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

Publication Type:

Journal Article

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; 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

Source:

Nature communications, Volume 6, p.7756 (2015)

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 'missing heritability' of this complex trait.