Our identification of strong associations with SNPs near to the candidate genes TAC3R and ESR1 supports the likely presence of further menarche loci, which did not meet the genome-wide significance threshold. Systematic assessment of functional genetic variants identified several further putative menarche loci. rs3101336, which tags a CNV near the BMI locus NEGR1, showed strong, but sub-genome-wide significant, association with age at menarche (P=3×10−7). Exploration of adipose tissue eQTLs also identified further putative menarche loci related to genes implicated in eating behaviour (BDNF), precocious puberty (DLK1) and pituitary function (PITX1). It has been suggested that lower levels of statistical significance may be applied to variants with prior biological candidacy, however this must be balanced against the desire to avoid false positives, and we suggest that these putative menarche loci require confirmation in further studies.
