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

EGG Consortium

doi:10.1038/s41588-019-0403-1

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

EGG Consortium

Barcelona Institute for Global Health
Pompeu Fabra University
Biomedical Research Networking Center in Epidemiology and Public Health (CiberESP)
Hospital del Mar
MRC Lifecourse Epidemiology Unit
University Hospital Southampton NHS Foundation Trust
University of Southampton
Subdirección de Salud Pública y Adicciones de Gipuzkoa
Instituto de Investigación Sanitaria Biodonostia
Sidra Medical and Research Center
Genomics Unit
University of Western Australia
University of Potsdam
University of Ferrara
Heidelberg University
Reproductive and Genetic Hospital of CITIC-Xiangya
Boston University
National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
University of Southern California
Centre Hospitalier Universitaire de Sherbrooke
Université de Sherbrooke
Harvard University
Massachusetts General Hospital
Cincinnati Children's Hospital Medical Center
University of Cincinnati
March of Dimes Prematurity Research Center Ohio Collaborative
University of Helsinki
University of California at San Diego
Amsterdam UMC
University of Southern Denmark
University of Valencia
Barcelona Supercomputing Center
Broad Institute
Royal Devon & Exeter NHS Foundation Trust
MOH Holdings Pte Ltd.
ICREA
Leipzig University
Imperial College London
Brigham and Women’s Hospital
Harokopio University
National University of Singapore
Singapore National Eye Center
Technical University of Denmark
Royal Perth Hospital
University of San Carlos - Philippines
National Institute for Health and Welfare
Helsinki University Hospital
Folkhalsan
University of Iowa
Stanford University
AstraZeneca
Brunel University London
University of South Australia
South Australian Health And Medical Research Institute
NIHR Bristol Biomedical Research Centre
University of Liverpool
University of Tartu
John Radcliffe Hospital
University of Queensland
University of Exeter
RIKEN
University of Oxford
University of Cambridge
University of Bergen
Norwegian Institute of Public Health
University of Bristol
Sahlgrenska University Hospital
Icahn School of Medicine at Mount Sinai
Statens Serum Institut
Wellcome Trust Sanger Institute
University of Oslo
Emory University
Northwestern University
University of Copenhagen
Amsterdam University Medical Centers
Children's Hospital of Philadelphia
Quantinuum Research LLC
Erasmus University Medical Center
Leiden University
Novo Nordisk Foundation
University of Lausanne
Swiss Institute of Bioinformatics
University of Oulu
Vrije Universiteit Amsterdam
Fimlab Laboratories
Tampere University
The University of Auckland
University College London
St Thomas’ Hospital Campus
University of Pennsylvania
University of North Carolina at Chapel Hill
Helmholtz Zentrum München - German Research Center for Environmental Health
Ludwig Maximilian University of Munich
University of Newcastle
Centre for Genomic Regulation
Pasqual Maragall Foundation
University of Edinburgh
Queensland Institute of Medical Research
Queen Mary University of London
University of Turku
University of Eastern Finland
KU Leuven
Flanders Institute for Biotechnology

Research output: Contribution to journal › Article › peer-review

414 Citations (Scopus)

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.

Original language	English
Pages (from-to)	804-814
Number of pages	11
Journal	Nature Genetics
Volume	51
Issue number	5
DOIs	https://doi.org/10.1038/s41588-019-0403-1
Publication status	Published - 1 May 2019
Externally published	Yes

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10.1038/s41588-019-0403-1

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@article{6f3727f6ef9d49cd988eca237a589583,

title = "Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors",

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.",

author = "\{EGG Consortium\} and Warrington, \{Nicole M.\} and Beaumont, \{Robin N.\} and Momoko Horikoshi and Day, \{Felix R.\} and {\O}yvind Helgeland and Charles Laurin and Jonas Bacelis and Shouneng Peng and Ke Hao and Bjarke Feenstra and Wood, \{Andrew R.\} and Anubha Mahajan and Jessica Tyrrell and Robertson, \{Neil R.\} and Rayner, \{N. William\} and Zhen Qiao and Moen, \{Gunn Helen\} and Marc Vaudel and Marsit, \{Carmen J.\} and Jia Chen and Michael Nodzenski and Schnurr, \{Theresia M.\} and Zafarmand, \{Mohammad H.\} and Bradfield, \{Jonathan P.\} and Niels Grarup and Kooijman, \{Marjolein N.\} and Ruifang Li-Gao and Frank Geller and Ahluwalia, \{Tarunveer S.\} and Lavinia Paternoster and Rico Rueedi and Ville Huikari and Hottenga, \{Jouke Jan\} and Lyytik{\"a}inen, \{Leo Pekka\} and Alana Cavadino and Sarah Metrustry and Cousminer, \{Diana L.\} and Ying Wu and Elisabeth Thiering and Wang, \{Carol A.\} and Have, \{Christian T.\} and Natalia Vilor-Tejedor and Joshi, \{Peter K.\} and Painter, \{Jodie N.\} and Ioanna Ntalla and Ronny Myhre and Niina Pitk{\"a}nen and \{van Leeuwen\}, \{Elisabeth M.\} and Raimo Joro and Vasiliki Lagou",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = may,

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doi = "10.1038/s41588-019-0403-1",

language = "English",

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T1 - Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

AU - EGG Consortium

AU - Warrington, Nicole M.

AU - Beaumont, Robin N.

AU - Horikoshi, Momoko

AU - Day, Felix R.

AU - Helgeland, Øyvind

AU - Laurin, Charles

AU - Bacelis, Jonas

AU - Peng, Shouneng

AU - Hao, Ke

AU - Feenstra, Bjarke

AU - Wood, Andrew R.

AU - Mahajan, Anubha

AU - Tyrrell, Jessica

AU - Robertson, Neil R.

AU - Rayner, N. William

AU - Qiao, Zhen

AU - Moen, Gunn Helen

AU - Vaudel, Marc

AU - Marsit, Carmen J.

AU - Chen, Jia

AU - Nodzenski, Michael

AU - Schnurr, Theresia M.

AU - Zafarmand, Mohammad H.

AU - Bradfield, Jonathan P.

AU - Grarup, Niels

AU - Kooijman, Marjolein N.

AU - Li-Gao, Ruifang

AU - Geller, Frank

AU - Ahluwalia, Tarunveer S.

AU - Paternoster, Lavinia

AU - Rueedi, Rico

AU - Huikari, Ville

AU - Hottenga, Jouke Jan

AU - Lyytikäinen, Leo Pekka

AU - Cavadino, Alana

AU - Metrustry, Sarah

AU - Cousminer, Diana L.

AU - Wu, Ying

AU - Thiering, Elisabeth

AU - Wang, Carol A.

AU - Have, Christian T.

AU - Vilor-Tejedor, Natalia

AU - Joshi, Peter K.

AU - Painter, Jodie N.

AU - Ntalla, Ioanna

AU - Myhre, Ronny

AU - Pitkänen, Niina

AU - van Leeuwen, Elisabeth M.

AU - Joro, Raimo

AU - Lagou, Vasiliki

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41588-019-0403-1

DO - 10.1038/s41588-019-0403-1

M3 - Article

C2 - 31043758

AN - SCOPUS:85065213720

SN - 1061-4036

VL - 51

SP - 804

EP - 814

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

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