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

2019; Nature Portfolio; Volume: 51; Issue: 5 Linguagem: Inglês

10.1038/s41588-019-0403-1

1546-1718

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, Nigel W. Rayner, Zhen Qiao, Gunn-Helen Moen, Marc Vaudel, Carmen J. 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 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, Henri Theil, Natàlia Vilor‐Tejedor, Peter K. Joshi, Jodie N. Painter, Ιωάννα Ντάλλα, Ronny Myhre, Niina Pitkänen, Jin‐Moo Lee, Raimo Joro, Vasiliki Lagou, Rebecca C. Richmond, Ana Espinosa, Sheila J. Barton, Hazel Inskip, John W. Holloway, Loreto Santa‐Marina, Xavier Estivill, Wei Ang, Julie 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 Mentch, Claudia Langenberg, Jian'an Luan, Robert A. Scott, Wei Zhao, Gibran Hemani, Susan M. Ring, Amanda J. Bennett, Kyle J. Gaulton, Juan Fernández‐Tajes, Natalie R. van Zuydam, Carolina Medina‐Gómez, 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, Cæcilie Trier, C.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 E. Medland, Beverley M. Shields, Bridget Knight, Jin Fang Chai, Kalliope Panoutsopoulou, Meike Bartels, Friman Sánchez, Jakob Stokholm, David Torrents, Rebecca Vinding, Sara M. Willems, Mustafa Atalay, Bo Chawes, Péter Kovács, Inga Prokopenko, Marcus A. Tuke, Hanieh Yaghootkar, Katherine S. Ruth, Samuel E. Jones, Po−Ru Loh, Anna Murray, Michael N. Weedon, Anke Tönjes, Michael Stümvoll, 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 Dedoussis, Yik‐Ying Teo, Seang‐Mei Saw, Grant W. Montgomery, Harry Campbell, James F. Wilson, Tanja G. M. Vrijkotte, Martine Vrijheid, Eco J. C. 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 Widén, Andrew T. Hattersley, Tim D. Spector, Mika Kähönen, Jorma Viikari, Terho Lehtimäki, Dorret I. Boomsma, Sylvain Sebért, Péter Vollenweider, Thorkild I. A. Sørensen, Hans Bisgaard, Klaus Bønnelykke, Jeffrey C. Murray, Mads Melbye, Ellen A. Nøhr, Dennis O. Mook‐Kanamori, Fernando Rivadeneira, Albert Hofman, Janine F. Felix, Vincent W. V. Jaddoe, Torben Hansen, Charlotta Pisinger, Allan Vaag, Oluf Pedersen, André G. Uitterlinden, Marjo‐Riitta Järvelin, Christopher Power, Elina Hyppönen, Denise Scholtens, William L. Lowe, George Davey Smith, Nicholas J. Timpson, Andrew P. Morris, Nicholas J. Wareham, Hákon Hákonarson, 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,

Pregnancy and preeclampsia studies

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.