Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

John R B Perry, Felix Day, Cathy E Elks, Patrick Sulem, Deborah J Thompson, Teresa Ferreira, Chunyan He, Daniel I Chasman, Tõnu Esko, Gudmar Thorleifsson, Eva Albrecht, Wei Q Ang, Tanguy Corre, Diana L Cousminer, Bjarke Feenstra, Nora Franceschini, Andrea Ganna, Andrew D Johnson, Sanela Kjellqvist, Kathryn L LunettaGeorge McMahon, Ilja M Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V Smith, Lisette Stolk, Alexander Teumer, Natalia Tšernikova, Emmi Tikkanen, Sheila Ulivi, Erin K Wagner, Najaf Amin, Laura J Bierut, Enda M Byrne, Jouke-Jan Hottenga, Daniel L Koller, Massimo Mangino, Tune H Pers, Laura M Yerges-Armstrong, Jing Hua Zhao, Irene L Andrulis, Hoda Anton-Culver, Femke Atsma, Stefania Bandinelli, George Davey Smith, Wendy L McArdle, Susan Ring, Nicholas J Timpson, Debbie Lawlor, Thorkild Sorensen, Australian Ovarian Cancer Study

Research output: Contribution to journalArticle (Academic Journal)peer-review

298 Citations (Scopus)


Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Original languageEnglish
Pages (from-to)92-97
Number of pages6
Issue number7520
Publication statusPublished - 2 Oct 2014


  • Adolescent
  • Age Factors
  • Alleles
  • Body Mass Index
  • Breast Neoplasms
  • Cardiovascular Diseases
  • Child
  • Diabetes Mellitus, Type 2
  • Europe
  • Female
  • Genetic Loci
  • Genome-Wide Association Study
  • Genomic Imprinting
  • Humans
  • Hypothalamo-Hypophyseal System
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins
  • Menarche
  • Obesity
  • Ovary
  • Parents
  • Polymorphism, Single Nucleotide
  • Potassium Channels, Tandem Pore Domain
  • Proteins
  • Quantitative Trait Loci
  • Receptors, GABA-B
  • Receptors, Retinoic Acid
  • Ribonucleoproteins

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