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

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity
Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity
The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 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.
2735-2747
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Cousminer, Diana L., Berry, Diane J., Timpson, Nicholas J., Ang, Wei, Thiering, Elisabeth, Byrne, Enda M., Taal, H. Rob, Huikari, Ville, Bradfield, Jonathan P., Kerkhof, Marjan, Groen-Blokhuis, Maria M., Kreiner-Møller, Eskil, Marinelli, Marcella, Holst, Claus, Leinonen, Jaakko T., Perry, John R. B., Surakka, Ida, Pietiläinen, Olli, Kettunen, Johannes, Anttila, Verneri, Kaakinen, Marika, Sovio, Ulla, Pouta, Anneli, Das, Shikta, Lagou, Vasiliki, Power, Chris, Prokopenko, Inga, Evans, David M., Kemp, John P., St Pourcain, Beate, Ring, Susan, Palotie, Aarno, Kajantie, Eero, Osmond, Clive, Lehtimäki, Terho, Viikari, Jorma S., Kähönen, Mika, Warrington, Nicole M., Lye, Stephen J., Palmer, Lyle J., Tiesler, Carla M. T., Flexeder, Claudia, Montgomery, Grant W., Medland, Sarah E., Hofman, Albert, Hakonarson, Hakon, Guxens, Mònica, Bartels, Meike, Salomaa, Veikko, Murabito, Joanne M., Kaprio, Jaakko, Sørensen, Thorkild I. A., Ballester, Ferran, Bisgaard, Hans, Boomsma, Dorret I., Koppelman, Gerard H., Grant, Struan F. A., Jaddoe, Vincent W. V., Martin, Nicholas G., Heinrich, Joachim, Pennell, Craig E., Raitakari, Olli T., Eriksson, Johan G., Smith, George Davey, Hyppönen, Elina, Järvelin, Marjo-Riitta, McCarthy, Mark I., Ripatti, Samuli and Widén, Elisabeth (2013) Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity. Human Molecular Genetics, 22 (13), 2735-2747. (doi:10.1093/hmg/ddt104). (PMID:23449627)

Record type: Article

Abstract

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 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.

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e-pub ahead of print date: 27 February 2013
Published date: 1 July 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 355131
URI: http://eprints.soton.ac.uk/id/eprint/355131
PURE UUID: ea8eed7a-ee06-43e8-a14a-4bd2dd6d340b
ORCID for Clive Osmond: ORCID iD orcid.org/0000-0002-9054-4655

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Date deposited: 09 Aug 2013 09:14
Last modified: 28 Oct 2023 01:39

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Contributors

Author: Diana L. Cousminer
Author: Diane J. Berry
Author: Nicholas J. Timpson
Author: Wei Ang
Author: Elisabeth Thiering
Author: Enda M. Byrne
Author: H. Rob Taal
Author: Ville Huikari
Author: Jonathan P. Bradfield
Author: Marjan Kerkhof
Author: Maria M. Groen-Blokhuis
Author: Eskil Kreiner-Møller
Author: Marcella Marinelli
Author: Claus Holst
Author: Jaakko T. Leinonen
Author: John R. B. Perry
Author: Ida Surakka
Author: Olli Pietiläinen
Author: Johannes Kettunen
Author: Verneri Anttila
Author: Marika Kaakinen
Author: Ulla Sovio
Author: Anneli Pouta
Author: Shikta Das
Author: Vasiliki Lagou
Author: Chris Power
Author: Inga Prokopenko
Author: David M. Evans
Author: John P. Kemp
Author: Beate St Pourcain
Author: Susan Ring
Author: Aarno Palotie
Author: Eero Kajantie
Author: Clive Osmond ORCID iD
Author: Terho Lehtimäki
Author: Jorma S. Viikari
Author: Mika Kähönen
Author: Nicole M. Warrington
Author: Stephen J. Lye
Author: Lyle J. Palmer
Author: Carla M. T. Tiesler
Author: Claudia Flexeder
Author: Grant W. Montgomery
Author: Sarah E. Medland
Author: Albert Hofman
Author: Hakon Hakonarson
Author: Mònica Guxens
Author: Meike Bartels
Author: Veikko Salomaa
Author: Joanne M. Murabito
Author: Jaakko Kaprio
Author: Thorkild I. A. Sørensen
Author: Ferran Ballester
Author: Hans Bisgaard
Author: Dorret I. Boomsma
Author: Gerard H. Koppelman
Author: Struan F. A. Grant
Author: Vincent W. V. Jaddoe
Author: Nicholas G. Martin
Author: Joachim Heinrich
Author: Craig E. Pennell
Author: Olli T. Raitakari
Author: Johan G. Eriksson
Author: George Davey Smith
Author: Elina Hyppönen
Author: Marjo-Riitta Järvelin
Author: Mark I. McCarthy
Author: Samuli Ripatti
Author: Elisabeth Widén

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