Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty

Diana L. Cousminer, Evangelia Stergiakouli, Diane J. Berry, Wei Ang, Maria M. Groen-Blokhuis, Antje Körner, Niina Siitonen, Ioanna Ntalla, Marcella Marinelli, John R B Perry, Johannes Kettunen, Rick Jansen, Ida Surakka, Nicholas J. Timpson, Susan Ring, George Mcmahon, Chris Power, Carol Wang, Mika Kähönen, Jorma ViikariTerho Lehtimäki, Christel M. Middeldorp, Hilleke E. Hulshoff Pol, Madlen Neef, Sebastian Weise, Katja Pahkala, Harri Niinikoski, Eleftheria Zeggini, Kalliope Panoutsopoulou, Mariona Bustamante, Brenda W J H Penninx, Joanne Murabito, Maties Torrent, George V. Dedoussis, Wieland Kiess, Dorret I. Boomsma, Craig E. Pennell, Olli T. Raitakari, Elina Hyppönen, George Davey Smith, Samuli Ripatti, Mark I. McCarthy, Elisabeth Widén

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74 Citations (Scopus)


Little is known about genes regulating male puberty. Further, while many identified pubertal timing 1variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9×10-9), amenarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6×10-5) and short adult stature (p = 7.5×10-6) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

Original languageEnglish
Pages (from-to)4452-4464
Number of pages13
JournalHuman molecular genetics
Issue number16
Publication statusPublished or Issued - 1 Jan 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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