Genome Biology (Jan 2024)
Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes
- Jonathan P. Bradfield,
- Rachel L. Kember,
- Anna Ulrich,
- Zhanna Balkhiyarova,
- Akram Alyass,
- Izzuddin M. Aris,
- Joshua A. Bell,
- K. Alaine Broadaway,
- Zhanghua Chen,
- Jin-Fang Chai,
- Neil M. Davies,
- Dietmar Fernandez-Orth,
- Mariona Bustamante,
- Ruby Fore,
- Amitavo Ganguli,
- Anni Heiskala,
- Jouke-Jan Hottenga,
- Carmen Íñiguez,
- Sayuko Kobes,
- Jaakko Leinonen,
- Estelle Lowry,
- Leo-Pekka Lyytikainen,
- Anubha Mahajan,
- Niina Pitkänen,
- Theresia M. Schnurr,
- Christian Theil Have,
- David P. Strachan,
- Elisabeth Thiering,
- Suzanne Vogelezang,
- Kaitlin H. Wade,
- Carol A. Wang,
- Andrew Wong,
- Louise Aas Holm,
- Alessandra Chesi,
- Catherine Choong,
- Miguel Cruz,
- Paul Elliott,
- Steve Franks,
- Christine Frithioff-Bøjsøe,
- W. James Gauderman,
- Joseph T. Glessner,
- Vicente Gilsanz,
- Kendra Griesman,
- Robert L. Hanson,
- Marika Kaakinen,
- Heidi Kalkwarf,
- Andrea Kelly,
- Joseph Kindler,
- Mika Kähönen,
- Carla Lanca,
- Joan Lappe,
- Nanette R. Lee,
- Shana McCormack,
- Frank D. Mentch,
- Jonathan A. Mitchell,
- Nina Mononen,
- Harri Niinikoski,
- Emily Oken,
- Katja Pahkala,
- Xueling Sim,
- Yik-Ying Teo,
- Leslie J. Baier,
- Toos van Beijsterveldt,
- Linda S. Adair,
- Dorret I. Boomsma,
- Eco de Geus,
- Mònica Guxens,
- Johan G. Eriksson,
- Janine F. Felix,
- Frank D. Gilliland,
- Penn Medicine Biobank,
- Torben Hansen,
- Rebecca Hardy,
- Marie-France Hivert,
- Jens-Christian Holm,
- Vincent W. V. Jaddoe,
- Marjo-Riitta Järvelin,
- Terho Lehtimäki,
- David A. Mackey,
- David Meyre,
- Karen L. Mohlke,
- Juha Mykkänen,
- Sharon Oberfield,
- Craig E. Pennell,
- John R. B. Perry,
- Olli Raitakari,
- Fernando Rivadeneira,
- Seang-Mei Saw,
- Sylvain Sebert,
- John A. Shepherd,
- Marie Standl,
- Thorkild I. A. Sørensen,
- Nicholas J. Timpson,
- Maties Torrent,
- Gonneke Willemsen,
- Elina Hypponen,
- Chris Power,
- The Early Growth Genetics Consortium,
- Mark I. McCarthy,
- Rachel M. Freathy,
- Elisabeth Widén,
- Hakon Hakonarson,
- Inga Prokopenko,
- Benjamin F. Voight,
- Babette S. Zemel,
- Struan F. A. Grant,
- Diana L. Cousminer
Affiliations
- Jonathan P. Bradfield
- Center for Applied Genomics, Children’s Hospital of Philadelphia
- Rachel L. Kember
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania
- Anna Ulrich
- Department of Clinical & Experimental Medicine, University of Surrey
- Zhanna Balkhiyarova
- Department of Clinical & Experimental Medicine, University of Surrey
- Akram Alyass
- Department of Health Research Methods, Evidence, and Impact, McMaster University
- Izzuddin M. Aris
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute
- Joshua A. Bell
- MRC Integrative Epidemiology Unit at the University of Bristol
- K. Alaine Broadaway
- Department of Genetics, University of North Carolina
- Zhanghua Chen
- Department of Population and Public Health Sciences, University of Southern California
- Jin-Fang Chai
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Neil M. Davies
- MRC Integrative Epidemiology Unit at the University of Bristol
- Dietmar Fernandez-Orth
- ISGlobal
- Mariona Bustamante
- ISGlobal
- Ruby Fore
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute
- Amitavo Ganguli
- Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
- Anni Heiskala
- Center for Life Course Health Research, University of Oulu
- Jouke-Jan Hottenga
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Carmen Íñiguez
- Department of Statistics and Computational Research, Universitat de València
- Sayuko Kobes
- Phoenix Epidemiology and Clinical Research Center, NIDDK, NIH
- Jaakko Leinonen
- Institute for Molecular Medicine Finland, University of Helsinki
- Estelle Lowry
- Center for Life Course Health Research, University of Oulu
- Leo-Pekka Lyytikainen
- Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University
- Anubha Mahajan
- Wellcome Centre for Human Genetics, University of Oxford
- Niina Pitkänen
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku
- Theresia M. Schnurr
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
- Christian Theil Have
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
- David P. Strachan
- Population Health Research Institute, St George’s, University of London
- Elisabeth Thiering
- Institute of Epidemiology, Helmholtz Zentrum München- German Research Center for Environmental Health
- Suzanne Vogelezang
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
- Kaitlin H. Wade
- MRC Integrative Epidemiology Unit at the University of Bristol
- Carol A. Wang
- School of Medicine and Public Health, Faculty of Medicine and Health, University of Newcastle
- Andrew Wong
- MRC Unit for Lifelong Health and Ageing at UCL
- Louise Aas Holm
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
- Alessandra Chesi
- Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia
- Catherine Choong
- Faculty of Health and Medical Sciences, University of Western Australia
- Miguel Cruz
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social
- Paul Elliott
- MRC Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College London, St Mary’s Campus
- Steve Franks
- Institute of Reproductive & Developmental Biology, Imperial College London
- Christine Frithioff-Bøjsøe
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
- W. James Gauderman
- Department of Population and Public Health Sciences, University of Southern California
- Joseph T. Glessner
- Center for Applied Genomics, Children’s Hospital of Philadelphia
- Vicente Gilsanz
- Center for Endocrinology, Diabetes & Metabolism, Children’s Hospital Los Angeles
- Kendra Griesman
- Haverford College
- Robert L. Hanson
- Phoenix Epidemiology and Clinical Research Center, NIDDK, NIH
- Marika Kaakinen
- Department of Clinical & Experimental Medicine, University of Surrey
- Heidi Kalkwarf
- Department of Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati
- Andrea Kelly
- Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine
- Joseph Kindler
- College of Family and Consumer Sciences, University of Georgia
- Mika Kähönen
- Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University
- Carla Lanca
- Singapore Eye Research Institute, Singapore National Eye Centre
- Joan Lappe
- Department of Medicine and College of Nursing, Creighton University School of Medicine
- Nanette R. Lee
- USC-Office of Population Studies Foundation, Inc, University of San Carlos
- Shana McCormack
- Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine
- Frank D. Mentch
- Center for Applied Genomics, Children’s Hospital of Philadelphia
- Jonathan A. Mitchell
- Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine
- Nina Mononen
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center - Tampere, Tampere University
- Harri Niinikoski
- Department of Pediatrics and Adolescent Medicine, Turku University Hospital and University of Turku
- Emily Oken
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute
- Katja Pahkala
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku
- Xueling Sim
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Yik-Ying Teo
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Leslie J. Baier
- Phoenix Epidemiology and Clinical Research Center, NIDDK, NIH
- Toos van Beijsterveldt
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Linda S. Adair
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina
- Dorret I. Boomsma
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Eco de Geus
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Mònica Guxens
- ISGlobal
- Johan G. Eriksson
- Institute of Clinical Medicine Department of General Practice and Primary Health Care, University of Helsinki
- Janine F. Felix
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
- Frank D. Gilliland
- Department of Population and Public Health Sciences, University of Southern California
- Penn Medicine Biobank
- Torben Hansen
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
- Rebecca Hardy
- Cohort and Longitudinal Studies Enhancement Resources (CLOSER), UCL Institute of Education
- Marie-France Hivert
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute
- Jens-Christian Holm
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
- Vincent W. V. Jaddoe
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
- Marjo-Riitta Järvelin
- Center for Life Course Health Research, University of Oulu
- Terho Lehtimäki
- Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center - Tampere, Tampere University
- David A. Mackey
- Lions Eye Institute, Centre for Ophthalmology and Visual Science, Centre for Eye Research Australia, University of Western Australia
- David Meyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University
- Karen L. Mohlke
- Department of Genetics, University of North Carolina
- Juha Mykkänen
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku
- Sharon Oberfield
- Division of Pediatric Endocrinology, Columbia University Medical Center
- Craig E. Pennell
- School of Medicine and Public Health, Faculty of Medicine and Health, University of Newcastle
- John R. B. Perry
- Metabolic Research Laboratory, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge
- Olli Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku
- Fernando Rivadeneira
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam
- Seang-Mei Saw
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Sylvain Sebert
- Center for Life Course Health Research, University of Oulu
- John A. Shepherd
- Department of Epidemiology and Population Science, University of Hawaii Cancer Center
- Marie Standl
- Institute of Epidemiology, Helmholtz Zentrum München- German Research Center for Environmental Health
- Thorkild I. A. Sørensen
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
- Nicholas J. Timpson
- MRC Integrative Epidemiology Unit at the University of Bristol
- Maties Torrent
- CIBER Epidemiología y Salud Pública (CIBERESP)
- Gonneke Willemsen
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Elina Hypponen
- UCL Great Ormond Street Institute of Child Health
- Chris Power
- UCL Great Ormond Street Institute of Child Health
- The Early Growth Genetics Consortium
- Mark I. McCarthy
- Wellcome Centre for Human Genetics, University of Oxford
- Rachel M. Freathy
- Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter
- Elisabeth Widén
- Institute for Molecular Medicine Finland, University of Helsinki
- Hakon Hakonarson
- Center for Applied Genomics, Children’s Hospital of Philadelphia
- Inga Prokopenko
- Department of Clinical & Experimental Medicine, University of Surrey
- Benjamin F. Voight
- Department of Genetics, University of Pennsylvania
- Babette S. Zemel
- Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine
- Struan F. A. Grant
- Center for Applied Genomics, Children’s Hospital of Philadelphia
- Diana L. Cousminer
- Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia
- DOI
- https://doi.org/10.1186/s13059-023-03136-z
- Journal volume & issue
-
Vol. 25,
no. 1
pp. 1 – 19
Abstract
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.
