A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

Author:

Bradfield Jonathan P12,Vogelezang Suzanne345,Felix Janine F345,Chesi Alessandra67,Helgeland Øyvind89,Horikoshi Momoko101112,Karhunen Ville13,Lowry Estelle14,Cousminer Diana L6715,Ahluwalia Tarunveer S161718,Thiering Elisabeth1920,Boh Eileen Tai-Hui21,Zafarmand Mohammad H2223,Vilor-Tejedor Natalia424252627,Wang Carol A28,Joro Raimo29,Chen Zhanghua30,Gauderman William J30,Pitkänen Niina3132,Parra Esteban J33,Fernandez-Rhodes Lindsay3435,Alyass Akram36,Monnereau Claire345,Curtin John A37,Have Christian T18,McCormack Shana E3839,Hollensted Mette18,Frithioff-Bøjsøe Christine1840,Valladares-Salgado Adan41,Peralta-Romero Jesus41,Teo Yik-Ying2142434445,Standl Marie19,Leinonen Jaakko T46,Holm Jens-Christian184047,Peters Triinu48,Vioque Jesus254950,Vrijheid Martine512425,Simpson Angela37,Custovic Adnan52,Vaudel Marc8,Canouil Mickaël53,Lindi Virpi54,Atalay Mustafa29,Kähönen Mika5556,Raitakari Olli T313257,van Schaik Barbera D C23,Berkowitz Robert I58,Cole Shelley A59,Voruganti V Saroja60,Wang Yujie61,Highland Heather M61,Comuzzie Anthony G62,Butte Nancy F63,Justice Anne E6164,Gahagan Sheila65,Blanco Estela65,Lehtimäki Terho6667,Lakka Timo A296869,Hebebrand Johannes48,Bonnefond Amélie5370,Grarup Niels18,Froguel Philippe5370,Lyytikäinen Leo-Pekka666771,Cruz Miguel41,Kobes Sayuko72,Hanson Robert L72,Zemel Babette S3873,Hinney Anke48,Teo Koon K3674,Meyre David3675,North Kari E6176,Gilliland Frank D30,Bisgaard Hans16,Bustamante Mariona512425,Bonnelykke Klaus16,Pennell Craig E28,Rivadeneira Fernando3477,Uitterlinden André G477,Baier Leslie J72,Vrijkotte Tanja G M22,Heinrich Joachim197879,Sørensen Thorkild I A188081,Saw Seang-Mei2182,Pedersen Oluf18,Hansen Torben18,Eriksson Johan838485,Widén Elisabeth46,McCarthy Mark I101186,Njølstad Pål R887,Power Christine88,Hyppönen Elina888990,Sebert Sylvain149192,Brown Christopher D93,Järvelin Marjo-Riitta1314919495,Timpson Nicholas J81,Johansson Stefan896ORCID,Hakonarson Hakon197,Jaddoe Vincent W V345,

Affiliation:

1. Center for Applied Genomics, Children’s Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

2. Quantinuum Research LLC, San Diego, CA, USA

3. The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

4. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

5. Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

6. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

7. Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

8. KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway

9. Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway

10. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

11. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

12. RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan

13. Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, UK

14. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, PO Box 8000, FI-90014 Oulun yliopisto, Finland

15. Department of Genetics, University of Pennsylvania, Philadelphia

16. Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital 2820, University of Copenhagen, Copenhagen, Denmark

17. Steno Diabetes Center Copenhagen, Gentofte, Denmark

18. Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

19. Helmholtz Zentrum München—German Research Center for Environmental Health, Institute of Epidemiology, Neuherberg, Germany

20. Ludwig Maximilians University of Munich, Dr. von Hauner Children’s Hospital, Munich, Germany

21. Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore

22. Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, The Netherlands

23. Department of Clinical Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, The Netherlands

24. Universitat Pompeu Fabra, Barcelona, Spain

25. CIBER de Epidemiología y Salud Pública, Madrid, Spain

26. Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain

27. BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain

28. School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle

29. Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Finland

30. Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA

31. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland

32. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20014, Finland

33. Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON, Canada

34. Department of Biobehavioral Health, Pennsylvania State University

35. Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

36. Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada

37. Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust

38. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

39. Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

40. The Children’s Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark

41. Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico

42. NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, 119077, Singapore

43. Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore

44. Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore

45. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore

46. Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Finland

47. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

48. Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Germany

49. University Miguel Hernandez, Alicante, Spain

50. ISABIAL–FISABIO Foundation, Alicante, Spain

51. ISGlobal, Institute for Global Health, Barcelona, Spain

52. Department of Paediatrics, Imperial College London, UK

53. CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, University of Lille, Lille, France

54. University of Eastern Finland Library, Kuopio, Finland

55. Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland

56. Department of Clinical Physiology, Finnish Cardiovascular Research Center—Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33014, Finland

57. Centre for Population Health Research, University of Turku and Turku University Hospital, Finland

58. Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA

59. Texas Biomedical Research Institute, San Antonio, TX

60. Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill

61. Department of Epidemiology, University of North Carolina at Chapel Hill

62. The Obesity Society

63. Department of Pediatrics, Baylor College of Medicine

64. Biomedical and Translational Informatics, Geisinger Health System

65. Center for Community Health, Department of Pediatrics, University of California at San Diego

66. Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland

67. Department of Clinical Chemistry, Finnish Cardiovascular Research Center—Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33014, Finland

68. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland

69. Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland

70. Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK

71. Department of Cardiology, Heart Center, Tampere University Hospital, Tampere 33521, Finland

72. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes Digestive and Kidney Diseases, NIH, USA

73. Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

74. Department of Medicine, McMaster University, Hamilton, ON, Canada

75. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

76. Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill

77. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

78. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig Maximilians University of Munich, University Hospital Munich, Munich, Germany

79. Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

80. Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

81. Medical Research Council Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK

82. Singapore Eye Research Institute, Singapore, Singapore

83. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

84. Folkhälsan Research Center, Helsink Finland

85. Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland

86. Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU

87. Department of Pediatrics and Adolescents, Haukeland University Hospital, Bergen, Norway

88. Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK

89. Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia

90. South Australian Health and Medical Research Institute, Adelaide, Australia

91. Biocenter Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland

92. Department for Genomics of Common Diseases, School of Medicine, Imperial College London, UK

93. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

94. Unit of Primary Health Care, Oulu University Hospital, OYS, Kajaanintie 50, 90220 Oulu, Finland

95. Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, Middlesex UB8 3PH, UK

96. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway

97. Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Abstract

Abstract Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Funder

American Diabetes Association

NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London

National Institute for Health Research (NIHR) Oxford Biomedical Research Centre

Wellcome

National Institutes of Health

Carolina Population Center

Publisher

Oxford University Press (OUP)

Subject

Genetics(clinical),Genetics,Molecular Biology,General Medicine

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