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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.

Rare coding variants and X-linked loci associated with age at menarche