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

Nicole Warrington, Robin Beaumont, Momoko Horikoshi, Felix R. Day, Øyvind 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 Marsit, Jia Chen, Michael Nodzenski, Theresia M. Schnurr, Mohammad Hadi Zafarmand, Jonathan P. Bradfield, Niels Grarup, Marjolein N. Kooijman, Ruifang Li-Gao, Frank Geller, Tarunveer Singh Ahluwalia, Lavinia Paternoster, Rico Rueedi, Ville Huikari, Jouke-Jan Hottenga, Leo-Pekka Lyytikäinen, Alana Cavadino, Sarah Metrustry, Diana L. Cousminer, Ying Wu, Elisabeth Paula Thiering, Carol A. Wang, Christian Theil Have, Natalia Vilor-Tejedor, Peter K. Joshi, Jodie N. Painter, Ioanna Ntalla, Ronny Myhre, Niina Pitkänen, 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, 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, Zoltán Kutalik, Pedro Marques-Vidal, Shikta Das, Gonneke Willemsen, Hamdi Mbarek, Martina Müller-Nurasyid, Marie Standl, Emil V. R. Appel, Cilius Esmann Fonvig, Caecilie Trier, Catharina E. M. van Beijsterveldt, Mario Murcia, Mariona Bustamante, Sílvia Bonàs-Guarch, David M. Hougaard, Josep M. Mercader, Allan Linneberg, Katharina E. Schraut, Penelope A. Lind, Sarah Elizabeth Medland, Beverley M. Shields, Bridget A. Knight, Jin-Fang Chai, Kalliope Panoutsopoulou, Meike Bartels, Friman Sánchez, Jakob Stokholm, David Torrents, Rebecca K. Vinding, Sara M. Willems, Mustafa Atalay, Bo L. Chawes, Peter Kovacs, Inga Prokopenko, Marcus A. Tuke, Hanieh Yaghootkar, Katherine S. Ruth, Samuel E. Jones, Po-Ru Loh, Anna Murray, Michael N. Weedon, Anke Tönjes, Michael Stumvoll, Kim Fleischer 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

  • 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 causallyBirth 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.show moreshow less

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Author details:Nicole WarringtonORCiD, Robin BeaumontORCiD, Momoko Horikoshi, Felix R. DayORCiDGND, Øyvind HelgelandORCiD, Charles LaurinORCiD, Jonas BacelisORCiD, Shouneng Peng, Ke Hao, Bjarke FeenstraORCiD, Andrew R. Wood, Anubha MahajanORCiD, Jessica Tyrrell, Neil R. Robertson, N. William RaynerORCiD, Zhen Qiao, Gunn-Helen MoenORCiD, Marc VaudelORCiDGND, Carmen MarsitORCiD, Jia Chen, Michael Nodzenski, Theresia M. SchnurrORCiD, Mohammad Hadi ZafarmandORCiD, Jonathan P. Bradfield, Niels GrarupORCiD, Marjolein N. Kooijman, Ruifang Li-GaoORCiD, Frank Geller, Tarunveer Singh AhluwaliaORCiD, Lavinia PaternosterORCiD, Rico Rueedi, Ville Huikari, Jouke-Jan HottengaORCiD, Leo-Pekka LyytikäinenORCiD, Alana CavadinoORCiD, Sarah Metrustry, Diana L. CousminerORCiD, Ying Wu, Elisabeth Paula ThieringORCiDGND, Carol A. WangORCiD, Christian Theil HaveORCiD, Natalia Vilor-Tejedor, Peter K. Joshi, Jodie N. PainterORCiD, Ioanna Ntalla, Ronny MyhreORCiD, Niina Pitkänen, Elisabeth M. van Leeuwen, Raimo Joro, Vasiliki Lagou, Rebecca C. RichmondORCiD, Ana Espinosa, Sheila J. BartonORCiD, Hazel M. InskipORCiD, John W. Holloway, Loreto Santa-MarinaORCiD, Xavier EstivillORCiD, Wei Ang, Julie A. MarshORCiD, Christoph ReichetzederORCiDGND, Letizia Marullo, Berthold HocherORCiDGND, Kathryn L. LunettaORCiD, Joanne M. Murabito, Caroline L. ReltonORCiD, Manolis KogevinasORCiD, Leda ChatziORCiD, Catherine AllardORCiD, Luigi Bouchard, Marie-France HivertORCiD, Ge Zhang, Louis J. Muglia, Jani HeikkinenORCiD, Camilla S. MorgenORCiD, Antoine H. C. van Kampen, Barbera D. C. van Schaik, Frank D. Mentch, Claudia LangenbergORCiD, Robert A. ScottORCiD, Jing Hua Zhao, Gibran HemaniORCiD, Susan M. Ring, Amanda J. Bennett, Kyle J. GaultonORCiD, Juan Fernandez-Tajes, Natalie R. van Zuydam, Carolina Medina-GomezORCiD, Hugoline G. de Haan, Frits R. RosendaalORCiD, Zoltán KutalikORCiD, Pedro Marques-VidalORCiD, Shikta DasORCiD, Gonneke WillemsenORCiD, Hamdi MbarekORCiD, Martina Müller-NurasyidORCiD, Marie StandlORCiDGND, Emil V. R. Appel, Cilius Esmann FonvigORCiD, Caecilie Trier, Catharina E. M. van Beijsterveldt, Mario MurciaORCiD, Mariona Bustamante, Sílvia Bonàs-GuarchORCiD, David M. HougaardORCiD, Josep M. MercaderORCiD, Allan LinnebergORCiD, Katharina E. Schraut, Penelope A. LindORCiD, Sarah Elizabeth MedlandORCiD, Beverley M. Shields, Bridget A. KnightORCiD, Jin-Fang Chai, Kalliope PanoutsopoulouORCiD, Meike BartelsORCiD, Friman SánchezORCiD, Jakob StokholmORCiD, David TorrentsORCiD, Rebecca K. VindingORCiD, Sara M. Willems, Mustafa Atalay, Bo L. Chawes, Peter KovacsORCiD, Inga Prokopenko, Marcus A. Tuke, Hanieh Yaghootkar, Katherine S. Ruth, Samuel E. Jones, Po-Ru Loh, Anna MurrayORCiD, Michael N. WeedonORCiD, Anke Tönjes, Michael Stumvoll, Kim Fleischer MichaelsenORCiDGND, 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 CampbellORCiD, James F. Wilson, Tanja G. M. Vrijkotte, Martine VrijheidORCiD, Eco J. C. N. de Geus, M. Geoffrey Hayes, Haja N. Kadarmideen, Jens-Christian HolmORCiD, Lawrence J. Beilin, Craig E. Pennell, Joachim HeinrichORCiD, 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 BisgaardORCiD, Klaus Bonnelykke, Jeffrey C. Murray, Mads Melbye, Ellen A. Nohr, Dennis O. Mook-Kanamori, Fernando RivadeneiraORCiD, Albert Hofman, Janine F. Felix, Vincent W. V. Jaddoe, Torben HansenORCiD, Charlotta Pisinger, Allan A. Vaag, Oluf PedersenORCiD, Andre G. Uitterlinden, Marjo-Riitta Jarvelin, Christine Power, Elina HypponenORCiD, Denise M. Scholtens, William L. Lowe, George Davey SmithORCiD, 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 JohanssonORCiD, Ken K. Ong, Mark I. McCarthy, John R. B. Perry, David M. Evans, Rachel M. Freathy
ISSN:1061-4036
ISSN:1546-1718
Pubmed ID:https://pubmed.ncbi.nlm.nih.gov/31043758
Title of parent work (English):Nature genetics
Publisher:Nature Publ. Group
Place of publishing:New York
Publication type:Article
Language:English
Date of first publication:2019/05/01
Publication year:2019
Creating corporation:EGG Consortium
Release date:2021/02/25
Volume:51
Issue:5
Number of pages:17
First page:804
Last Page:+
Funding institution:Diabetes UKDiabetes UK [17/0005594]; European Research CouncilEuropean Research Council (ERC) [323195]; Medical Research CouncilMedical Research Council UK (MRC) [MC_PC_15018, MC_UU_12011/4, MC_UU_00011/6, MC_UU_12013/4, MR/M005070/1, MR/J012165/1, MC_UU_00011/1, G9815508, G0601261, MC_UU_00011/5, MC_UP_A620_1017, MC_UU_12015/1, MC_UU_12013/3, G1001357]; NIEHS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [R01 ES022223, R21 ES028226, R24 ES028507, P30 ES019776, P30 ES023515, R01 ES029212]; Wellcome TrustWellcome Trust [202802, 104150, 098395, 205915, 098381, 212259, 088806]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
Peer review:Referiert
Publishing method:Open Access / Green Open-Access
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