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Nature. 2016 Oct 13;538(7624):248-252. doi: 10.1038/nature19806. Epub 2016 Sep 28.

Genome-wide associations for birth weight and correlations with adult disease.

Horikoshi M#1,2, Beaumont RN#3, Day FR#4, Warrington NM#5,6, Kooijman MN#7,8,9, Fernandez-Tajes J#1, Feenstra B10, van Zuydam NR1,2, Gaulton KJ1,11, Grarup N12, Bradfield JP13, Strachan DP14, Li-Gao R15, Ahluwalia TS12,16,17, Kreiner E16, Rueedi R18,19, Lyytikäinen LP20,21, Cousminer DL22,23,24, Wu Y25, Thiering E26,27, Wang CA6, Have CT12, Hottenga JJ28, Vilor-Tejedor N29,30,31, Joshi PK32, Boh ETH33, Ntalla I34,35, Pitkänen N36, Mahajan A1, van Leeuwen EM8, Joro R37, Lagou V1,38,39, Nodzenski M40, Diver LA41, Zondervan KT1,42, Bustamante M29,30,31,43, Marques-Vidal P44, Mercader JM45, Bennett AJ2, Rahmioglu N1, Nyholt DR46, Ma RCW47,48,49, Tam CHT47, Tam WH50; CHARGE Consortium Hematology Working Group, Ganesh SK51, van Rooij FJ8, Jones SE3, Loh PR52,53, Ruth KS3, Tuke MA3, Tyrrell J3,54, Wood AR3, Yaghootkar H3, Scholtens DM40, Paternoster L55,56, Prokopenko I1,57, Kovacs P58, Atalay M37, Willems SM8, Panoutsopoulou K59, Wang X33, Carstensen L10, Geller F10, Schraut KE32, Murcia M31,60, van Beijsterveldt CE28, Willemsen G28, Appel EVR12, Fonvig CE12,61, Trier C12,61, Tiesler CM26,27, Standl M26, Kutalik Z19,62, Bonas-Guarch S45, Hougaard DM63,64, Sánchez F45,65, Torrents D45,66, Waage J16, Hollegaard MV63,64, de Haan HG15, Rosendaal FR15, Medina-Gomez C7,8,67, Ring SM55,56, Hemani G55,56, McMahon G56, Robertson NR1,2, Groves CJ2, Langenberg C4, Luan J4, Scott RA4, Zhao JH4, Mentch FD13, MacKenzie SM41, Reynolds RM68; Early Growth Genetics (EGG) Consortium, Lowe WL Jr69, Tönjes A70, Stumvoll M58,70, Lindi V37, Lakka TA37,71,72, van Duijn CM8, Kiess W73, Körner A58,73, Sørensen TI55,56,74,75, Niinikoski H76,77, Pahkala K36,78, Raitakari OT36,79, Zeggini E59, Dedoussis GV35, Teo YY33,80,81, Saw SM33,82, Melbye M10,83,84, Campbell H32, Wilson JF32,85, Vrijheid M29,30,31, de Geus EJ28,86, Boomsma DI28, Kadarmideen HN87, Holm JC12,61, Hansen T12, Sebert S88,89, Hattersley AT3, Beilin LJ90, Newnham JP6, Pennell CE6, Heinrich J26,91, Adair LS92, Borja JB93,94, Mohlke KL25, Eriksson JG95,96,97, Widén EE22, Kähönen M98,99, Viikari JS100,101, Lehtimäki T20,21, Vollenweider P44, Bønnelykke K16, Bisgaard H16, Mook-Kanamori DO15,102,103, Hofman A7,8, Rivadeneira F7,8,67, Uitterlinden AG7,8,67, Pisinger C104, Pedersen O12, Power C105, Hyppönen E105,106,107, Wareham NJ4, Hakonarson H13,23,108, Davies E41, Walker BR68, Jaddoe VW7,8,9, Jarvelin MR88,89,109,110, Grant SF13,23,108,111, Vaag AA83,112, Lawlor DA55,56, Frayling TM3, Davey Smith G55,56, Morris AP1,113,114, Ong KK4,115, Felix JF7,8,9, Timpson NJ55,56, Perry JR4, Evans DM5,55,56, McCarthy MI1,2,116, Freathy RM3,55.

Author information

1
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
2
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
3
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK.
4
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
5
The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
6
School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.
7
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
8
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
9
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
10
Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark.
11
Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
12
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
13
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
14
Population Health Research Institute, St George's University of London, London, Cranmer Terrace, UK.
15
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
16
COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
17
Steno Diabetes Center, Gentofte, Denmark.
18
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
19
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
20
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
21
Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
22
Institute for Molecular Medicine, Finland (FIMM), University of Helsinki, Helsinki, Finland.
23
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
24
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
25
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
26
Institute of Epidemiology I, Helmholtz Zentrum München- German Research Center for Environmental Health, Neuherberg, Germany.
27
Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany.
28
Netherlands Twin Register, Department of Biological Psychology, VU University, Amsterdam, the Netherlands.
29
ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
30
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
31
CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
32
Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, UK.
33
Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore.
34
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
35
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
36
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
37
Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio, Finland.
38
KUL - University of Leuven, Department of Neurosciences, Leuven, Belgium.
39
Translational Immunology Laboratory, VIB, Leuven, Belgium.
40
Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, USA.
41
Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
42
Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK.
43
Center for Genomic Regulation (CRG), Barcelona, Spain.
44
Department of Internal Medicine, Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
45
Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
46
Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia.
47
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.
48
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.
49
Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China.
50
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.
51
Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
52
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
53
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
54
European Centre for Environment and Human Health, University of Exeter, Truro, UK.
55
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
56
School of Social and Community Medicine, University of Bristol, Bristol, UK.
57
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
58
IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
59
Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
60
FISABIO-Universitat Jaume I-Universitat de València, Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain.
61
The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark.
62
Institute of Social and Preventive Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
63
Danish Center for Neonatal Screening, Statens Serum Institute, Copenhagen, Denmark.
64
Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark.
65
Computer Sciences Department, Barcelona Supercomputing Center, Barcelona, Spain.
66
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
67
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
68
BHF Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, Scotland, UK.
69
Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, USA.
70
Medical Department, University of Leipzig, Leipzig, Germany.
71
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
72
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
73
Pediatric Research Center, Department of Women´s & Child Health, University of Leipzig, Leipzig, Germany.
74
Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
75
Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.
76
Department of Pediatrics, Turku University Hospital, Turku, Finland.
77
Department of Physiology, University of Turku, Turku, Finland.
78
Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, Turku, Finland.
79
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
80
Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
81
Life Sciences Institute, National University of Singapore, Singapore, Singapore.
82
Singapore Eye Research Institute, Singapore, Singapore.
83
Department of Clinical Medicine, Copenhagen University, Copenhagen, Denmark.
84
Department of Medicine, Stanford School of Medicine, Stanford, California, USA.
85
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK.
86
EMGO Institute for Health and Care Research, VU University and VU University Medical Center, Amsterdam, the Netherlands.
87
Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
88
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
89
Biocenter Oulu, University of Oulu, Finland.
90
School of Medicine and Pharmacology, Royal Perth Hospital Unit, The University of Western Australia, Perth, Australia.
91
Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Inner City Clinic, University Hospital Munich, Ludwig Maximilian University of Munich, Munich, Germany.
92
Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
93
USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines.
94
Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines.
95
National Institute for Health and Welfare, Helsinki, Finland.
96
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
97
Folkhälsan Research Center, Helsinki, Finland.
98
Department of Clinical Physiology, Tampere University Hopital, Tampere, Finland.
99
Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland.
100
Division of Medicine, Turku University Hospital, Turku, Finland.
101
Department of Medicine, University of Turku, Turku, Finland.
102
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
103
Epidemiology Section, BESC Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
104
Research Center for Prevention and Health Capital Region, Center for Sundhed, Rigshospitalet - Glostrup, Copenhagen University, Glostrup, Denmark.
105
Population, Policy and Practice, UCL Institute of Child Health, University College London, London, UK.
106
Centre for Population Health Research, School of Health Sciences, and Sansom Institute, University of South Australia, Adelaide, Australia.
107
South Australian Health and Medical Research Institute, Adelaide, Australia.
108
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
109
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK.
110
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
111
Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
112
Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark.
113
Department of Biostatistics, University of Liverpool, Liverpool, UK.
114
Estonian Genome Center, University of Tartu, Tartu, Estonia.
115
Department of Paediatrics, University of Cambridge, Cambridge, UK.
116
Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.
#
Contributed equally

Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

PMID:
27680694
PMCID:
PMC5164934
DOI:
10.1038/nature19806
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

One of the authors discloses competing financial interests: Krina Zondervan has a scientific collaboration with Bayer HealthCare Ltd. and Population Diagnostics Inc.

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