open access publication

Article, 2024

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

Genome Biology, ISSN 1474-760X, 1465-6906, 1465-6914, Volume 25, 1, Page 22, 10.1186/s13059-023-03136-z

Contributors

Bradfield, Jonathan P [1] Kember, Rachel Lorraine 0000-0001-8820-2659 [2] Ulrich, Anna [3] [4] Balkhiyarova, Zhanna R 0000-0003-3553-7126 [3] [4] Alyass, Akram [5] Aris, Izzuddin Mohd 0000-0002-9239-7476 [6] Bell, Joshua A. [7] Broadaway, K Alaine [8] Chen, Zhanghua [9] Chai, Jin-Fang 0000-0003-3770-1137 [10] [11] Davies, Neil Martin 0000-0002-2460-0508 [7] [12] Fernández-Orth, Dietmar 0000-0002-1237-3192 [13] Bustamante, Mariona 0000-0003-0127-2860 [13] Fore, Ruby 0009-0009-0396-1484 [6] Ganguli, Amitavo [1] Heiskala, Anni [14] Hottenga, Jouke-Jan [15] Iñiguez, Carmen 0000-0002-5156-0732 [16] [17] Kobes, Sayuko [18] Leinonen, Jaakko T 0000-0001-7530-6918 [19] Lowry, Estelle [14] Lyytikäinen, Leo-Pekka 0000-0002-7200-5455 [20] [21] Mahajan, Anubha [22] Pitkänen, Niina [23] [24] Schnurr, Theresia Maria 0000-0002-6573-4959 [25] Have, Christian Theil 0000-0002-8634-4781 [25] Strachan, David P [26] Thiering, Elisabeth 0000-0002-5429-9584 [27] [28] Vogelezang, Suzanne [29] Wade, Kaitlin Hazel 0000-0003-3362-6280 [7] Wang, Carol A [30] [31] Wong, Andrew [32] Holm, Louise Aas 0000-0002-5439-5429 [25] [33] Chesi, Alessandra 0000-0002-0954-7446 [1] Choong, Catherine [34] Cruz, Miguel Angel 0000-0001-9985-6172 [35] Elliott, Paul 0000-0002-7511-5684 [3] Franks, Steve [3] Frithioff-Bøjsøe, Christine 0000-0002-5005-7780 [25] [33] Gauderman, William James [9] Glessner, Joseph T 0000-0001-5131-2811 [1] Gilsanz, Vicente [36] Griesman, Kendra [37] Hanson, Robert L. [18] Kaakinen, Marika [3] [4] Kalkwarf, Heidi J 0000-0001-9030-8401 [38] [39] Kelly, Andrea [1] [2] Kindler, Joseph [40] Kähönen, Mika A P 0000-0002-4510-7341 [20] [21] Lanca, Carla Costa 0000-0001-9918-787X [41] Lappe, Joan M [42] Lee, Nanette Requintina [43] Mccormack, Shana Erin 0000-0002-1143-4459 [1] [2] Mentch, Frank D [1] Mitchell, Jonathan A [1] [2] Mononen, Nina [21] [44] Niinikoski, Harri 0000-0002-7071-918X [23] Oken, Emily 0000-0003-2513-3339 [6] Pahkala, Katja A 0000-0001-9338-4397 [23] [24] Sim, Xue Ling 0000-0002-1233-7642 [10] [11] Teo, Yik-Ying [10] [11] Baier, Leslie J 0000-0002-8773-9670 [18] Van Beijsterveldt, Toos C E M 0000-0002-6617-4201 [15] Adair, Linda S [8] Boomsma, Dorothea Irene 0000-0002-7099-7972 [15] [45] De Geus, Eco J C N 0000-0001-6022-2666 [15] Guxens, Mònica 0000-0002-8624-0333 [13] [17] [46] Eriksson, Johan Gunnar 0000-0002-2516-2060 [10] [47] [48] Felix, Janine Frédérique 0000-0002-9801-5774 [29] Gilliland, Frank Davis 0000-0002-9033-7269 [9] Biobank, Penn Medicine Hansen, Torben 0000-0001-8748-3831 [25] Hardy, Rebecca [49] Hivert, Marie-France 0000-0001-7752-2585 [6] Holm, Jens-Christian 0000-0003-4653-342X [25] [33] Jaddoe, Vincent W V W 0000-0003-2939-0041 [29] Järvelin, Marjo-Riitta R 0000-0002-2149-0630 [3] [14] [50] Lehtimäki, Terho J 0000-0002-2555-4427 [21] [44] Mackey, David Anthony 0000-0001-7914-4709 [34] [51] Meyre, David 0000-0003-4850-7444 [5] [52] [53] Mohlke, Karen L [8] Mykkänen, Juha [23] [24] Oberfield, Sharon E 0000-0001-9652-1107 [54] Pennell, Craig Edward 0000-0002-0937-6165 [30] [31] [55] Perry, John R B [56] [57] Raitakari, Olli Tuomas [23] [24] Rivadeneira, Fernando F 0000-0001-9435-9441 [29] Saw, Seang-Mei 0000-0001-7166-796X [10] [11] Sebert, Sylvain [3] [14] Shepherd, John A [58] Standl, Marie 0000-0002-5345-2049 [28] Sørensen, Thorkild Ingvor Arrild 0000-0003-4821-430X [25] Timpson, Nicholas John 0000-0002-7141-9189 [7] Torrent, Maties [17] [59] Willemsen, Gonneke A H M 0000-0003-3755-0236 [15] Hyppönen, Elina 0000-0003-3670-9399 [49] [60] [61] Power, Chris [49] Mccarthy, Mark Ian 0000-0002-4393-0510 [22] [62] Freathy, Rachel M 0000-0003-4152-2238 [63] Widén, Elisabeth I M [19] Hakonarson, Hakon [1] [2] Prokopenko, Inga 0000-0003-1624-7457 [4] [64] Voight, Benjamin Franklin 0000-0002-6205-9994 [2] Zemel, Babette S 0000-0002-6164-7348 [1] [2] Grant, Struan F A 0000-0003-2025-5302 (Corresponding author) [1] [2] Cousminer, Diana L (Corresponding author) [1] [2] [65]

Affiliations

  1. [1] Children's Hospital of Philadelphia
    2. [NORA names: United States; America, North; OECD];
  2. [2] University of Pennsylvania
    3. [NORA names: United States; America, North; OECD];
  3. [3] Imperial College London
    4. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  4. [4] University of Surrey
    5. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  5. [5] McMaster University
    6. [NORA names: Canada; America, North; OECD];

Abstract

BackgroundPubertal 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.ResultsLarge-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.ConclusionWe 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.

Keywords

AIDS, Biobank, ConclusionWe, HOMA-IR, Penn, Penn Medicine Biobank, UK Biobank, adolescent growth, adult health outcomes, adulthood, age, aged 5, analysis, associated with higher risk, association, association studies, atrial fibrillation, bone mineral density, cancer, cohort, correlation analysis, course, data, density, determinants of growth, early puberty, fasting insulin, fibrillation, fine-mapping, genetic analysis, genetic association, genetic correlation analysis, genetic determinants, genetic mechanisms, genetic relationships, genome-wide significant loci, growth, growth model, growth pattern, growth spurt, growth trajectories, health, health outcomes, height growth, heritability, high risk, higher bone mineral density, insulin, intensity, life, life course, lifelong health, lifelong impact, loci, lung, lung cancer, magnitude, mechanism, mineral density, model, outcomes, patterns, pediatric cohort, phenome-wide association study, phenotype, pubertal growth, pubertal growth patterns, pubertal growth spurt, pubertal height growth, puberty, relationship, results, results aid, risk, samples, significant loci, spurt, study, super-imposition, tempo, time, traits in adulthood, trajectory, trans-ancestry, translation, type, type 2 diabetes, years

Funders

  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Center for Advancing Translational Sciences
  • Academy of Finland
  • Medical Research Foundation
  • Diabetes UK
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
  • Medical Research Council
  • Wellcome Trust
  • European Commission
  • National Heart Lung and Blood Institute

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