Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity

Diana L. Cousminer, Diane J. Berry, Nicholas J. Timpson, Wei Ang, Elisabeth Thiering, Enda M. Byrne, H. Rob Taal, Ville Huikari, Jonathan P. Bradfield, Marjan Kerkhof, Maria M. Groen-Blokhuis, Eskil Kreiner-Moller, Marcella Marinelli, Claus Holst, Jaakko T. Leinonen, John R. B. Perry, Ida Surakka, Olli Pietilainen, Johannes Kettunen, Verneri AnttilaMarika Kaakinen, Ulla Sovio, Anneli Pouta, Shikta Das, Vasiliki Lagou, Chris Power, Inga Prokopenko, David M. Evans, John P. Kemp, Beate St Pourcain, Susan Ring, Aarno Palotie, Eero Kajantie, Clive Osmond, Terho Lehtimaki, Jorma S. Viikari, Mika Kahonen, Nicole M. Warrington, Stephen J. Lye, Lyle J. Palmer, Carla M. T. Tiesler, Claudia Flexeder, Grant W. Montgomery, Sarah E. Medland, Albert Hofman, Hakon Hakonarson, Monica Guxens, Meike Bartels, Thorkild I. A. Sorensen, George Davey Smith, ReproGen Consortium, Early Growth Genetics EGG

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

107 Citations (Scopus)

Abstract

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growthfactors.Although little is knownabout the underlying genetics,growthvariabilityduring puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associatedwith pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlyingmechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth andmaturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 3 10 -8 ) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits. © The Author 2013. Published by Oxford University Press. All rights reserved.
Original languageEnglish
Pages (from-to)2735-2747
Number of pages13
JournalHuman Molecular Genetics
Volume22
Issue number13
DOIs
Publication statusPublished - 1 Jul 2013

Keywords

  • CHROMOSOME 16P11.2
  • POPULATION COHORT
  • FACTOR RECEPTOR-3
  • AGE
  • MENARCHE
  • MUTATIONS
  • VARIANTS
  • OBESITY
  • BIRTH
  • ACHONDROPLASIA

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