Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes
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
https://urn.fi/URN:NBN:fi-fe2025082785952
Tiivistelmä
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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