Format

Send to

Choose Destination
Sci Adv. 2019 Sep 4;5(9):eaaw3095. doi: 10.1126/sciadv.aaw3095. eCollection 2019 Sep.

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Couto Alves A1,2, De Silva NMG1, Karhunen V1, Sovio U3,4, Das S1,5, Taal HR6,7, Warrington NM8,9, Lewin AM1,10, Kaakinen M11,12,13, Cousminer DL14,15,16, Thiering E17,18, Timpson NJ19,20, Bond TA1, Lowry E21, Brown CD22, Estivill X23,24,25,26, Lindi V15, Bradfield JP27, Geller F28, Speed D29,30, Coin LJM1,31, Loh M1,21,32, Barton SJ33,34, Beilin LJ35, Bisgaard H36, Bønnelykke K36, Alili R37, Hatoum IJ37,38,39, Schramm K40,41, Cartwright R1,42, Charles MA43, Salerno V1, Clément K37,43, Claringbould AAJ44; BIOS Consortium, van Duijn CM45, Moltchanova E46, Eriksson JG47,48,49, Elks C50, Feenstra B28, Flexeder C17, Franks S42, Frayling TM51, Freathy RM51, Elliott P1,52,53, Widén E16, Hakonarson H14,27,54,55, Hattersley AT51, Rodriguez A1,56, Banterle M10, Heinrich J17, Heude B43, Holloway JW57, Hofman A6,45, Hyppönen E58,59,60, Inskip H33,34, Kaplan LM38,39, Hedman AK61,62, Läärä E63, Prokisch H40,41, Grallert H64,65, Lakka TA15,66,67, Lawlor DA19,20, Melbye M28,68,69, Ahluwalia TS36, Marinelli M25,26,70, Millwood IY71,72, Palmer LJ73, Pennell CE8, Perry JR50, Ring SM19,20,74, Savolainen MJ75, Rivadeneira F45,76, Standl M17, Sunyer J24,25,26,70, Tiesler CMT17,18, Uitterlinden AG45,76, Schierding W77, O'Sullivan JM77,78, Prokopenko I11,13,61,79, Herzig KH80,81,82,83, Smith GD19,20, O'Reilly P1,84, Felix JF6,7,45, Buxton JL85, Blakemore AIF86,87, Ong KK50, Jaddoe VWV6,45, Grant SFA14,27,54,55, Sebert S1,21,80, McCarthy MI61,79,88, Järvelin MR1,21,80,82,86,89; Early Growth Genetics (EGG) Consortium.

Author information

1
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
2
School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK.
3
Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK.
4
NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
5
MRC Unit for Lifelong Health and Ageing at UCL, University College London, London, UK.
6
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
7
Department of Paediatrics, Erasmus MC, Sophia Children's Hospital, Rotterdam, Netherlands.
8
Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Western Australia, Australia.
9
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia.
10
Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
11
Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.
12
Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
13
Department of Clinical and Experimental Medicine, School of Biosciences and Medicine, University of Surrey, Surrey, UK.
14
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
15
Institute of Biomedicine, Department of Physiology, University of Eastern Finland, Kuopio, Finland.
16
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
17
Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich Neuherberg, Germany.
18
Division of Metabolic Diseases and Nutritional Medicine, Dr von Hauner Children's Hospital, Ludwig-Maximilians University Munich, Munich, Germany.
19
MRC Integrative Epidemiology Unit at the University of Bristol and NIHR Bristol Biomedical Research Center, Bristol, UK.
20
Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
21
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
22
Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
23
Genomics and Disease Group, Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.
24
Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain.
25
Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain.
26
Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.
27
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
28
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
29
Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark.
30
UCL Genetics Institute, University College London, London, UK.
31
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
32
Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (ASTAR) Singapore, Singapore.
33
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.
34
NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
35
Medical School, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia.
36
COPSAC, The Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
37
CRNH Ile de France, Hôpital Pitié-Salpêtrière, Paris, France.
38
Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.
39
Department of Medicine, Harvard Medical School, Boston, MA, USA.
40
Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
41
Institute of Human Genetics, Technische Universität München, München, Germany.
42
Institute for Reproductive and Developmental Biology, Imperial College London, London, UK.
43
Inserm, UMR 1153 (CRESS), Paris Descartes University, Villejuif, Paris, France.
44
University Medical Centre Groningen, Department of Genetics, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
45
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
46
Department of Mathematics and Statistics, University of Canterbury, Christchurch, New Zealand.
47
Department of General Practice and Primary Health Care, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.
48
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
49
Folkhalsan Research Center, Helsinki, Finland.
50
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
51
Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter, UK.
52
National Institute for Health Research, Imperial College Biomedical Research Centre, London, UK.
53
Health Data Research UK London, Imperial College London, London, UK.
54
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
55
Institute of Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
56
School of Psychology, College of Social Science, University of Lincoln Brayford Pool Lincoln, Lincolnshire, UK.
57
Human Genetics and Medical Genomics, Faculty of Medicine, University of Southampton, Southampton, UK.
58
South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
59
Great Ormond Street Hospital Institute of Child Health, University College London, London, UK.
60
Australian Centre for Precision Health, University of South Australia Cancer Research Institute, North Terrace, Adelaide, South Australia, Australia.
61
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
62
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
63
Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland.
64
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
65
German Center for Diabetes Research (DZD), Neuherberg, Germany.
66
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
67
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
68
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
69
Department of Medicine, Stanford University Medical School, Stanford, CA, USA.
70
ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
71
Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Old Road Campus, Oxford, UK.
72
Medical Research Council Population Health Research Unit (MRC PHRU) at the University of Oxford, Oxford, UK.
73
School of Public Health and Robinson Research Institute, University of Adelaide, Adelaide, Australia.
74
Avon Longitudinal Study of Parents and Children, School of Social and Community Medicine, University of Bristol, Bristol, UK.
75
Division of Internal Medicine, and Biocenter of Oulu, Faculty of Medicine, Oulu University, Oulu, Finland.
76
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
77
Liggins Institute, University of Auckland, Auckland, New Zealand.
78
A Better Start-National Science, Challenge, University of Auckland, Auckland, New Zealand.
79
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, UK.
80
Biocenter Oulu, University of Oulu, Oulu, Finland.
81
Research Unit of Biomedicine, University Oulu, Oulu, Finland.
82
Medical Research Center and Oulu University Hospital, University of Oulu, Oulu, Finland.
83
Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
84
MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK.
85
School of Life Sciences, Pharmacy and Chemistry, Kingston University, Kingston upon Thames, UK.
86
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.
87
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK.
88
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
89
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center