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

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.