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

Cousminer D.L., Berry D.J., Timpson N.J., Ang W., Thiering E., Byrne E.M., Rob Taal H., Huikari V., Bradfield J.P., Kerkhof M., Groen-Blokhuis M.M., Kreiner-Moller E., Marinelli M., Holst C., Leinonen J.T., Perry J.R.B., Surakka I., Pietilainen O., Kettunen J., Anttila V., Kaakinen M., Sovio U., Pouta A., Das S., Lagou V., Power C., Prokopenko I., Evans D.M., Kemp J.P., St Pourcain B., Ring S., Palotie A., Kajantie E., Osmond C., Lehtimaki T., Viikari J.S., Kahonen M., Warrington N.M., Lye S.J., Palmer L.J., Tiesler C.M.T., Flexeder C., Montgomery G.W., Medland S.E., Hofman A., Hakonarson H., Guxens M., Bartels M., Salomaa V., Murabito J.M., Kaprio J., Sorensen T.I.A., Ballester F., Bisgaard H., Boomsma D.I., Koppelman G.H., Grant S.F.A., Jaddoe V.W.V., Martin N.G., Heinrich J., Pennell C.E., Raitakari O.T., Eriksson J.G., Smith G.D., Hypponen E., Jarvelin M.-R., McCarthy M.I., Ripatti S., Widen E., Early Growth Genetics (EGG) Consortium and Middeldorp, Christel (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


Author Cousminer D.L.
Berry D.J.
Timpson N.J.
Ang W.
Thiering E.
Byrne E.M.
Rob Taal H.
Huikari V.
Bradfield J.P.
Kerkhof M.
Groen-Blokhuis M.M.
Kreiner-Moller E.
Marinelli M.
Holst C.
Leinonen J.T.
Perry J.R.B.
Surakka I.
Pietilainen O.
Kettunen J.
Anttila V.
Kaakinen M.
Sovio U.
Pouta A.
Das S.
Lagou V.
Power C.
Prokopenko I.
Evans D.M.
Kemp J.P.
St Pourcain B.
Ring S.
Palotie A.
Kajantie E.
Osmond C.
Lehtimaki T.
Viikari J.S.
Kahonen M.
Warrington N.M.
Lye S.J.
Palmer L.J.
Tiesler C.M.T.
Flexeder C.
Montgomery G.W.
Medland S.E.
Hofman A.
Hakonarson H.
Guxens M.
Bartels M.
Salomaa V.
Murabito J.M.
Kaprio J.
Sorensen T.I.A.
Ballester F.
Bisgaard H.
Boomsma D.I.
Koppelman G.H.
Grant S.F.A.
Jaddoe V.W.V.
Martin N.G.
Heinrich J.
Pennell C.E.
Raitakari O.T.
Eriksson J.G.
Smith G.D.
Hypponen E.
Jarvelin M.-R.
McCarthy M.I.
Ripatti S.
Widen E.
Early Growth Genetics (EGG) Consortium
Middeldorp, Christel
Title Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
1460-2083
Publication date 2013-07-01
Year available 2013
Sub-type Article (original research)
DOI 10.1093/hmg/ddt104
Open Access Status DOI
Volume 22
Issue 13
Start page 2735
End page 2747
Total pages 13
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
1312 Molecular Biology
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.
Formatted 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.
Keyword Biochemistry & Molecular Biology
Genetics & Heredity
Biochemistry & Molecular Biology
Genetics & Heredity
BIOCHEMISTRY & MOLECULAR BIOLOGY
GENETICS & HEREDITY
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 120315
213506
241944
A7960034
MOP-82893
21000074
HEALTH-F4-2007-201413
QLG1-CT-2000-01643
ERC-230374
CIRIT 1999SGR 00241
1RC2MH089 995-01
01 AK 803 A-H
CB06/02/0041
G0601653
R01 HD056465
AA-12502
5R01HL087679-02
1RL1MH083268-01
403981
NWO/SPI 56-464-14192
SAF2008-00357
NWO 480-04-004
U01 DK062418
74882
75617
076467
RD1634
FP7/2007-2013
HEALTH-F4-2007-201413
9M048
613608
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Queensland Brain Institute Publications
Child Health Research Centre Publications
 
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