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

Nicole M Warrington, Robin N 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 J Marsit, Jia Jue Johannes ChenMichael 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 Lyytikäinen, 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 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, EGG Consortium, 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, Zoltán Kutalik, Pedro Marques-Vidal, Shikta Das, Gonneke Willemsen, Hamdi Mbarek, Martina Müller-Nurasyid, Marie Standl, Emil V R Appel, Cilius E Fonvig, Caecilie Trier, Catharina E M van Beijsterveldt, Mario Murcia, Mariona Bustamante, Sílvia 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 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 F Michaelsen, Aino-Maija Eloranta, Timo A Lakka, Cornelia M van Duijn, Wieland Kiess, Antje Körner, 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 Widén, Andrew T Hattersley, Tim D Spector, Mika Kähönen, Jorma S Viikari, Terho Lehtimäki, Dorret I Boomsma, Sylvain Sebert, Peter Vollenweider, Thorkild I A Sørensen, Hans Flinker Bisgaard, Klaus Bønnelykke, 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, André G Uitterlinden, Marjo-Riitta Järvelin, Christine Power, Elina Hyppönen, 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, Pål R Njølstad, Stefan Johansson, Ken K Ong, Mark I McCarthy, John R B Perry, David M Evans, Rachel M Freathy*

*Corresponding author for this work

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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 languageEnglish
JournalNature Genetics
Volume51
Issue number5
Pages (from-to)804-814
ISSN1061-4036
DOIs
Publication statusPublished - 2019

Cite this

Warrington, N. M., Beaumont, R. N., Horikoshi, M., Day, F. R., Helgeland, Ø., Laurin, C., Bacelis, J., Peng, S., Hao, K., Feenstra, B., Wood, A. R., Mahajan, A., Tyrrell, J., Robertson, N. R., Rayner, N. W., Qiao, Z., Moen, G-H., Vaudel, M., Marsit, C. J., ... Freathy, R. M. (2019). Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nature Genetics, 51(5), 804-814. https://doi.org/10.1038/s41588-019-0403-1