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

KL Lunetta, FR Day, P Sulem, KS Ruth, JY Tung, DA Hinds, T Esko, CE Elks, E Altmaier, CY He, JE Huffman, E Mihailov, E Porcu, A Robino, LM Rose, UM Schick, Lisette Stolk, A Teumer, DJ Thompson, M TragliaCA Wang, LM Yerges-Armstrong, AC Antoniou, C Barbieri, AD Coviello, F Cucca, EW Demerath, AM Dunning, I Gandin, ML Grove, DF Gudbjartsson, LJ Hocking, Bert Hofman, JY Huang, RD Jackson, D Karasik, J Kriebel, Edmee Lange, LA Lange, C Langenberg, X Li, JA Luan, R Magi, AC Morrison, S Padmanabhan, A Pirie, O Polasek, D Porteous, AP Reiner, Fernando Rivadeneira, I Rudan, CF Sala, D Schlessinger, RA Scott, D Stockl, Jenny Visser, U Volker, D Vozzi, JG Wilson, M Zygmunt, E Boerwinkle, JE Buring, L Crisponi, DF Easton, C Hayward, FB Hu, SM (Simin) Liu, A Metspalu, CE Pennell, PM Ridker, K Strauch, EA Streeten, D Toniolo, André Uitterlinden, S Ulivi, H Volzke, NJ Wareham, M Wellons, N Franceschini, DI Chasman, U Thorsteinsdottir, A Murray, K Stefansson, JM Murabito, KK Ong, JRB Perry, NG Forouhi, ND Kerrison, SJ Sharp, M Sims, I Barroso, P Deloukas, MI McCarthy, L Arriola, B Balkau, A Barricarte, H Boeing, PW Franks, C Gonzalez, S Grioni, R Kaaks, TJ Key, C Navarro, PM Nilsson, K Overvad, D Palli, S Panico, JR Quiros, O Rolandsson, C Sacerdote, MJ (Maria-Jose) Sanchez, N Slimani, A Tjonneland, R Tumino, DL van der A, YT van der Schouw, E Riboli, BH Smith, A (Archie) Campbell, IJ Deary, AM McIntosh

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More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding 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 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 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 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
Original languageUndefined/Unknown
JournalNature Communications
Publication statusPublished - 2015

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