Candidate gene studies for age at menarche have largely focussed on genes involved in sex steroid-hormone biosynthesis and metabolism, highlighted through animal models or human cases with extreme delayed puberty or hypogonadotrophic hypogonadism31. We examined 8,770 SNPs in 16 candidate genes31–33 and their surrounding regions (+/−300kb) for association with age at menarche in our GWA meta-analysis sample (Supplementary Table 12). SNPs in the regions of TAC3R (top hit: rs17034046; P=3.4×10−7, ~19kb upstream of TAC3R) and ESR1 (top hit: rs9383922; P=2.2×10−6, 110kb upstream of ESR1) were significantly associated with age at menarche after correction for multiple testing (Bonferroni threshold for 8,770 independent tests was P<5.7×10−6). Rare deleterious mutations in TAC3R, encoding a receptor for Neurokinin B, and in its ligand TAC3 have been found in families affected by hypogonadotropic hypogonadism and pubertal failure31. ESR1 encodes an estrogen receptor that is essential for sexual development and reproductive function, and polymorphisms in ESR1 have previously been nominally associated with age at menarche33.
