Rare coding variants and X-linked loci associated with age at menarche.
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.
Lunetta, KL; Day, FR; Sulem, P; Ruth, KS; Tung, JY; Hinds, DA; Esko, T; Elks, CE; Altmaier, E; He, C; Huffman, JE; Mihailov, E; Porcu, E; Robino, A; Rose, LM; Schick, UM; Stolk, L; Teumer, A; Thompson, DJ; Traglia, M; Wang, CA; Yerges-Armstrong, LM; Antoniou, AC; Barbieri, C; Coviello, AD; Cucca, F; Demerath, EW; Dunning, AM; Gandin, I; Grove, ML; Gudbjartsson, DF; Hocking, LJ; Hofman, A; Huang, J; Jackson, RD; Karasik, D; Kriebel, J; Lange, EM; Lange, LA; Langenberg, C; Li, X; Luan, J; Mägi, R; Morrison, AC; Padmanabhan, S; Pirie, A; Polasek, O; Porteous, D; Reiner, AP; Rivadeneira, F; Rudan, I; Sala, CF; Schlessinger, D; Scott, RA; Stöckl, D; Visser, JA; Völker, U; Vozzi, D; Wilson, JG; Zygmunt, M; EPIC-InterAct Consortium, ; Generation Scotland, ; Boerwinkle, E; Buring, JE; Crisponi, L; Easton, DF; Hayward, C; Hu, FB; Liu, S; Metspalu, A; Pennell, CE; Ridker, PM; Strauch, K; Streeten, EA; Toniolo, D; Uitterlinden, AG; Ulivi, S; Völzke, H; Wareham, NJ; Wellons, M; Franceschini, N; Chasman, DI; Thorsteinsdottir, U; Murray, A; Stefansson, K; Murabito, JM; Ong, KK; Perry, JRB
Volume / Issue
Start / End Page
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)