian'anMägi, ReedikMorrison, Alanna C.Padmanabhan, SandoshPirie, AilithPolasek, OzrenPorteous, DavidReiner, Alex P.Rivadeneira, FernandoRudan, IgorSala, Cinzia F.Schlessinger, DavidScott, Robert A.Stöckl, DorisVisser, Jenny A.Völker, UweVozzi, DiegoWilson, James G.Zygmunt, MarekBoerwinkle, EricBuring, Julie E.Crisponi, LauraEaston, Douglas F.Hayward, CarolineHu, Frank B.Liu, SiminMetspalu, AndresPennell, Craig E.Ridker, Paul M.Strauch, KonstantinStreeten, Elizabeth A.Toniolo, DanielaUitterlinden, André G.Ulivi, SheilaVölzke, HenryWareham, Nicholas J.Wellons, MelissaFranceschini, NoraChasman, Daniel I.Thorsteinsdottir, UnnurMurray, AnnaStefansson, KariMurabito, Joanne M.Ong, Ken K.Perry, John R. B.2016-03-182016-03-182015-08-04Lunetta, K. L., Day, F. R., Sulem, P., Ruth, K. S., Tung, J. Y., Hinds, D. A., … Perry, J. R. B. (2015). Rare coding variants and X-linked loci associated with age at menarche. Nature Communications, 6, 7756. http://doi.org/10.1038/ncomms87562041-1723https://hdl.handle.net/1805/8938More 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.en-USAttribution 3.0 United Stateschromosomeslocimutationsgenescodingmenarcheclinical codingfatty acidsx chromosomeproteinshomeostasismutationgenomeamidesArticle