. 2024 Jan 16;25(1):22.

doi: 10.1186/s13059-023-03136-z.

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

Jonathan P Bradfield^{1

2}, Rachel L Kember³, Anna Ulrich^{4

5}, Zhanna Balkhiyarova^{4

5

6}, Akram Alyass⁷, Izzuddin M Aris⁸, Joshua A Bell⁹, K Alaine Broadaway¹⁰, Zhanghua Chen¹¹, Jin-Fang Chai¹², Neil M Davies^{9

13

14}, Dietmar Fernandez-Orth¹⁵, Mariona Bustamante¹⁵, Ruby Fore⁸, Amitavo Ganguli², Anni Heiskala¹⁶, Jouke-Jan Hottenga¹⁷, Carmen Íñiguez^{18

19

20}, Sayuko Kobes²¹, Jaakko Leinonen²², Estelle Lowry¹⁶, Leo-Pekka Lyytikainen^{23

24}, Anubha Mahajan²⁵, Niina Pitkänen^{26

27}, Theresia M Schnurr²⁸, Christian Theil Have²⁸, David P Strachan²⁹, Elisabeth Thiering^{30

31}, Suzanne Vogelezang^{32

33

34}, Kaitlin H Wade^{9

13}, Carol A Wang^{35

36}, Andrew Wong³⁷, Louise Aas Holm^{28

38}, Alessandra Chesi³⁹, Catherine Choong⁴⁰, Miguel Cruz⁴¹, Paul Elliott⁴², Steve Franks⁴³, Christine Frithioff-Bøjsøe^{28

38}, W James Gauderman¹¹, Joseph T Glessner¹, Vicente Gilsanz⁴⁴, Kendra Griesman⁴⁵, Robert L Hanson²¹, Marika Kaakinen^{4

43}, Heidi Kalkwarf⁴⁶, Andrea Kelly^{47

48}, Joseph Kindler⁴⁹, Mika Kähönen^{23

24}, Carla Lanca⁵⁰, Joan Lappe⁵¹, Nanette R Lee⁵², Shana McCormack^{47

48}, Frank D Mentch¹, Jonathan A Mitchell^{47

53}, Nina Mononen^{54

55}, Harri Niinikoski^{56

57}, Emily Oken^{8

58}, Katja Pahkala^{26

27

59}, Xueling Sim¹², Yik-Ying Teo¹², Leslie J Baier²¹, Toos van Beijsterveldt¹⁷, Linda S Adair⁶⁰, Dorret I Boomsma^{17

61}, Eco de Geus¹⁷, Mònica Guxens^{15

19

62}, Johan G Eriksson^{63

64

65}, Janine F Felix^{32

34}, Frank D Gilliland¹¹, Penn Medicine Biobank, Torben Hansen²⁸, Rebecca Hardy⁶⁶, Marie-France Hivert⁸, Jens-Christian Holm^{28

38

67}, Vincent W V Jaddoe^{32

34}, Marjo-Riitta Järvelin^{16

68

69}, Terho Lehtimäki^{54

55}, David A Mackey⁷⁰, David Meyre^{7

71

72

73}, Karen L Mohlke¹⁰, Juha Mykkänen^{26

27}, Sharon Oberfield⁷⁴, Craig E Pennell^{35

36

75}, John R B Perry^{76

77}, Olli Raitakari^{26

27

78}, Fernando Rivadeneira^{33

79}, Seang-Mei Saw¹², Sylvain Sebert^{16

68}, John A Shepherd⁸⁰, Marie Standl³⁰, Thorkild I A Sørensen^{28

81}, Nicholas J Timpson⁹, Maties Torrent^{19

82}, Gonneke Willemsen¹⁷, Elina Hypponen^{83

84

85}, Chris Power⁸³; Early Growth Genetics Consortium; Mark I McCarthy^{25

86}, Rachel M Freathy⁸⁷, Elisabeth Widén²², Hakon Hakonarson^{1

47}, Inga Prokopenko^{4

6

88}, Benjamin F Voight^{89

90

91}, Babette S Zemel^{47

53}, Struan F A Grant^{92

93

94

95

96

97}, Diana L Cousminer^{98

99

100

101}

Affiliations

¹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
² Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
³ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
⁴ Department of Clinical & Experimental Medicine, University of Surrey, Guildford, UK.
⁵ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
⁶ People-Centred Artificial Intelligence Institute, University of Surrey, Guildford, UK.
⁷ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
⁸ Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, 02215, USA.
⁹ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
¹⁰ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
¹¹ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, 90032, USA.
¹² Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
¹³ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.
¹⁴ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁵ ISGlobal, Barcelona, Spain.
¹⁶ Center for Life Course Health Research, University of Oulu, Oulu, Finland.
¹⁷ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁸ Department of Statistics and Computational Research, Universitat de València, Valencia, Spain.
¹⁹ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
²⁰ Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
²¹ Phoenix Epidemiology and Clinical Research Center, NIDDK, NIH, Bethesda, USA.
²² Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
²³ Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland.
²⁴ Department of Clinical Physiology, Tampere University Hospital, 33521, Tampere, Finland.
²⁵ Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
²⁶ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
²⁷ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
²⁸ Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
²⁹ Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.
³⁰ Institute of Epidemiology, Helmholtz Zentrum München- German Research Center for Environmental Health, Neuherberg, Germany.
³¹ Division of Metabolic and Nutritional Medicine, Dr. Von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany.
³² The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
³³ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
³⁴ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
³⁵ School of Medicine and Public Health, Faculty of Medicine and Health, University of Newcastle, Callaghan, NSW, 2308, Australia.
³⁶ Hunter Medical Research Institute, Newcastle, NSW, 2305, Australia.
³⁷ MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
³⁸ Department of Pediatrics, The Children's Obesity Clinic, Copenhagen University Hospital Holbæk, Holbæk, Denmark.
³⁹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴⁰ Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.
⁴¹ Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
⁴² MRC Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK.
⁴³ Institute of Reproductive & Developmental Biology, Imperial College London, London, UK.
⁴⁴ Center for Endocrinology, Diabetes & Metabolism, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁴⁵ Haverford College, Haverford, PA, USA.
⁴⁶ Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
⁴⁷ Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
⁴⁸ Division of Endocrinology & Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁴⁹ College of Family and Consumer Sciences, University of Georgia, Athens, GA, USA.
⁵⁰ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
⁵¹ Department of Medicine and College of Nursing, Creighton University School of Medicine, Omaha, NB, USA.
⁵² USC-Office of Population Studies Foundation, Inc, University of San Carlos, Cebu, Philippines.
⁵³ Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁵⁴ Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center - Tampere, Tampere University, 33014, Tampere, Finland.
⁵⁵ Department of Clinical Chemistry, Fimlab Laboratories, 33520, Tampere, Finland.
⁵⁶ Department of Pediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, Turku, Finland.
⁵⁷ Department of Physiology, University of Turku, Turku, Finland.
⁵⁸ Department of Nutrition, Harvard T.H Chan School of Public Health, Boston, MA, 02115, USA.
⁵⁹ Paavo Nurmi Centre, Unit for Health and Physical Activity, University of Turku, Turku, Finland.
⁶⁰ Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
⁶¹ Amsterdam Reproduction & Development (AR&D) Research Institute, Amsterdam, the Netherlands.
⁶² Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁶³ Institute of Clinical Medicine Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
⁶⁴ Folkhälsan Research Center, Helsinki, Finland.
⁶⁵ Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁶⁶ Cohort and Longitudinal Studies Enhancement Resources (CLOSER), UCL Institute of Education, London, UK.
⁶⁷ The Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶⁸ Department of Epidemiology and Biostatistics, School of Public Health, MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK.
⁶⁹ Unit of Primary Health Care, Oulu University Hospital, OYS, Kajaanintie 50, 90220, Oulu, Finland.
⁷⁰ Lions Eye Institute, Centre for Ophthalmology and Visual Science, Centre for Eye Research Australia, University of Western Australia, Perth, WA, Australia.
⁷¹ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
⁷² Inserm UMR_S1256 Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, Nancy, France.
⁷³ Department of Biochemistry-Molecular Biology-Nutrition, University Hospital Centre of Nancy, Nancy, France.
⁷⁴ Division of Pediatric Endocrinology, Columbia University Medical Center, New York, NY, USA.
⁷⁵ Department of Maternity and Gynaecology, John Hunter Hospital, Newcastle, NSW, 2305, Australia.
⁷⁶ Metabolic Research Laboratory, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
⁷⁷ MRC Epidemiology Unit, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
⁷⁸ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁷⁹ Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸⁰ Department of Epidemiology and Population Science, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁸¹ Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸² Fundació Institut d'Investigació Sanitària Illes Balears - IdISBa, Palma, Spain.
⁸³ UCL Great Ormond Street Institute of Child Health, London, UK.
⁸⁴ Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
⁸⁵ South Australian Health and Medical Research Institute, Adelaide, Australia.
⁸⁶ Current Address: Genentech, 1 DNA Way, San Francisco, CA, 94080, USA.
⁸⁷ Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, EX2 5DW, UK.
⁸⁸ UMR 8199 - EGID, Institut Pasteur de Lille, CNRS, University of Lille, 59000, Lille, France.
⁸⁹ Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹⁰ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹¹ Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹² Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹³ Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁴ Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁵ Division of Endocrinology & Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁶ Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁷ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁸ Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. diana.l.cousminer@gsk.com.
⁹⁹ Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA. diana.l.cousminer@gsk.com.
¹⁰⁰ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. diana.l.cousminer@gsk.com.
¹⁰¹ Currently Employed By GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA, 19426, USA. diana.l.cousminer@gsk.com.

PMID: 38229171
PMCID: PMC10790528
DOI: 10.1186/s13059-023-03136-z

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

Jonathan P Bradfield et al. Genome Biol. 2024.

. 2024 Jan 16;25(1):22.

doi: 10.1186/s13059-023-03136-z.

Authors

Affiliations

¹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
² Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
³ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
⁴ Department of Clinical & Experimental Medicine, University of Surrey, Guildford, UK.
⁵ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
⁶ People-Centred Artificial Intelligence Institute, University of Surrey, Guildford, UK.
⁷ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada.
⁸ Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, 02215, USA.
⁹ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
¹⁰ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
¹¹ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, 90032, USA.
¹² Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
¹³ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.
¹⁴ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁵ ISGlobal, Barcelona, Spain.
¹⁶ Center for Life Course Health Research, University of Oulu, Oulu, Finland.
¹⁷ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁸ Department of Statistics and Computational Research, Universitat de València, Valencia, Spain.
¹⁹ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
²⁰ Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain.
²¹ Phoenix Epidemiology and Clinical Research Center, NIDDK, NIH, Bethesda, USA.
²² Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
²³ Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland.
²⁴ Department of Clinical Physiology, Tampere University Hospital, 33521, Tampere, Finland.
²⁵ Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
²⁶ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
²⁷ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
²⁸ Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
²⁹ Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.
³⁰ Institute of Epidemiology, Helmholtz Zentrum München- German Research Center for Environmental Health, Neuherberg, Germany.
³¹ Division of Metabolic and Nutritional Medicine, Dr. Von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany.
³² The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
³³ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
³⁴ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
³⁵ School of Medicine and Public Health, Faculty of Medicine and Health, University of Newcastle, Callaghan, NSW, 2308, Australia.
³⁶ Hunter Medical Research Institute, Newcastle, NSW, 2305, Australia.
³⁷ MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
³⁸ Department of Pediatrics, The Children's Obesity Clinic, Copenhagen University Hospital Holbæk, Holbæk, Denmark.
³⁹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴⁰ Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.
⁴¹ Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
⁴² MRC Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK.
⁴³ Institute of Reproductive & Developmental Biology, Imperial College London, London, UK.
⁴⁴ Center for Endocrinology, Diabetes & Metabolism, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁴⁵ Haverford College, Haverford, PA, USA.
⁴⁶ Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH, USA.
⁴⁷ Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
⁴⁸ Division of Endocrinology & Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁴⁹ College of Family and Consumer Sciences, University of Georgia, Athens, GA, USA.
⁵⁰ Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
⁵¹ Department of Medicine and College of Nursing, Creighton University School of Medicine, Omaha, NB, USA.
⁵² USC-Office of Population Studies Foundation, Inc, University of San Carlos, Cebu, Philippines.
⁵³ Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁵⁴ Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center - Tampere, Tampere University, 33014, Tampere, Finland.
⁵⁵ Department of Clinical Chemistry, Fimlab Laboratories, 33520, Tampere, Finland.
⁵⁶ Department of Pediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, Turku, Finland.
⁵⁷ Department of Physiology, University of Turku, Turku, Finland.
⁵⁸ Department of Nutrition, Harvard T.H Chan School of Public Health, Boston, MA, 02115, USA.
⁵⁹ Paavo Nurmi Centre, Unit for Health and Physical Activity, University of Turku, Turku, Finland.
⁶⁰ Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
⁶¹ Amsterdam Reproduction & Development (AR&D) Research Institute, Amsterdam, the Netherlands.
⁶² Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁶³ Institute of Clinical Medicine Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
⁶⁴ Folkhälsan Research Center, Helsinki, Finland.
⁶⁵ Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁶⁶ Cohort and Longitudinal Studies Enhancement Resources (CLOSER), UCL Institute of Education, London, UK.
⁶⁷ The Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶⁸ Department of Epidemiology and Biostatistics, School of Public Health, MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK.
⁶⁹ Unit of Primary Health Care, Oulu University Hospital, OYS, Kajaanintie 50, 90220, Oulu, Finland.
⁷⁰ Lions Eye Institute, Centre for Ophthalmology and Visual Science, Centre for Eye Research Australia, University of Western Australia, Perth, WA, Australia.
⁷¹ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
⁷² Inserm UMR_S1256 Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, Nancy, France.
⁷³ Department of Biochemistry-Molecular Biology-Nutrition, University Hospital Centre of Nancy, Nancy, France.
⁷⁴ Division of Pediatric Endocrinology, Columbia University Medical Center, New York, NY, USA.
⁷⁵ Department of Maternity and Gynaecology, John Hunter Hospital, Newcastle, NSW, 2305, Australia.
⁷⁶ Metabolic Research Laboratory, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
⁷⁷ MRC Epidemiology Unit, School of Clinical Medicine, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
⁷⁸ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁷⁹ Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁸⁰ Department of Epidemiology and Population Science, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁸¹ Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸² Fundació Institut d'Investigació Sanitària Illes Balears - IdISBa, Palma, Spain.
⁸³ UCL Great Ormond Street Institute of Child Health, London, UK.
⁸⁴ Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
⁸⁵ South Australian Health and Medical Research Institute, Adelaide, Australia.
⁸⁶ Current Address: Genentech, 1 DNA Way, San Francisco, CA, 94080, USA.
⁸⁷ Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, EX2 5DW, UK.
⁸⁸ UMR 8199 - EGID, Institut Pasteur de Lille, CNRS, University of Lille, 59000, Lille, France.
⁸⁹ Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹⁰ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹¹ Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁹² Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹³ Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁴ Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁵ Division of Endocrinology & Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁶ Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁷ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. grants@email.chop.edu.
⁹⁸ Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. diana.l.cousminer@gsk.com.
⁹⁹ Department of Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA. diana.l.cousminer@gsk.com.
¹⁰⁰ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. diana.l.cousminer@gsk.com.
¹⁰¹ Currently Employed By GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA, 19426, USA. diana.l.cousminer@gsk.com.

PMID: 38229171
PMCID: PMC10790528
DOI: 10.1186/s13059-023-03136-z

Erratum in

Author Correction: Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes.
Bradfeld JP, Kember RL, Ulrich A, Balkhiyarova 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, Frithiof-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; Penn Medicine Biobank; Hansen T, Hardy R, Hivert MF, Holm JC, Jaddoe VWV, Järvelin MR, Lehtimäki T, Mackey DA, Meyre D, Mohlke KL, Mykkänen J, Oberfeld 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… See abstract for full author list ➔ Bradfeld JP, et al. Genome Biol. 2024 May 21;25(1):129. doi: 10.1186/s13059-024-03276-w. Genome Biol. 2024. PMID: 38773652 Free PMC article. No abstract available.

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.

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Conflict of interest statement

Diana L. Cousminer is an employee of and shareholder of GlaxoSmithKline (GSK). Mark McCarthy is employed by Genentech and a holder of Roche stock. John Perry is an employee and shareholder of Adrestia Therapeutics. Christine Frithioff-Bøjsøe is currently employed at Novo Nordisk. This work is unrelated to any activities at these companies.

Figures

**Fig. 1**
Mean peak height velocity (cm/year) vs. mean age at peak height velocity (years) for cohorts of diverse ancestral backgrounds. Yellow and purple lines represent a linear model fit to APHV ~ PHV × sex. The shaded bars represent the standard deviation of the linear regression. The samples included 19 cohorts of European ancestry, 3 African American cohorts, 2 East Asian cohorts, and 5 American Native or Hispanic cohorts

**Fig. 2**
Six phenotypes assessed by GWAS. The top panel shows a typical growth curve for boys (blue) and girls (red), with age (years) on the x-axis and height gain (cm/year) on the y-axis. First, we included three simple height or height-difference phenotypes as previously assessed [14]: (I) The take-off phase of the pubertal growth spurt (height at age 10 in girls and 12 in boys); (II) total pubertal growth, between ages 8 and adult; and (III) late pubertal growth, between ages 14 and adult. Additionally, we included three phenotypes derived from SITAR longitudinal modeling: (IV) a-size; (V) b-timing; and (VI) c-intensity. The black line represents the mean population growth curve for a cohort (by sex). Each individual gets a random effect for the three parameters; for example, if a subject is taller than their peers (upper red line), they get a positive value for a-size, while a shorter individual (lower line in panel IV) gets a negative value. A subject who enters their growth spurt earlier than the mean (left line in panel V) gets a negative value for b-timing, while a subject growing later (right line in panel V) gets a positive value. Finally, a subject who grows faster than the population mean (steeper line in panel VI) receives a positive value for c-intensity, while a subject growing slower (shallower line in panel VI) gets a negative value for c-intensity

**Fig. 3**
Genetic correlation (rg) between pubertal growth and anthropometric traits. A Correlation with adiposity traits. B Correlation with body size traits. 10F/12 M, height at age 10 years in girls and age 12 years in boys; 14–adult, height difference between age 14 years and adult; 8–adult, height difference between age 8 years and adult; a-size, SITAR-derived height across the growth trajectory; c-intensity, SITAR-derived tempo of the pubertal growth spurt

**Fig. 4**
Genetic correlation (rg) of pubertal growth with adult health outcomes. A Bone and glycemic outcomes, including femoral neck and lumbar spine bone mineral density and three glycemic traits. B Lung cancer and lung function outcomes. C Cardiac and lipid outcomes. D Neuropsychiatric outcomes and overall wellbeing (parents’ age at death). LDL, low-density lipoprotein; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment for insulin resistance; PEF, peak expiratory flow; FVC, forced vital capacity; FEV1, forced exhalation volume in 1 s; ALS, Amyotrophic lateral sclerosis. 10F/12 M, height at age 10 years in girls and age 12 years in boys; 14–adult, height difference between age 14 years and adult; 8–adult, height difference between age 8 years and adult; a-size, SITAR-derived height across the growth trajectory; c-intensity, SITAR-derived tempo of the pubertal growth spurt

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References

1. Palmert MR, Boepple PA. Variation in the timing of puberty: clinical spectrum and genetic investigation. J Clin Endocrinol Metab. 2001;86:2364–2368. - PubMed
1. Silventoinen K, et al. Genetic regulation of growth from birth to 18 years of age: The Swedish young male twins study. Am J Hum Biol. 2008;20:292–298. - PubMed
1. Ohlsson C, et al. Secular Trends in Pubertal Growth Acceleration in Swedish Boys Born From 1947 to 1996. JAMA Pediatr. 2019;173:860–865. - PMC - PubMed
1. Lai FY, et al. Adult height and risk of 50 diseases: a combined epidemiological and genetic analysis. BMC Med. 2018;16:187. - PMC - PubMed
1. Antonisamy B, et al. Weight Gain and Height Growth during Infancy, Childhood, and Adolescence as Predictors of Adult Cardiovascular Risk. J Pediatr. 2017;180:53–61.e3. - PMC - PubMed

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

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

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