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

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.

SUBMITTER: Cousminer DL

PROVIDER: S-EPMC3674797 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

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

Human molecular genetics 20130227 13

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 und ...[more]

PMID: 23449627

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Project description:BackgroundExposure to per- and polyfluoroalkyl substances (PFAS) may disrupt pubertal timing. Higher PFAS plasma concentrations have been associated with later pubertal timing in girls, but cross-sectional findings may be explained by reverse causation.ObjectivesTo assess prospective associations between PFAS plasma concentrations in mid-childhood and markers of pubertal timing in male and female adolescents.MethodsWe studied 640 children in Project Viva, a Boston-area prospective cohort. We examined associations of plasma concentrations of 6 PFAS measured at mean 7.9 (SD 0.8) years (2007-2010) with markers of pubertal timing. Parents reported a 5-item pubertal development score at early adolescence (mean 13.1 (SD 0.8) years) and reported age at menarche annually. We calculated age at peak height velocity using research and clinical measures of height. We used sex-specific linear and Cox proportional hazards regression to estimate associations of single PFAS with outcomes, and we used Bayesian Kernel Machine Regression (BKMR) to estimate associations of the PFAS mixture with outcomes.ResultsPlasma concentrations were highest for perfluorooctane sulfonate (PFOS) [median (IQR) 6.4(5.6) ng/mL], followed by perfluorooctanoate (PFOA) [4.4(3.0) ng/mL]. In early adolescence, girls were further along in puberty than boys [pubertal development score mean (SD) 2.9 (0.7) for girls and 2.2(0.7) for boys; age at peak height velocity mean (SD) 11.2y (1.0) for girls and 13.1y (1.0) for boys]. PFAS was associated with later markers of pubertal timing in girls only. For example, each doubling of PFOA was associated with lower pubertal development score (-0.18 units; 95% CI: -0.30, -0.06) and older age at peak height velocity (0.23 years; 95% CI: 0.06, 0.40)]. We observed similar associations for PFOS, perfluorodecanoate (PFDA), and the PFAS mixture. PFAS plasma concentrations were not associated with age at menarche or markers of pubertal timing in boys.DiscussionHigher PFAS plasma concentrations in mid-childhood were associated with later onset of puberty in girls.

Dataset Information

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

Publications

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

Similar Datasets

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