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

Nicole M. Warrington; Inga Prokopenko; Robin N. Beaumont; Momoko Horikoshi; Felix R. Day; Oyvind Helgeland; Charles Laurin; Jonas Bacelis; Shouneng Peng; Ke Hao; Bjarke Feenstra; Andrew R. Wood; Anubha Mahajan; Jessica Tyrrell; Neil R. Robertson; N. William Rayner; Zhen Qiao; Gunn-Helen Moen; Marc Vaudel; Carmen J. Marsit; Jia Chen; Michael Nodzenski; Theresia M. Schnurr; Mohammad H. Zafarmand; Jonathan P. Bradfield; Niels Grarup; Marjolein N. Kooijman; Ruifang Li-Gao; Frank Geller; Tarunveer S. Ahluwalia; Lavinia Paternoster; Rico Rueedi; Ville Huikari; Jouke-Jan Hottenga; Leo-Pekka Lyytikainen; Alana Cavadino; Sarah Metrustry; Diana L. Cousminer; Ying Wu; Elisabeth Thiering; Carol A. Wang; Christian T. Have; Natalia Vilor-Tejedor; Peter K. Joshi; Jodie N. Painter; Ioanna Ntalla; Ronny Myhre; Niina Pitkanen; Elisabeth M. van Leeuwen; Raimo Joro; Vasiliki Lagou; Rebecca C. Richmond; Ana Espinosa; Sheila J. Barton; Hazel M. Inskip; John W. Holloway; Loreto Santa-Marina; Xavier Estivill; Wei Ang; Julie A. Marsh; Christoph Reichetzeder; Letizia Marullo; Berthold Hocher; Kathryn L. Lunetta; Joanne M. Murabito; Caroline L. Relton; Manolis Kogevinas; Leda Chatzi; Catherine Allard; Luigi Bouchard; Marie-France Hivert; Ge Zhang; Louis J. Muglia; Jani Heikkinen; Camilla S. Morgen; Antoine H. C. van Kampen; Barbera D. C. van Schaik; Frank D. Mentch; Claudia Langenberg; Jian'an Luan; Robert A. Scott; Jing Hua Zhao; Gibran Hemani; Susan M. Ring; Amanda J. Bennett; Kyle J. Gaulton; Juan Fernandez-Tajes; Natalie R. van Zuydam; Carolina Medina-Gomez; Hugoline G. de Haan; Frits R. Rosendaal; Zoltan Kutalik; Pedro Marques-Vidal; Shikta Das; Gonneke Willemsen; Hamdi Mbarek; Martina Mueller-Nurasyid; Marie Standl; Emil V. R. Appel; Cilius E. Fonvig; Caecilie Trier; Catharina E. M. van Beijsterveldt; Mario Murcia; Mariona Bustamante; Silvia Bonas-Guarch; David M. Hougaard; Josep M. Mercader; Allan Linneberg; Katharina E. Schraut; Penelope A. Lind; Sarah E. Medland; Beverley M. Shields; Bridget A. Knight; Jin-Fang Chai; Kalliope Panoutsopoulou; Meike Bartels; Friman Sanchez; Jakob Stokholm; David Torrents; Rebecca K. Vinding; Sara M. Willems; Mustafa Atalay; Bo L. Chawes; Peter Kovacs; Marcus A. Tuke; Hanieh Yaghootkar; Katherine S. Ruth; Samuel E. Jones; Po-Ru Loh; Anna Murray; Michael N. Weedon; Anke Toenjes; Michael Stumvoll; Kim F. Michaelsen; Aino-Maija Eloranta; Timo A. Lakka; Cornelia M. van Duijn; Wieland Kiess; Antje Koerner; Harri Niinikoski; Katja Pahkala; Olli T. Raitakari; Bo Jacobsson; Eleftheria Zeggini; George V. Dedoussis; Yik-Ying Teo; Seang-Mei Saw; Grant W. Montgomery; Harry Campbell; James F. Wilson; Tanja G. M. Vrijkotte; Martine Vrijheid; Eco J. C. N. de Geus; M. Geoffrey Hayes; Haja N. Kadarmideen; Jens-Christian Holm; Lawrence J. Beilin; Craig E. Pennell; Joachim Heinrich; Linda S. Adair; Judith B. Borja; Karen L. Mohlke; Johan G. Eriksson; Elisabeth E. Widen; Andrew T. Hattersley; Tim D. Spector; Mika Kaehoenen; Jorma S. Viikari; Terho Lehtimaeki; Dorret I. Boomsma; Sylvain Sebert; Peter Vollenweider; Thorkild I. A. Sorensen; Hans Bisgaard; Klaus Bonnelykke; Jeffrey C. Murray; Mads Melbye; Ellen A. Nohr; Dennis O. Mook-Kanamori; Fernando Rivadeneira; Albert Hofman; Janine F. Felix; Vincent W. V. Jaddoe; Torben Hansen; Charlotta Pisinger; Allan A. Vaag; Oluf Pedersen; Andre G. Uitterlinden; Marjo-Riitta Jarvelin; Christine Power; Elina Hypponen; Denise M. Scholtens; William L. Lowe; George Davey Smith; Nicholas J. Timpson; Andrew P. Morris; Nicholas J. Wareham; Hakon Hakonarson; Struan F. A. Grant; Timothy M. Frayling; Debbie A. Lawlor; Pal R. Njolstad; Stefan Johansson; Ken K. Ong; Mark I. McCarthy; John R. B. Perry; David M. Evans; Rachel M. Freathy; EGG Consortium

doi:10.1038/s41588-019-0403-1

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

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

Nicole M. Warrington, Inga Prokopenko, Robin N. Beaumont, Momoko Horikoshi, Felix R. Day, Oyvind Helgeland, Charles Laurin, Jonas Bacelis, Shouneng Peng, Ke Hao, …

Nature genetics, Vol.51(5), pp.804-814

05/2019

DOI: https://doi.org/10.1038/s41588-019-0403-1

PMCID: PMC6522365

PMID: 31043758

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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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Title: Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors
Creators: Nicole M. Warrington - University of Queensland
Inga Prokopenko - University of Oxford
Robin N. Beaumont - University of Exeter
Momoko Horikoshi - RIKEN
Felix R. Day - University of Cambridge
Oyvind Helgeland - University of Bergen
Charles Laurin - University of Bristol
Jonas Bacelis - Sahlgrens Univ Hosp, Dept Obstet & Gynecol, Gothenburg, Sweden
Shouneng Peng - Supreme Council Of Health
Ke Hao - Supreme Council Of Health
Bjarke Feenstra - Veterinary Biological and Research Institute
Andrew R. Wood - University of Exeter
Anubha Mahajan - University of Oxford
Jessica Tyrrell - University of Exeter
Neil R. Robertson - University of Oxford
N. William Rayner - University of Oxford
Zhen Qiao - University of Queensland
Gunn-Helen Moen - College Station Medical Center
Marc Vaudel - University of Bergen
Carmen J. Marsit - Emory University
Jia Chen - Supreme Council Of Health
Michael Nodzenski - Northwestern Univ, Feinberg Sch Med, Div Biostat, Dept Prevent Med, Chicago, IL 60611 USA
Theresia M. Schnurr - University of Copenhagen
Mohammad H. Zafarmand - University of Amsterdam
Jonathan P. Bradfield - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Niels Grarup - University of Copenhagen
Marjolein N. Kooijman - Erasmus MC
Ruifang Li-Gao - Leiden University
Frank Geller - Veterinary Biological and Research Institute
Tarunveer S. Ahluwalia - University of Copenhagen
Lavinia Paternoster - University of Bristol
Rico Rueedi - University of Lausanne
Ville Huikari - University of Oulu
Jouke-Jan Hottenga - University of Amsterdam
Leo-Pekka Lyytikainen - Fimlab
Alana Cavadino - University of Auckland
Sarah Metrustry - Kings Coll London, St Thomas Hosp, Dept Twin Res, London, England
Diana L. Cousminer - Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA
Ying Wu - Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA
Elisabeth Thiering - Helmholtz Zentrum München
Carol A. Wang - Supreme Council Of Health
Christian T. Have - University of Copenhagen
Natalia Vilor-Tejedor - Barcelona Inst Sci & Technol, Ctr Genom Regulat, Barcelona, Spain
Peter K. Joshi - University of Edinburgh
Jodie N. Painter - College Station Medical Center
Ioanna Ntalla - Queen Mary University of London
Ronny Myhre - Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, Oslo, Norway
Niina Pitkanen - University of Turku
Elisabeth M. van Leeuwen - Erasmus MC
Raimo Joro - University of Eastern Finland
Vasiliki Lagou - University of Oxford
Rebecca C. Richmond - University of Bristol
Ana Espinosa - Barcelona Institute for Global Health
Sheila J. Barton - University of Southampton
Hazel M. Inskip - University of Southampton
John W. Holloway - University of Southampton
Loreto Santa-Marina - CIBER Epidemiol & Salud Publ, Madrid, Spain
Xavier Estivill - College Station Medical Center
Wei Ang - University of Western Australia
Julie A. Marsh - University of Western Australia
Christoph Reichetzeder - University of Potsdam
Letizia Marullo - University of Ferrara
Berthold Hocher - Heidelberg Univ, Univ Med Ctr Mannheim, Dept Med 5, Heidelberg, Germany
Kathryn L. Lunetta - Boston University
Joanne M. Murabito - Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Caroline L. Relton - University of Bristol
Manolis Kogevinas - Barcelona Institute for Global Health
Leda Chatzi - Supreme Council Of Health
Catherine Allard - Ctr Hosp Univ Sherbrooke, Ctr Rech, Sherbrooke, PQ, Canada
Luigi Bouchard - Ctr Hosp Univ Sherbrooke, Ctr Rech, Sherbrooke, PQ, Canada
Marie-France Hivert - Supreme Council Of Health
Ge Zhang - College Station Medical Center
Louis J. Muglia - College Station Medical Center
Jani Heikkinen - University of Helsinki
Camilla S. Morgen - University of Copenhagen
Antoine H. C. van Kampen - University of Amsterdam
Barbera D. C. van Schaik - University of Amsterdam
Frank D. Mentch - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Claudia Langenberg - University of Cambridge
Jian'an Luan - University of Cambridge
Robert A. Scott - University of Cambridge
Jing Hua Zhao - University of Cambridge
Gibran Hemani - University of Bristol
Susan M. Ring - University of Bristol
Amanda J. Bennett - University of Oxford
Kyle J. Gaulton - University of Oxford
Juan Fernandez-Tajes - University of Oxford
Natalie R. van Zuydam - University of Oxford
Carolina Medina-Gomez - Univ Med Ctr Rotterdam, Generat R Study Grp, Erasmus MC, Rotterdam, Netherlands
Hugoline G. de Haan - Leiden University
Frits R. Rosendaal - Leiden University
Zoltan Kutalik - Swiss Inst Bioinformat, Lausanne, Switzerland
Pedro Marques-Vidal - College Station Medical Center
Shikta Das - College Station Medical Center
Gonneke Willemsen - University of Amsterdam
Hamdi Mbarek - University of Amsterdam
Martina Mueller-Nurasyid - Helmholtz Zentrum München
Marie Standl - Helmholtz Zentrum München
Emil V. R. Appel - University of Copenhagen
Cilius E. Fonvig - University of Copenhagen
Caecilie Trier - University of Copenhagen
Catharina E. M. van Beijsterveldt - University of Amsterdam
Mario Murcia - CIBER Epidemiol & Salud Publ, Madrid, Spain
Mariona Bustamante - Barcelona Institute for Global Health
Silvia Bonas-Guarch - Barcelona Supercomp Ctr, Joint BSC CGR IRB Res Program Computat Biol, Barcelona, Spain
David M. Hougaard - Veterinary Biological and Research Institute
Josep M. Mercader - Barcelona Supercomp Ctr, Joint BSC CGR IRB Res Program Computat Biol, Barcelona, Spain
Allan Linneberg - University of Copenhagen
Katharina E. Schraut - University of Edinburgh
Penelope A. Lind - College Station Medical Center
Sarah E. Medland - College Station Medical Center
Beverley M. Shields - University of Exeter
Bridget A. Knight - University of Exeter
Jin-Fang Chai - Supreme Council Of Health
Kalliope Panoutsopoulou - Wellcome Sanger Institute
Meike Bartels - University of Amsterdam
Friman Sanchez - Barcelona Supercomp Ctr, Joint BSC CGR IRB Res Program Computat Biol, Barcelona, Spain
Jakob Stokholm - University of Copenhagen
David Torrents - Barcelona Supercomp Ctr, Joint BSC CGR IRB Res Program Computat Biol, Barcelona, Spain
Rebecca K. Vinding - University of Copenhagen
Sara M. Willems - Erasmus MC
Mustafa Atalay - University of Eastern Finland
Bo L. Chawes - University of Copenhagen
Peter Kovacs - Institute of Inland Fisheries in Potsdam-Sacrow
Marcus A. Tuke - University of Exeter
Hanieh Yaghootkar - University of Exeter
Katherine S. Ruth - University of Exeter
Samuel E. Jones - University of Exeter
Po-Ru Loh - Broad Institute
Anna Murray - University of Exeter
Michael N. Weedon - University of Exeter
Anke Toenjes - College Station Medical Center
Michael Stumvoll - Institute of Inland Fisheries in Potsdam-Sacrow
Kim F. Michaelsen - University of Copenhagen
Aino-Maija Eloranta - University of Eastern Finland
Timo A. Lakka - University of Eastern Finland
Cornelia M. van Duijn - Erasmus MC
Wieland Kiess - Univ Leipzig, Dept Womens & Child Hlth, Pediat Res Ctr, Leipzig, Germany
Antje Koerner - Institute of Inland Fisheries in Potsdam-Sacrow
Harri Niinikoski - Turku Univ Hosp, Dept Pediat, Turku, Finland
Katja Pahkala - University of Turku
Olli T. Raitakari - University of Turku
Bo Jacobsson - Norwegian Inst Publ Hlth, Dept Genet & Bioinformat, Domain Hlth Data & Digitalisat, Oslo, Norway
Eleftheria Zeggini - Wellcome Sanger Institute
George V. Dedoussis - Harokopio University of Athens
Yik-Ying Teo - Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore
Seang-Mei Saw - Supreme Council Of Health
Grant W. Montgomery - College Station Medical Center
Harry Campbell - University of Edinburgh
James F. Wilson - University of Edinburgh
Tanja G. M. Vrijkotte - University of Amsterdam
Martine Vrijheid - Barcelona Institute for Global Health
Eco J. C. N. de Geus - University of Amsterdam
M. Geoffrey Hayes - Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Dept Med, Chicago, IL 60611 USA
Haja N. Kadarmideen - BIO
Jens-Christian Holm - University of Copenhagen
Lawrence J. Beilin - University of Western Australia
Craig E. Pennell - Supreme Council Of Health
Joachim Heinrich - Helmholtz Zentrum München
Linda S. Adair - Univ N Carolina, Dept Nutr, Chapel Hill, NC 27515 USA
Judith B. Borja - University of San Carlos
Karen L. Mohlke - Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA
Johan G. Eriksson - Natl Inst Hlth & Welf, Helsinki, Finland
Elisabeth E. Widen - University of Helsinki
Andrew T. Hattersley - University of Exeter
Tim D. Spector - Kings Coll London, St Thomas Hosp, Dept Twin Res, London, England
Mika Kaehoenen - Tampere University
Jorma S. Viikari - College Station Medical Center
Terho Lehtimaeki - Fimlab
Dorret I. Boomsma - University of Amsterdam
Sylvain Sebert - University of Oulu
Peter Vollenweider - College Station Medical Center
Thorkild I. A. Sorensen - University of Bristol
Hans Bisgaard - University of Copenhagen
Klaus Bonnelykke - University of Copenhagen
Jeffrey C. Murray - University of Iowa
Mads Melbye - Veterinary Biological and Research Institute
Ellen A. Nohr - University of Southern Denmark
Dennis O. Mook-Kanamori - Leiden University
Fernando Rivadeneira - Erasmus MC
Albert Hofman - Erasmus MC
Janine F. Felix - Univ Med Ctr Rotterdam, Generat R Study Grp, Erasmus MC, Rotterdam, Netherlands
Vincent W. V. Jaddoe - Erasmus MC
Torben Hansen - University of Copenhagen
Charlotta Pisinger - University of Copenhagen
Allan A. Vaag - University of Copenhagen
Oluf Pedersen - University of Copenhagen
Andre G. Uitterlinden - Erasmus MC
Marjo-Riitta Jarvelin - University of Oulu
Christine Power - Ormond
Elina Hypponen - Ormond
Denise M. Scholtens - Northwestern Univ, Feinberg Sch Med, Div Biostat, Dept Prevent Med, Chicago, IL 60611 USA
William L. Lowe - Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Dept Med, Chicago, IL 60611 USA
George Davey Smith - University of Bristol
Nicholas J. Timpson - University of Bristol
Andrew P. Morris - University of Oxford
Nicholas J. Wareham - University of Cambridge
Hakon Hakonarson - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Struan F. A. Grant - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA
Timothy M. Frayling - University of Exeter
Debbie A. Lawlor - University of Bristol
Pal R. Njolstad - University of Bergen
Stefan Johansson - University of Bergen
Ken K. Ong - University of Cambridge
Mark I. McCarthy - University of Oxford
John R. B. Perry - University of Cambridge
David M. Evans - University of Queensland
Rachel M. Freathy - University of Exeter
EGG Consortium
Publication Details: Nature genetics, Vol.51(5), pp.804-814
Publisher: Nature Research
Number of pages: 17
Date published: 05/2019
Grant note: G1001357 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) P30ES019776 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS)
Identifiers: 99817446202346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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