Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes
Creators: name: Raitakari, Olli
name: Torrent, Maties
name: Grant, Struan F. A.
name: Mitchell, Jonathan A.
name: Kindler, Joseph
name: Oken, Emily
name: Wang, Carol A.
name: Kobes, Sayuko
name: Fore, Ruby
name: Perry, John R. B.
name: Heiskala, Anni
name: Hivert, Marie-France
name: Ulrich, Anna
name: Sebert, Sylvain
name: Bell, Joshua A.
name: Aris, Izzuddin M.
name: Kelly, Andrea
name: Gauderman, W. James
name: Teo, Yik-Ying
name: Chesi, Alessandra
name: Cruz, Miguel
name: Pitkänen, Niina
name: Bustamante, Mariona
name: Hansen, Torben
name: Boomsma, Dorret I.
name: Kember, Rachel L.
name: de Geus, Eco
name: Glessner, Joseph T.
name: Leinonen, Jaakko
name: Willemsen, Gonneke
name: Frithioff-Bøjsøe, Christine
name: Hypponen, Elina
name: Rivadeneira, Fernando
name: Holm, Jens-Christian
name: Mykkänen, Juha
name: Penn Medicine Biobank
name: Hanson, Robert L.
name: Kalkwarf, Heidi
name: Pahkala, Katja
name: McCarthy, Mark I.
name: Freathy, Rachel M.
name: Lyytikainen, Leo-Pekka
name: Elliott, Paul
name: Shepherd, John A.
name: Lehtimäki, Terho
name: Strachan, David P.
name: Baier, Leslie J.
name: Gilsanz, Vicente
name: van Beijsterveldt, Toos
name: Cousminer, Diana L.
name: Kähönen, Mika
name: Hakonarson, Hakon
name: Schnurr, Theresia M.
name: Power, Chris
name: Alyass, Akram
name: Järvelin, Marjo-Riitta
name: Sørensen, Thorkild I. A.
name: Timpson, Nicholas J.
name: Mentch, Frank D.
name: Chen, Zhanghua
name: Mohlke, Karen L.
name: Niinikoski, Harri
name: Wade, Kaitlin H.
name: Zemel, Babette S.
name: Íñiguez, Carmen
name: Fernandez-Orth, Dietmar
name: McCormack, Shana
name: Balkhiyarova, Zhanna
name: Ganguli, Amitavo
name: Hardy, Rebecca
name: Meyre, David
name: Eriksson, Johan G.
name: Felix, Janine F.
name: Pennell, Craig E.
name: Hottenga, Jouke-Jan
name: Sim, Xueling
name: Wong, Andrew
name: Lowry, Estelle
name: Holm, Louise Aas
name: Choong, Catherine
name: Mahajan, Anubha
name: Voight, Benjamin F.
name: Lee, Nanette R.
name: Saw, Seang-Mei
name: Jaddoe, Vincent W. V.
name: Lappe, Joan
name: Oberfield, Sharon
name: Guxens, Mònica
name: Vogelezang, Suzanne
name: Franks, Steve
name: Prokopenko, Inga
name: Have, Christian Theil
name: Bradfield, Jonathan P.
name: Lanca, Carla
name: Standl, Marie
name: Mackey, David A.
name: Gilliland, Frank D.
name: Thiering, Elisabeth
name: Griesman, Kendra
name: Adair, Linda S.
name: Kaakinen, Marika
name: Mononen, Nina
name: Broadaway, K. Alaine
name: Widén, Elisabeth
name: Chai, Jin-Fang
name: Davies, Neil M.
Publisher: name: Springer Nature
Year: 2024

description: 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.