Rare coding variants and X-linked loci associated with age at menarche.
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 None., Generation Scotland None., 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.
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.