A1 Refereed original research article in a scientific journal
Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes
Authors: Bradfield JP, Kember RL, Ulrich A, Balkiyarova Z, Alyass A, Aris IM, Bell JA, Broadaway KA, Chen Z, Chai JF, Davies NM, Fernandez-Orth D, Bustamante M, Fore R, Ganguli A, Heiskala A, Hottenga JJ, Íñiguez C, Kobes S, Leinonen J, Lowry E, Lyytikainen LP, Mahajan A, Pitkänen N, Schnurr TM, Have CT, Strachan DP, Thiering E, Vogelezang S, Wade KH, Wang CA, Wong A, Holm LA, Chesi A, Choong C, Cruz M, Elliott P, Franks S, Frithioff-Bøjsøe C, Gauderman WJ, Glessner JT, Gilsanz V, Griesman K, Hanson RL, Kaakinen M, Kalkwarf H, Kelly A, Kindler J, Kähönen M, Lanca C, Lappe J, Lee NR, McCormack S, Mentch FD, Mitchell JA, Mononen N, Niinikoski H, Oken E, Pahkala K, Sim X, Teo YY, Baier LJ, van Beijsterveldt T, Adair LS, Boomsma DI, de Geus E, Guxens M, Eriksson JG, Felix JF, Gilliland FD, Biobank PM, Hansen T, Hardy R, Hivert MF, Holm JC, Jaddoe VWV, Järvelin MR, Lehtimäki T, Mackey DA, Meyre D, Mohlke KL, Mykkänen J, Oberfield S, Pennell CE, Perry JRB, Raitakari O, Rivadeneira F, Saw SM, Sebert S, Shepherd JA, Standl M, Sørensen TIA, Timpson NJ, Torrent M, Willemsen G, Hypponen E, Power C, Early Growth Genetics Consortium, McCarthy MI, Freathy RM, Widén E, Hakonarson H, Prokopenko I, Voight BF, Zemel BS, Grant SFA, Cousminer DL
Publication year: 2024
Journal: Genome Biology
Journal name in source: Genome biology
Journal acronym: Genome Biol
Article number: 24
Volume: 25
Issue: 1
ISSN: 1474-7596
eISSN: 1474-760X
DOI: https://doi.org/10.1186/s13059-023-03136-z
Web address : https://doi.org/10.1186/s13059-023-03136-z
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/387205213
Additional information: Author Correction: Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes / Genome Biology volume 25, Article number: 129 (2024) / https://doi.org/10.1186/s13059-024-03276-w ; DOI: 10.1186/s13059-024-03276-w
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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Funding information in the publication:
Cohort funding can be found in the Supplementary Data. S.F.A.G. is funded by R01 HD056465 and the Daniel B. Burke Endowed Chair for Diabetes Research. K.A.B is funded by the National Institutes of Health (T32HL129982). M.McC is a Wellcome Trust Investigator (funding through 212259/Z/18/Z). K.P. is funded by an Academy of Finland research fellowship (no. 322112). J.P. is supported by the Medical Research Council (Unit programs: MC_UU_12015/2, MC_UU_00006/2). R.M.F. is supported by a Wellcome Senior Research Fellowship (WT220390). S.F. is supported by an MRC (UK) Programme grant (G0802782). I.P. and Z.B. are funded by the Diabetes UK (BDA number: 20/0006307), the European Union’s Horizon 2020 research and innovation programme (LONGITOOLS, H2020-SC1-2019–874739). I.P. is supported by Agence Nationale de la Recherche (PreciDIAB, ANR-18-IBHU-0001), by the European Union through the “Fonds européen de développement regional” (FEDER), by the “Conseil Régional des Hauts-de-France” (Hauts-de-France Regional Council) and by the “Métropole Européenne de Lille” (MEL, European Metropolis of Lille).
