title: 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.
authors: Institute for Molecular Medicine, and Department of Public Health, University of Helsinki, Helsinki, Finland.
authors: Diana L
authors: DL
authors: Cousminer
authors: Diane J
authors: DJ
authors: Berry
authors: Nicholas J
authors: NJ
authors: Timpson
authors: Wei
authors: W
authors: Ang
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authors: Thiering
authors: Enda M
authors: EM
authors: Byrne
authors: H Rob
authors: HR
authors: Taal
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authors: Huikari
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authors: Bradfield
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authors: Kerkhof
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authors: Kreiner-Møller
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authors: Marinelli
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authors: Perry
authors: Ida
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authors: Surakka
authors: Olli
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authors: Pietiläinen
authors: Johannes
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authors: Kettunen
authors: Verneri
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authors: Kaakinen
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authors: Power
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authors: Prokopenko
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authors: DM
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authors: Kemp
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authors: St Pourcain
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authors: Palotie
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authors: Kajantie
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authors: Lehtimäki
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authors: JS
authors: Viikari
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authors: Kähönen
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authors: Warrington
authors: Stephen J
authors: SJ
authors: Lye
authors: Lyle J
authors: LJ
authors: Palmer
authors: Carla M T
authors: CM
authors: Tiesler
authors: Claudia
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authors: Flexeder
authors: Grant W
authors: GW
authors: Montgomery
authors: Sarah E
authors: SE
authors: Medland
authors: Albert
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authors: Hofman
authors: Hakon
authors: H
authors: Hakonarson
authors: Mònica
authors: M
authors: Guxens
authors: Meike
authors: M
authors: Bartels
authors: Veikko
authors: V
authors: Salomaa
authors: Joanne M
authors: JM
authors: Murabito
authors: Jaakko
authors: J
authors: Kaprio
authors: Thorkild I A
authors: TI
authors: Sørensen
authors: Ferran
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authors: Ballester
authors: Hans
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authors: Bisgaard
authors: Dorret I
authors: DI
authors: Boomsma
authors: Gerard H
authors: GH
authors: Koppelman
authors: Struan F A
authors: SF
authors: Grant
authors: Vincent W V
authors: VW
authors: Jaddoe
authors: Nicholas G
authors: NG
authors: Martin
authors: Joachim
authors: J
authors: Heinrich
authors: Craig E
authors: CE
authors: Pennell
authors: Olli T
authors: OT
authors: Raitakari
authors: Johan G
authors: JG
authors: Eriksson
authors: George Davey
authors: GD
authors: Smith
authors: Elina
authors: E
authors: Hyppönen
authors: Marjo-Riitta
authors: MR
authors: Järvelin
authors: Mark I
authors: MI
authors: McCarthy
authors: Samuli
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authors: Ripatti
authors: Elisabeth
authors: E
authors: Widén
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000293:Adolescent; D000367:Age Factors; D001827:Body Height / Q000235:genetics*; D015992:Body Mass Index; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008572:Menarche; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011627:Puberty / Q000235:genetics*; D040641:Quantitative Trait Loci; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult
chemical_list: D016212:Transforming Growth Factor beta; D048052:Mitogen-Activated Protein Kinase 3