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

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

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.