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Nat Genet. 2019 May;51(5):804-814. doi: 10.1038/s41588-019-0403-1. Epub 2019 May 1.

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Warrington NM1, Beaumont RN2, Horikoshi M3,4,5, Day FR6, Helgeland Ø7,8,9, Laurin C10,11, Bacelis J12, Peng S13,14, Hao K13,14, Feenstra B15, Wood AR2, Mahajan A4,5, Tyrrell J2,16, Robertson NR4,5, Rayner NW4,5,17, Qiao Z1, Moen GH18,19, Vaudel M7, Marsit CJ20, Chen J21, Nodzenski M22, Schnurr TM23, Zafarmand MH24,25, Bradfield JP26,27, Grarup N23, Kooijman MN28,29,30, Li-Gao R31, Geller F15, Ahluwalia TS23,32,33, Paternoster L10, Rueedi R34,35, Huikari V36, Hottenga JJ37,38,39, Lyytikäinen LP40,41, Cavadino A42,43, Metrustry S44, Cousminer DL45,46, Wu Y47, Thiering E48,49, Wang CA50, Have CT23, Vilor-Tejedor N51,52, Joshi PK53, Painter JN54, Ntalla I55, Myhre R56, Pitkänen N57, van Leeuwen EM29, Joro R58, Lagou V4,59,60, Richmond RC10,11, Espinosa A61,62,63,64, Barton SJ65, Inskip HM65,66, Holloway JW67, Santa-Marina L63,68,69, Estivill X70,71, Ang W72, Marsh JA72, Reichetzeder C73, Marullo L74, Hocher B75,76, Lunetta KL77,78, Murabito JM78,79, Relton CL10,11, Kogevinas M61,62,63,64, Chatzi L80, Allard C81, Bouchard L81,82,83, Hivert MF84,85,86, Zhang G87,88,89, Muglia LJ87,88,89, Heikkinen J90; EGG Consortium, Morgen CS91, van Kampen AHC92,93, van Schaik BDC92, Mentch FD26, Langenberg C6, Luan J6, Scott RA6, Zhao JH6, Hemani G10,11, Ring SM10,11, Bennett AJ5, Gaulton KJ4,94, Fernandez-Tajes J4, van Zuydam NR4,5, Medina-Gomez C28,29,95, de Haan HG31, Rosendaal FR31, Kutalik Z35,96, Marques-Vidal P97, Das S98, Willemsen G37,38,39, Mbarek H37,38,39,99, Müller-Nurasyid M100,101,102, Standl M48, Appel EVR23, Fonvig CE23,103,104, Trier C23,103, van Beijsterveldt CEM38, Murcia M63,105, Bustamante M61,62,63, Bonas-Guarch S106, Hougaard DM107, Mercader JM106,108,109, Linneberg A110,111, Schraut KE53, Lind PA54, Medland SE54, Shields BM112, Knight BA112, Chai JF113, Panoutsopoulou K17, Bartels M37,38,39, Sánchez F106,114, Stokholm J32, Torrents D106,115, Vinding RK32, Willems SM29, Atalay M58, Chawes BL32, Kovacs P116, Prokopenko I4,117, Tuke MA2, Yaghootkar H2, Ruth KS2, Jones SE2, Loh PR118,119, Murray A2, Weedon MN2, Tönjes A120, Stumvoll M116,120, Michaelsen KF121, Eloranta AM58, Lakka TA58,122,123, van Duijn CM29, Kiess W124, Körner A116,124, Niinikoski H125,126, Pahkala K57,127, Raitakari OT57,128, Jacobsson B9,12, Zeggini E17,129, Dedoussis GV130, Teo YY113,131,132, Saw SM113,133, Montgomery GW54, Campbell H53, Wilson JF53,134, Vrijkotte TGM24, Vrijheid M61,62,63, de Geus EJCN37,38,39, Hayes MG135, Kadarmideen HN136, Holm JC23,103, Beilin LJ137, Pennell CE50, Heinrich J48,138, Adair LS139, Borja JB140,141, Mohlke KL47, Eriksson JG142,143,144, Widén EE90, Hattersley AT2,112, Spector TD44, Kähönen M145,146, Viikari JS147,148, Lehtimäki T40,41, Boomsma DI37,38,39,99, Sebert S36,149,150,151, Vollenweider P97, Sørensen TIA10,23,91, Bisgaard H32, Bønnelykke K32, Murray JC152, Melbye M15,153, Nohr EA154, Mook-Kanamori DO31,155, Rivadeneira F28,29,95, Hofman A29, Felix JF28,29,30, Jaddoe VWV28,29,30, Hansen T23, Pisinger C156, Vaag AA110,157, Pedersen O23, Uitterlinden AG28,29,95, Järvelin MR36,149,150,158,159, Power C43, Hyppönen E43,160,161, Scholtens DM22, Lowe WL Jr135, Davey Smith G10,11,162, Timpson NJ10,11, Morris AP4,163,164, Wareham NJ6, Hakonarson H26,45,165, Grant SFA26,45,46,165, Frayling TM2, Lawlor DA10,11,162, Njølstad PR7,8, Johansson S7,166, Ong KK6,167, McCarthy MI4,5,168, Perry JRB6, Evans DM169,170,171, Freathy RM172,173.

Author information

1
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
2
Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Royal Devon and Exeter Hospital, Exeter, UK.
3
RIKEN Centre for Integrative Medical Sciences, Laboratory for Endocrinology, Metabolism and Kidney Diseases, Yokohama, Japan.
4
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
5
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
6
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
7
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
8
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
9
Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
10
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
11
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
12
Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden.
13
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
14
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15
Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark.
16
European Centre for Environment and Human Health, University of Exeter, Truro, UK.
17
Wellcome Sanger Institute, Hinxton, UK.
18
Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
19
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
20
Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
21
Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
22
Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
23
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
24
Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
25
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
26
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
27
Quantinuum Research, San Diego, CA, USA.
28
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
29
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
30
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
31
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
32
Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
33
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
34
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
35
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
36
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
37
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
38
Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
39
Amsterdam Public Health, Amsterdam, the Netherlands.
40
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
41
Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
42
Section of Epidemiology and Biostatistics, School of Population Health, University of Auckland, Auckland, New Zealand.
43
Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
44
Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.
45
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
46
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
47
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
48
Institute of Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany.
49
Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany.
50
School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, New South Wales, Australia.
51
Center for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
52
Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
53
Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
54
QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Queensland, Australia.
55
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
56
Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
57
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
58
Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.
59
Department of Neuroscience, Katholieke Universiteit Leuven, Leuven, Belgium.
60
VIB Center for Brain and Disease Research, Leuven, Belgium.
61
ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
62
Universitat Pompeu Fabra, Barcelona, Spain.
63
CIBER de Epidemiología y Salud Pública, Madrid, Spain.
64
Hospital del Mar Medical Research Institute, Barcelona, Spain.
65
Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
66
NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.
67
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
68
Subdirección de Salud Pública y Adicciones de Gipuzkoa, San Sebastián, Spain.
69
Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain.
70
Sidra Medicine Research Department, Sidra Medicine, Doha, Qatar.
71
Genomics Unit, Dexeus Woman's Health, Barcelona, Spain.
72
Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Western Australia, Australia.
73
Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
74
Department of Life Sciences and Biotechnology, Genetic Section, University of Ferrara, Ferrara, Italy.
75
Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.
76
Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.
77
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
78
Framingham Heart Study, Framingham, MA, USA.
79
Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
80
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
81
Centre de recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
82
ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, Quebec, Canada.
83
Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
84
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, USA.
85
Diabetes Center, Massachusetts General Hospital, Boston, MA, USA.
86
Department of Medicine, Universite de Sherbrooke, Sherbooke, Quebec, Canada.
87
Human Genetics Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
88
Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
89
March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA.
90
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
91
Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
92
Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
93
Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
94
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
95
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
96
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
97
Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
98
Medical Research Council Unit for Lifelong Health and Ageing at UCL, Institute of Cardiovascular Sciences, University College London, London, UK.
99
Amsterdam Reproduction and Development, Amsterdam, the Netherlands.
100
Institute of Genetic Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany.
101
Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany.
102
Division of Genetic Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
103
Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark.
104
Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.
105
FISABIO-Universitat Jaume I-Universitat de València, Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain.
106
Joint BSC-CGR-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
107
Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
108
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
109
Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
110
Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
111
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark.
112
NIHR Exeter Clinical Research Facility, University of Exeter College of Medicine and Health and Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
113
Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore.
114
Computer Sciences Department, Barcelona Supercomputing Center, Barcelona, Spain.
115
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
116
IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
117
Section of Genomics of Common Disease, Department of Medicine, Imperial College London, London, UK.
118
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
119
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
120
Medical Department, University of Leipzig, Leipzig, Germany.
121
Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
122
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
123
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
124
Pediatric Research Center, Department of Women's andChild Health, University of Leipzig, Leipzig, Germany.
125
Department of Pediatrics, Turku University Hospital, Turku, Finland.
126
Department of Physiology, University of Turku, Turku, Finland.
127
Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, University of Turku, Turku, Finland.
128
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
129
Institute of Translational Genomics, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany.
130
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
131
Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
132
Life Sciences Institute, National University of Singapore, Singapore, Singapore.
133
Singapore Eye Research Institute, Singapore, Singapore.
134
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
135
Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
136
Quantitative and Systems Genomics Group, Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark.
137
School of Medicine, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia.
138
Institute and Outpatient Clinic for Occupational Social and Environmental Medicine, Inner City Clinic, University Hospital Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
139
Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
140
USC-Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines.
141
Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines.
142
National Institute for Health and Welfare, Helsinki, Finland.
143
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
144
Folkhälsan Research Center, Helsinki, Finland.
145
Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
146
Department of Clinical Physiology, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
147
Division of Medicine, Turku University Hospital, Turku, Finland.
148
Department of Medicine, University of Turku, Turku, Finland.
149
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
150
Biocenter Oulu, University of Oulu, Oulu, Finland.
151
Department of Genomics of Complex Diseases, Imperial College London, London, UK.
152
Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
153
Department of Medicine, Stanford School of Medicine, Stanford, CA, USA.
154
Research Unit for Gynaecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
155
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
156
Research Center for Prevention and Health, Center for Sundhed, Rigshospitalet Glostrup, Copenhagen University, Glostrup, Denmark.
157
Cardiovascular, Renal and Metabolism, Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
158
Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland.
159
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.
160
Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, South Australia, Australia.
161
South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
162
NIHR Bristol Biomedical Research Centre, Bristol, UK.
163
Department of Biostatistics, University of Liverpool, Liverpool, UK.
164
Estonian Genome Center, University of Tartu, Tartu, Estonia.
165
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
166
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
167
Department of Paediatrics, University of Cambridge, Cambridge, UK.
168
NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
169
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. d.evans1@uq.edu.au.
170
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK. d.evans1@uq.edu.au.
171
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. d.evans1@uq.edu.au.
172
Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Royal Devon and Exeter Hospital, Exeter, UK. r.freathy@ex.ac.uk.
173
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK. r.freathy@ex.ac.uk.

Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

PMID:
31043758
PMCID:
PMC6522365
DOI:
10.1038/s41588-019-0403-1
[Indexed for MEDLINE]
Free PMC Article

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