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

Nat Commun. 2015 Aug 4:6:7756. doi: 10.1038/ncomms8756.

Abstract

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.

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Amides
  • Autoantigens / genetics*
  • Cell Cycle Proteins
  • Chromosomes, Human, X / genetics
  • Codon, Nonsense
  • Energy Metabolism / genetics
  • Fatty Acids
  • Female
  • Gene Frequency
  • Genes, X-Linked / genetics
  • Genetic Variation
  • Genotype
  • Humans
  • Hypogonadism / genetics
  • Immunoglobulins / genetics*
  • Laminin / genetics*
  • Membrane Proteins / genetics*
  • Menarche / genetics*
  • Middle Aged
  • Mutation, Missense
  • Penetrance
  • Phenotype
  • Proteins / genetics*
  • RNA Interference
  • RNA-Binding Proteins / genetics*
  • Receptors, Neurokinin-3 / genetics*
  • Signal Transduction / genetics
  • White People / genetics
  • Young Adult

Substances

  • ALMS1 protein, human
  • Amides
  • Autoantigens
  • Cell Cycle Proteins
  • Codon, Nonsense
  • Fatty Acids
  • IGSF1 protein, human
  • Immunoglobulins
  • Laminin
  • Membrane Proteins
  • Proteins
  • RNA-Binding Proteins
  • Receptors, Neurokinin-3
  • TACR3 protein, human
  • TNRC6A protein, human
  • laminin beta2
  • PRKAG1 protein, human
  • AMP-Activated Protein Kinases