Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

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Abstract Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

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External Organisations
The Children's Hospital of Philadelphia; University of Pennsylvania; Imperial College London; McMaster University; Harvard University; University of Bristol; University of North Carolina at Chapel Hill; University of Southern California; National University of Singapore; Norwegian University of Science and Technology; Barcelona Institute for Global Health; University of Oulu; VU Medical Centre (Amsterdam); University of Valencia; National Institute on Aging; University of Helsinki; Tampere University; University of Oxford; Turku University Hospital; University of Copenhagen; University of London; Ludwig Maximilian University of Munich; Erasmus MC; University of Newcastle; Hunter Medical Research Institute; MRC Unit for Lifelong Health and Ageing; Centro Medico Nacional Siglo XXI; Children's Hospital Los Angeles; Haverford College; Cincinnati Children's Hospital Medical Center; University of Georgia; Singapore National Eye Center; Creighton University; University of San Carlos - Philippines; University of Turku; Pompeu Fabra University; University College London; Centre Hospitalier Universitaire de Nancy; Columbia University; John Hunter Hospital; University of Cambridge; Helmholtz Zentrum München - German Research Center for Environmental Health; Balearic Islands Health Research Institute (IdISBa); University of Exeter; University of Surrey

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Joshua A. Bell (Contributor); Carol A. Wang (Contributor); Andrew Wong (Contributor); Craig E. Pennell (Contributor); John A. Shepherd (Contributor)Jonathan P. Bradfield (Contributor); Rachel L. Kember (Contributor); Anna Ulrich (Contributor); Zhanna Balkiyarova (Contributor); Akram Alyass (Contributor); Izzuddin M. Aris (Contributor); K. Alaine Broadaway (Contributor); Zhanghua Chen (Contributor); Jin-Fang Chai (Contributor); Neil M. Davies (Contributor); Dietmar Fernandez-Orth (Contributor); Mariona Bustamante (Contributor); Ruby Fore (Contributor); Amitavo Ganguli (Contributor); Anni Heiskala (Contributor); Jouke-Jan Hottenga (Contributor); Carmen Íñiguez (Contributor); Sayuko Kobes (Contributor); Jaakko Leinonen (Contributor); Estelle Lowry (Contributor); Leo-Pekka Lyytikainen (Contributor); Anubha Mahajan (Contributor); Niina Pitkänen (Contributor); Theresia M. Schnurr (Contributor); Christian Theil Have (Contributor); David P. Strachan (Contributor); Elisabeth Thiering (Contributor); Suzanne Vogelezang (Contributor); Kaitlin H. Wade (Contributor); Louise Aas Holm (Contributor); Alessandra Chesi (Contributor); Miguel Cruz (Contributor); Paul Elliott (Contributor); Steve Franks (Contributor); Christine Frithioff-Bøjsøe (Contributor); W. James Gauderman (Contributor); Joseph T. Glessner (Contributor); Vicente Gilsanz (Contributor); Kendra Griesman (Contributor); Robert L. Hanson (Contributor); Marika Kaakinen (Contributor); Heidi Kalkwarf (Contributor); Andrea Kelly (Contributor); Joseph Kindler (Contributor); Mika Kähönen (Contributor); Carla Lanca (Contributor); Joan Lappe (Contributor); Nanette R. Lee (Contributor); Shana McCormack (Contributor); Frank D. Mentch (Contributor); Jonathan A. Mitchell (Contributor); Nina Mononen (Contributor); Harri Niinikoski (Contributor); Emily Oken (Contributor); Katja Pahkala (Contributor); Xueling Sim (Contributor); Yik-Ying Teo (Contributor); Leslie J. Baier (Contributor); Toos van Beijsterveldt (Contributor); Linda S. Adair (Contributor); Dorret I. Boomsma (Contributor); Eco de Geus (Contributor); Mònica Guxens (Contributor); Johan G. Eriksson (Contributor); Janine F. Felix (Contributor); Frank D. Gilliland (Contributor); Penn Medicine Biobank (Contributor); Torben Hansen (Contributor); Rebecca Hardy (Contributor); Marie-France Hivert (Contributor); Jens-Christian Holm (Contributor); Vincent W. V. Jaddoe (Contributor); Marjo-Riitta Järvelin (Contributor); Terho Lehtimäki (Contributor); David Meyre (Contributor); Karen L. Mohlke (Contributor); Juha Mykkänen (Contributor); Sharon Oberfield (Contributor); John R. B. Perry (Contributor); Olli Raitakari (Contributor); Fernando Rivadeneira (Contributor); Seang-Mei Saw (Contributor); Sylvain Sebert (Contributor); Marie Standl (Contributor); Thorkild I. A. Sørensen (Contributor); Nicholas J. Timpson (Contributor); Maties Torrent (Contributor); Gonneke Willemsen (Contributor); Elina Hypponen (Contributor); Chris Power (Contributor); Mark I. McCarthy (Contributor); Rachel M. Freathy (Contributor); Elisabeth Widén (Contributor); Hakon Hakonarson (Contributor); Inga Prokopenko (Contributor); Benjamin F. Voight (Contributor); Babette S. Zemel (Contributor); Struan F. A. Grant (Contributor); Diana L. Cousminer (Contributor)