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Hum Mol Genet. 2019 Jul 5. pii: ddz161. doi: 10.1093/hmg/ddz161. [Epub ahead of print]

A Trans-ancestral Meta-Analysis of Genome-Wide Association Studies Reveals Loci Associated with Childhood Obesity.

Bradfield JP1,2, Vogelezang S3,4,5, Felix JF3,4,5, Chesi A6,7, Helgeland Ø8,9, Horikoshi M10,11,12, Karhunen V13, Lowry E14, Cousminer DL6,7,15, Ahluwalia TS16,17,18, Thiering E19,20, Boh ET21, Zafarmand MH22,23, Vilor-Tejedor N24,25,26,27,28, Wang CA29, Joro R30, Chen Z31, Gauderman WJ31, Pitkänen N32,33, Parra EJ34, Fernandez-Rhodes L35,36, Alyass A37, Monnereau C3,4,5, Curtin JA38, Have CT18, McCormack SE39,40, Hollensted M18, Frithioff-Bøjsøe C18,41, Valladares-Salgado A42, Peralta-Romero J42, Teo YY21,43,44,45,46, Standl M19, Leinonen JT47, Holm JC18,41,48, Peters T49, Vioque J26,50,51, Vrijheid M24,25,26, Simpson A38, Custovic A52, Vaudel M8, Canouil M53, Lindi V54, Atalay M30, Kähönen M55,56, Raitakari OT32,33,57, van Schaik BDC23, Berkowitz RI58, Cole SA59, Voruganti VS60, Wang Y61, Highland HM61, Comuzzie AG62, Butte NF63, Justice AE61,64, Gahagan S65, Blanco E65, Lehtimäki T66,67, Lakka TA30,68,69, Hebebrand J49, Bonnefond A53,70, Grarup N18, Froguel P53,70, Lyytikäinen LP66,67,71, Cruz M42, Kobes S72, Hanson RL72, Zemel BS39,73, Hinney A49, Teo KK37,74, Meyre D37,75, North KE61,76, Gilliland FD31, Bisgaard H16, Bustamante M24,25,26, Bonnelykke K16, Pennell CE29, Rivadeneira F3,4,77, Uitterlinden AG4,77, Baier LJ72, Vrijkotte TGM22, Heinrich J19,78,79, Sørensen TIA18,80,81, Saw SM21,82, Pedersen O18, Hansen T18, Eriksson J83,84,85, Widén E47, McCarthy MI10,11,86, Njølstad PR8,87, Power C88, Hyppönen E88,89,90, Sebert S14,91,92, Brown CD93, Järvelin MR13,14,91,94,95, Timpson NJ81, Johansson S8,96, Hakonarson H1,97, Jaddoe VWV3,4,5, Grant SFA1,6,7,15,39,40,97; Early Growth Genetics Consortium.

Author information

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, United States of America.
7
Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
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, United Kingdom.
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
ISGlobal, Institute for Global Health, Barcelona, Spain.
25
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
26
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
27
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.
28
BarcelonaBeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
29
School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle.
30
Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Finland.
31
Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.
32
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland.
33
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20014, Finland.
34
Department of Anthropology, University of Toronto at Mississauga, Mississauga, Ontario, Canada.
35
Department of Biobehavioral Health, Pennsylvania State University.
36
Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
37
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
38
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.
39
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
40
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
41
The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark.
42
Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
43
NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, 119077, Singapore.
44
Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
45
Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore.
46
Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore.
47
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Finland.
48
University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
49
Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Germany.
50
University Miguel Hernandez, Alicante, Spain.
51
ISABIAL-FISABIO Foundation, Alicante, Spain.
52
Department of Paediatrics, Imperial College London, UK.
53
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), 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, United Kingdom.
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, United States of America.
74
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
75
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, 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, University of Pennsylvania, Perelman School of Medicine, 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, United Kingdom.
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

Although hundreds of GWAS-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 thirty studies consisting of up to 13,005 cases (≥95th percentile of 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 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing eighteen 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 in 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 ten 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.

PMID:
31504550
DOI:
10.1093/hmg/ddz161

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