Rare coding variants and X-linked loci associated with age at menarche
Authors: Lunetta Kathryn L. , Day Felix R. , Sulem Patrick , Ruth Katherine S. , Tung Joyce Y. , Hinds David A. , Esko Tõnu , Elks Cathy E. , Altmaier Elisabeth , He Chunyan , Huffman Jennifer E. , Mihailov Evelin , Porcu Eleonora , Robino Antonietta , Rose Lynda M. , Schick Ursula M. , Stolk Lisette , Teumer Alexander , Thompson Deborah J. , Traglia Michela , Wang Carol A. , Yerges-Armstrong Laura M. , Antoniou Antonis C. , Barbieri Caterina , Coviello Andrea D. , Cucca Francesco , Demerath Ellen W. , Dunning Alison M. , Gandin Ilaria , Grove Megan L. , Gudbjartsson Daniel F. , Hocking Lynne J. , Hofman Albert , Huang Jinyan , Jackson Rebecca D. , Karasik David , Kriebel Jennifer , Lange Ethan M. , Lange Leslie A. , Langenberg Claudia , Li Xin , Luan Jian'an , Mägi Reedik , Morrison Alanna C. , Padmanabhan Sandosh , Pirie Ailith , Polasek Ozren , Porteous David , Reiner Alex P. , Rivadeneira Fernando , Rudan Igor , Sala Cinzia F. , Schlessinger David , Scott Robert A. , Stöckl Doris , Visser Jenny A. , Völker Uwe , Vozzi Diego , Wilson James G. , Zygmunt Marek ,   EPIC-InterAct Consortium, Forouhi Nita G. , Kerrison Nicola D. , Sharp Stephen J. , Sims Matt , Barroso Inês , Deloukas Panos , McCarthy Mark I. , Arriola Larraitz , Balkau Beverley , Barricarte Aurelio , Boeing Heiner , Franks Paul W. , Gonzalez Carlos , Grioni Sara , Kaaks Rudolf , Key Timothy J. , Navarro Carmen , Nilsson Peter M. , Overvad Kim , Palli Domenico , Panico Salvatore , Quirós J Ramón , Rolandsson Olov , Sacerdote Carlotta , Sánchez María‐José , Slimani Nadia , Tjonneland Anne , Tumino Rosario , van der A Daphne L. , van der Schouw Yvonne T. , Riboli Elio ,   Generation Scotland, Smith Blair H. , Campbell Archie , Deary Ian J. , McIntosh Andrew M. , Boerwinkle Eric , Buring Julie E. , Crisponi Laura , Easton Douglas F. , Hayward Caroline , Hu Frank B. , Liu Simin , Metspalu Andres , Pennell Craig E. , Ridker Paul M. , Strauch Konstantin , Streeten Elizabeth A. , Toniolo Daniela , Uitterlinden André G. , Ulivi Sheila , Völzke Henry , Wareham Nicholas J. , Wellons Melissa , Franceschini Nora , Chasman Daniel I. , Thorsteinsdottir Unnur , Murray Anna , Stefansson Kari , Murabito Joanne M. , Ong Ken K. , Perry John R. B. 
Published: August 2015

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.