TY - JOUR T1 - Rare coding variants and X-linked loci associated with age at menarche. JF - Nat Commun Y1 - 2015 A1 - Lunetta, Kathryn L A1 - Day, Felix R A1 - Sulem, Patrick A1 - Ruth, Katherine S A1 - Tung, Joyce Y A1 - Hinds, David A A1 - Esko, Tõnu A1 - Elks, Cathy E A1 - Altmaier, Elisabeth A1 - He, Chunyan A1 - Huffman, Jennifer E A1 - Mihailov, Evelin A1 - Porcu, Eleonora A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Schick, Ursula M A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Traglia, Michela A1 - Wang, Carol A A1 - Yerges-Armstrong, Laura M A1 - Antoniou, Antonis C A1 - Barbieri, Caterina A1 - Coviello, Andrea D A1 - Cucca, Francesco A1 - Demerath, Ellen W A1 - Dunning, Alison M A1 - Gandin, Ilaria A1 - Grove, Megan L A1 - Gudbjartsson, Daniel F A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Huang, Jinyan A1 - Jackson, Rebecca D A1 - Karasik, David A1 - Kriebel, Jennifer A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langenberg, Claudia A1 - Li, Xin A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Porteous, David A1 - Reiner, Alex P A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Sala, Cinzia F A1 - Schlessinger, David A1 - Scott, Robert A A1 - Stöckl, Doris A1 - Visser, Jenny A A1 - Völker, Uwe A1 - Vozzi, Diego A1 - Wilson, James G A1 - Zygmunt, Marek A1 - Boerwinkle, Eric A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Easton, Douglas F A1 - Hayward, Caroline A1 - Hu, Frank B A1 - Liu, Simin A1 - Metspalu, Andres A1 - Pennell, Craig E A1 - Ridker, Paul M A1 - Strauch, Konstantin A1 - Streeten, Elizabeth A A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Wellons, Melissa A1 - Franceschini, Nora A1 - Chasman, Daniel I A1 - Thorsteinsdottir, Unnur A1 - Murray, Anna A1 - Stefansson, Kari A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Perry, John R B AB -

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.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26239645?dopt=Abstract ER -