Three novel menarche loci were found in/near further genes implicated in the regulation of energy homeostasis and body weight in animal models: rs6589964 (P=1.9×10−12) lies ~18kb from BSX; rs10423674 (P=5.9×10−9) is intronic in CRTC1; and rs4840046 (P=2.4×10−8) lies ~160kb from MCHR2. BSX encodes a DNA binding protein and transcriptional activator. In the mouse Bsx is expressed specifically in the pineal gland, telencephalic septum, hypothalamic pre-mammillary body and arcuate nucleus, and is necessary for postnatal growth, locomotory behaviour, expression of the genes Npy and Agrp, and for the hyperphagic phenotype in leptin deficiency21. CRTC1 encodes the CREB regulated transcription coactivator 1, an activator of cellular gene expression. Crtc1(−/−) mice are hyperphagic, obese and infertile, and females have low circulating luteinizing hormone levels22. Leptin potentiates the effects of Crtc1 transcriptional activity, and Crtc1 over-expression in hypothalamic cells increases expression of Kisspeptin, which in turn activates secretion of gonadotrophin releasing hormone Kiss1 gene. MCHR2 encodes the melanin concentrating hormone receptor 2, an orphan G protein-coupled receptor which shows high affinity binding to the hypothalamic neuropeptide melanin-concentrating hormone (MCH), which regulates nutrient intake and energy homeostasis via MCHR123. Furthermore, MCH directly inhibits GnRH neurons and thereby links energy balance to reproduction24.
