Meta-Analysis

. 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

Alexessander Couto Alves^{1

2}, N Maneka G De Silva¹, Ville Karhunen¹, Ulla Sovio^{3

4}, Shikta Das^{1

5}, H Rob Taal^{6

7}, Nicole M Warrington^{8

9}, Alexandra M Lewin^{1

10}, Marika Kaakinen^{11

12

13}, Diana L Cousminer^{14

15

16}, Elisabeth Thiering^{17

18}, Nicholas J Timpson^{19

20}, Tom A Bond¹, Estelle Lowry²¹, Christopher D Brown²², Xavier Estivill^{23

24

25

26}, Virpi Lindi¹⁵, Jonathan P Bradfield²⁷, Frank Geller²⁸, Doug Speed^{29

30}, Lachlan J M Coin^{1

31}, Marie Loh^{1

21

32}, Sheila J Barton^{33

34}, Lawrence J Beilin³⁵, Hans Bisgaard³⁶, Klaus Bønnelykke³⁶, Rohia Alili³⁷, Ida J Hatoum^{37

38

39}, Katharina Schramm^{40

41}, Rufus Cartwright^{1

42}, Marie-Aline Charles⁴³, Vincenzo Salerno¹, Karine Clément^{37

43}, Annique A J Claringbould⁴⁴; BIOS Consortium; Cornelia M van Duijn⁴⁵, Elena Moltchanova⁴⁶, Johan G Eriksson^{47

48

49}, Cathy Elks⁵⁰, Bjarke Feenstra²⁸, Claudia Flexeder¹⁷, Stephen Franks⁴², Timothy M Frayling⁵¹, Rachel M Freathy⁵¹, Paul Elliott^{1

52

53}, Elisabeth Widén¹⁶, Hakon Hakonarson^{14

27

54

55}, Andrew T Hattersley⁵¹, Alina Rodriguez^{1

56}, Marco Banterle¹⁰, Joachim Heinrich¹⁷, Barbara Heude⁴³, John W Holloway⁵⁷, Albert Hofman^{6

45}, Elina Hyppönen^{58

59

60}, Hazel Inskip^{33

34}, Lee M Kaplan^{38

39}, Asa K Hedman^{61

62}, Esa Läärä⁶³, Holger Prokisch^{40

41}, Harald Grallert^{64

65}, Timo A Lakka^{15

66

67}, Debbie A Lawlor^{19

20}, Mads Melbye^{28

68

69}, Tarunveer S Ahluwalia³⁶, Marcella Marinelli^{25

26

70}, Iona Y Millwood^{71

72}, Lyle J Palmer⁷³, Craig E Pennell⁸, John R Perry⁵⁰, Susan M Ring^{19

20

74}, Markku J Savolainen⁷⁵, Fernando Rivadeneira^{45

76}, Marie Standl¹⁷, Jordi Sunyer^{24

25

26

70}, Carla M T Tiesler^{17

18}, Andre G Uitterlinden^{45

76}, William Schierding⁷⁷, Justin M O'Sullivan^{77

78}, Inga Prokopenko^{11

13

61

79}, Karl-Heinz Herzig^{80

81

82

83}, George Davey Smith^{19

20}, Paul O'Reilly^{1

84}, Janine F Felix^{6

7

45}, Jessica L Buxton⁸⁵, Alexandra I F Blakemore^{86

87}, Ken K Ong⁵⁰, Vincent W V Jaddoe^{6

45}, Struan F A Grant^{14

27

54

55}, Sylvain Sebert^{1

21

80}, Mark I McCarthy^{61

79

88}, Marjo-Riitta Järvelin^{1

21

80

82

86

89}; Early Growth Genetics (EGG) Consortium

Affiliations

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.

PMID: 31840077
PMCID: PMC6904961
DOI: 10.1126/sciadv.aaw3095

Meta-Analysis

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

Alexessander Couto Alves et al. Sci Adv. 2019.

. 2019 Sep 4;5(9):eaaw3095.

doi: 10.1126/sciadv.aaw3095. eCollection 2019 Sep.

Authors

Affiliations

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.

PMID: 31840077
PMCID: PMC6904961
DOI: 10.1126/sciadv.aaw3095

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.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

PubMed Disclaimer

Figures

**Fig. 1. Regional association and forest plot of the novel genome-wide significant locus associated with BMI-AP.**
Purple diamond indicates the most significantly associated SNP in stage 1 meta-analysis, and circles represent the other SNPs in the region, with coloring from blue to red corresponding to r² values from 0 to 1 with the index SNP. The SNP position refers to the National Center for Biotechnology Information (NCBI) build 36. Estimated recombination rates are from HapMap build 36. Forest plots from the meta-analysis for each of the identified loci are plotted abreast. Effect size [95% confidence interval (CI)] in each individual study, discovery, follow-up, and combined meta-analysis stages is presented from fixed-effects models (heterogeneity of the SNP rs9436303 in *LEPR/LEPROT*; see fig. S6). At this locus, there was heterogeneity between the studies in discovery (I² = 72.1%, P = 0.01) and combined stage (I² = 59.3%, P = 0.002) fixed-effects meta-analyses that was mainly due to LISA-D, EDEN, and the larger well-defined NFBC1966 study (fig. S6, A and D). Removing the studies that showed inflated results from meta-analyses did not change the point estimates (fig. S6, C, F, and G). Both fixed- and random-effects models gave very similar results (fig. S6, B and E).

**Fig. 2. Tissue-specific posterior probabilities (PPs) of colocalization for *LEPR* and *LEPROT*.**
PP of eQTL and GWAS SNP sharing a causal variant regulating the gene expression levels of (A) *LEPR* and (B) *LEPROT*. Colocalization reported for GTEX eQTLs data in 34 tissues that express at least one of the genes. Bar plot color-coded according to the –log₁₀ P value eQTL direct lookup in the corresponding GTEx tissue of the GWAS SNP. *LEPR* and *LEPROT* eQTLs colocalized with BMI-AP variant rs9436303.

**Fig. 3. Genetic correlations between five early growth traits and a subset of 37 phenotypes.**
Only a selected list of 37 phenotypes is represented on the correlation matrix. Genetic correlation results for all 72 phenotypes are given in table S16. Blue, positive genetic correlation; red, negative genetic correlation. The correlation matrix underneath represents the genetic correlation among the five early growth traits themselves. The size of the colored squares is proportional to the P value, where larger squares represent a smaller P value. Genetic correlations that are different from 0 at P < 0.05 are marked with an asterisk. The genetic correlations that are different from 0 at an FDR of 1% are marked with a circle. Genetic correlations estimated with stage 1 meta-analysis GWAS summary statistics from the current and literature studies using LD score regression.

**Fig. 4. Adult BMI GRS analysis of early growth traits.**
Scatter plots show the effect size estimates (SD units) of the 97 adult BMI-associated SNP in GIANT consortium in the x axis and the corresponding effect size estimates (SD units) of the looked-up SNP of stage 1 meta-analysis GWAS on (A) BMI-AR and (B) Age-AR in the y axis. The effect size of the adult BMI increasing allele is plotted. The solid red line is the estimated effect of the GRS on the early growth phenotype, taking into account the uncertainty of the point estimates. The dashed line is the 95% CI of the predicted effect. Stage 1 meta-analysis GWAS SNPs with P < 0.05 are plotted with a solid circle and labeled with the nearest gene name. The scatter plots of the other early growth phenotypes are given in fig. S10.

**Fig. 5. Proposed model of child BMI suggesting the superimposition of two biological phenomena under the genetic control of different loci.**
The schematic diagram shows the four genome-wide significant loci associated with early childhood growth traits and highlights the fact that only SNPs associated with phenotypes ascertained at AR are associated with adult BMI. The red curve represents the mean BMI trajectory from birth to puberty in the NFBC1966 cohort.

See this image and copyright information in PMC

References

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

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

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