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.
Original language | English |
---|---|
Pages (from-to) | 2735-2747 |
Number of pages | 13 |
Journal | Human molecular genetics |
Volume | 22 |
Issue number | 13 |
DOIs | |
Publication status | Published or Issued - 1 Jul 2013 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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In: Human molecular genetics, Vol. 22, No. 13, 01.07.2013, p. 2735-2747.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity
AU - Cousminer, Diana L.
AU - Berry, Diane J.
AU - Timpson, Nicholas J.
AU - Ang, Wei
AU - Thiering, Elisabeth
AU - Byrne, Enda M.
AU - Rob Taal, H.
AU - Huikari, Ville
AU - Bradfield, Jonathan P.
AU - Kerkhof, Marjan
AU - Groen-Blokhuis, Maria M.
AU - Kreiner-Møller, Eskil
AU - Marinelli, Marcella
AU - Holst, Claus
AU - Leinonen, Jaakko T.
AU - Perry, John R B
AU - Surakka, Ida
AU - Pietiläinen, Olli
AU - Kettunen, Johannes
AU - Anttila, Verneri
AU - Kaakinen, Marika
AU - Sovio, Ulla
AU - Pouta, Anneli
AU - Das, Shikta
AU - Lagou, Vasiliki
AU - Power, Chris
AU - Prokopenko, Inga
AU - Evans, David M.
AU - Kemp, John P.
AU - St Pourcain, Beate
AU - Ring, Susan
AU - Palotie, Aarno
AU - Kajantie, Eero
AU - Osmond, Clive
AU - Lehtimäki, Terho
AU - Viikari, Jorma S.
AU - Kähönen, Mika
AU - Warrington, Nicole M.
AU - Lye, Stephen J.
AU - Palmer, Lyle J.
AU - Tiesler, Carla M T
AU - Flexeder, Claudia
AU - Montgomery, Grant W.
AU - Medland, Sarah E.
AU - Hofman, Albert
AU - Hakonarson, Hakon
AU - Guxens, Mónica
AU - Bartels, Meike
AU - Salomaa, Veikko
AU - Murabito, Joanne M.
AU - Kaprio, Jaakko
AU - Sørensen, Thorkild I A
AU - Ballester, Ferran
AU - Bisgaard, Hans
AU - Boomsma, Dorret I.
AU - Koppelman, Gerard H.
AU - Grant, Struan F A
AU - Jaddoe, Vincent W V
AU - Martin, Nicholas G.
AU - Heinrich, Joachim
AU - Pennell, Craig E.
AU - Raitakari, Olli T.
AU - Eriksson, Johan G.
AU - Smith, George Davey
AU - Hyppönen, Elina
AU - Järvelin, Marjo Riitta
AU - McCarthy, Mark I.
AU - Ripatti, Samuli
AU - Widén, Elisabeth
N1 - Funding Information: This work was supported by the Academy of Finland (grant numbers 120315, 134839, 129297, 218029, 209072, 129255, 126925, 121584, 124282, 129378, 117787, 41071, 100499, 205585, 118555, 104781, 120315, 129418, 141054); Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers 213506, 129680); Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498); Australian Research Council (grant numbers A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921); British Heart Foundation; Canadian Institutes of Health Research (grant number MOP-82893); Conselleria de Sanitat Generalitat Valenciana, and Fundación Roger Torné; Dutch Asthma Fonds; Emil Aal-tonen Foundation; Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development (grant number 21000074); European Commission (ENGAGE project and grant agreement HEALTH-F4-2007-201413; EURO-BLCS, Framework 5 award QLG1-CT-2000-01643); European Research Council (grant number ERC-230374); Finnish Cultural Foundation; Finnish Foundation of Cardiovascular Research; Fundació La Marató de TV3, Generalitat de Catalunya (grant number CIRIT 1999SGR 00241); Genomics of Developmental Trajectories in Twins (grant number 1RC2MH089 995-01); German Bundesministerium fuer Forschung und Technology (grant numbers 01 AK 803 A-H, 01 IG 07015 G); Infants Research Foundation; Institute Development Award from the Children’s Hospital of Philadelphia; Instituto de Salud Carlos III (grant numbers CB06/02/0041, G03/176, FIS PI041436, PI081151, PI041705, PS09/00432, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/ 1213, 07/0314, 09/02647); Juho Vainio Foundation; Ludwig-Maximilians-University’s innovative research priority project MC-Health; Medical Research Council (grant numbers G0601653, G0000934, G0500539, G0600705, G0601653); National Institutes of Health (grant numbers R01 HD056465, 5R01MH63706:02); National Institute for Alcohol Abuse and Alcoholism (grant numbers AA-12502, AA-09203, AA-08315); NIH Heart, Lung and Blood Institute (grant number 5R01HL087679-02) through the STAMPEED program (grant number 1RL1MH083268-01); National Health and Medical Research Council of Australia (grant numbers 403981, 003209); Netherlands Organization for Scientific research (grant number NWO/SPI 56-464-14192); Spanish Ministry of Science and Innovation (grant number SAF2008-00357); Stichting Astmabestrijding and Ministry of the Environment; Social Insurance Institution of Finland; Telethon Institute for Child Health Research and Women; Twin-family database for behavior genetics and genomics studies (grant number NWO 480-04-004); Type 1 Diabetes Genetics Consortium (grant number U01 DK062418); Paavo Nurmi Foundation; Raine Medical Research Foundation; Research Development Award from the Cotswold Foundation; UK Medical Research Council (grant number 74882); University of Bristol; University of Western Australia; University Hospital Oulu; University of Oulu (grant number 75617); UWA Faculty of Medicine, Dentistry and Health Sciences; Wellcome Trust (grant numbers 076467, 068545/Z/02, 084762MA); and ZonMw: the Netherlands Organisation for Health Research and Development. Personal funding was provided by the Helsinki Biomedical Graduate Program to D.L.C.; Netherlands Organization for Health Research and Development (grant numbers ZonMw 90700303, 916.10159) to V.W.V.J.; Dutch Kidney Foundation (grant number C08.2251) to H.R.T.; MRC Centre for Causal Analyses in Translational Epidemiology (grant number RD1634) to G.D.S., D.M.E. and N.J.T.; European Community’s Seventh Framework Programme (grant number FP7/2007-2013) and ENGAGE project, grant agreement HEALTH-F4-2007-201413 to I.P. and V.L.; Tampere and Turku University Hospital Medical Funds (grant numbers 9M048, 9N035) to T.L.; Tampere Tuberculosis Foundation to T.L.; National Health and Medical Research Council (grant number 613608) to E.M.B. and Fellowship Scheme to G.W.M.; and Wellcome Trust Sir Henry Wellcome Postdoctoral Research Fellow (grant number 092447/Z/10/Z) to J.R.B.P. J.P.K. is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA).
PY - 2013/7/1
Y1 - 2013/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878901283&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt104
DO - 10.1093/hmg/ddt104
M3 - Article
C2 - 23449627
AN - SCOPUS:84878901283
SN - 0964-6906
VL - 22
SP - 2735
EP - 2747
JO - Human molecular genetics
JF - Human molecular genetics
IS - 13
ER -