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Warrington, Nicole ; Beaumont, Robin ; Horikoshi, Momoko ; Day, Felix R. ; Helgeland, Øyvind ; Laurin, Charles ; Bacelis, Jonas ; Peng, Shouneng ; Hao, Ke ; Feenstra, Bjarke ; Wood, Andrew R. ; Mahajan, Anubha ; Tyrrell, Jessica ; Robertson, Neil R. ; Rayner, N. William ; Qiao, Zhen ; Moen, Gunn-Helen ; Vaudel, Marc ; Marsit, Carmen ; Chen, Jia ; Nodzenski, Michael ; Schnurr, Theresia M. ; Zafarmand, Mohammad Hadi ; Bradfield, Jonathan P. ; Grarup, Niels ; Kooijman, Marjolein N. ; Li-Gao, Ruifang ; Geller, Frank ; Ahluwalia, Tarunveer Singh ; Paternoster, Lavinia ; Rueedi, Rico ; Huikari, Ville ; Hottenga, Jouke-Jan ; Lyytikäinen, Leo-Pekka ; Cavadino, Alana ; Metrustry, Sarah ; Cousminer, Diana L. ; Wu, Ying ; Thiering, Elisabeth Paula ; Wang, Carol A. ; Have, Christian Theil ; Vilor-Tejedor, Natalia ; Joshi, Peter K. ; Painter, Jodie N. ; Ntalla, Ioanna ; Myhre, Ronny ; Pitkänen, Niina ; van Leeuwen, Elisabeth M. ; Joro, Raimo ; Lagou, Vasiliki ; Richmond, Rebecca C. ; Espinosa, Ana ; Barton, Sheila J. ; Inskip, Hazel M. ; Holloway, John W. ; Santa-Marina, Loreto ; Estivill, Xavier ; Ang, Wei ; Marsh, Julie A. ; Reichetzeder, Christoph ; Marullo, Letizia ; Hocher, Berthold ; Lunetta, Kathryn L. ; Murabito, Joanne M. ; Relton, Caroline L. ; Kogevinas, Manolis ; Chatzi, Leda ; Allard, Catherine ; Bouchard, Luigi ; Hivert, Marie-France ; Zhang, Ge ; Muglia, Louis J. ; Heikkinen, Jani ; Morgen, Camilla S. ; van Kampen, Antoine H. C. ; van Schaik, Barbera D. C. ; Mentch, Frank D. ; Langenberg, Claudia ; Scott, Robert A. ; Zhao, Jing Hua ; Hemani, Gibran ; Ring, Susan M. ; Bennett, Amanda J. ; Gaulton, Kyle J. ; Fernandez-Tajes, Juan ; van Zuydam, Natalie R. ; Medina-Gomez, Carolina ; de Haan, Hugoline G. ; Rosendaal, Frits R. ; Kutalik, Zoltán ; Marques-Vidal, Pedro ; Das, Shikta ; Willemsen, Gonneke ; Mbarek, Hamdi ; Müller-Nurasyid, Martina ; Standl, Marie ; Appel, Emil V. R. ; Fonvig, Cilius Esmann ; Trier, Caecilie ; van Beijsterveldt, Catharina E. M. ; Murcia, Mario ; Bustamante, Mariona ; Bonàs-Guarch, Sílvia ; Hougaard, David M. ; Mercader, Josep M. ; Linneberg, Allan ; Schraut, Katharina E. ; Lind, Penelope A. ; Medland, Sarah Elizabeth ; Shields, Beverley M. ; Knight, Bridget A. ; Chai, Jin-Fang ; Panoutsopoulou, Kalliope ; Bartels, Meike ; Sánchez, Friman ; Stokholm, Jakob ; Torrents, David ; Vinding, Rebecca K. ; Willems, Sara M. ; Atalay, Mustafa ; Chawes, Bo L. ; Kovacs, Peter ; Prokopenko, Inga ; Tuke, Marcus A. ; Yaghootkar, Hanieh ; Ruth, Katherine S. ; Jones, Samuel E. ; Loh, Po-Ru ; Murray, Anna ; Weedon, Michael N. ; Tönjes, Anke ; Stumvoll, Michael ; Michaelsen, Kim Fleischer ; Eloranta, Aino-Maija ; Lakka, Timo A. ; van Duijn, Cornelia M. ; Kiess, Wieland ; Koerner, Antje ; Niinikoski, Harri ; Pahkala, Katja ; Raitakari, Olli T. ; Jacobsson, Bo ; Zeggini, Eleftheria ; Dedoussis, George V. ; Teo, Yik-Ying ; Saw, Seang-Mei ; Montgomery, Grant W. ; Campbell, Harry ; Wilson, James F. ; Vrijkotte, Tanja G. M. ; Vrijheid, Martine ; de Geus, Eco J. C. N. ; Hayes, M. Geoffrey ; Kadarmideen, Haja N. ; Holm, Jens-Christian ; Beilin, Lawrence J. ; Pennell, Craig E. ; Heinrich, Joachim ; Adair, Linda S. ; Borja, Judith B. ; Mohlke, Karen L. ; Eriksson, Johan G. ; Widen, Elisabeth E. ; Hattersley, Andrew T. ; Spector, Tim D. ; Kaehoenen, Mika ; Viikari, Jorma S. ; Lehtimaeki, Terho ; Boomsma, Dorret I. ; Sebert, Sylvain ; Vollenweider, Peter ; Sorensen, Thorkild I. A. ; Bisgaard, Hans ; Bonnelykke, Klaus ; Murray, Jeffrey C. ; Melbye, Mads ; Nohr, Ellen A. ; Mook-Kanamori, Dennis O. ; Rivadeneira, Fernando ; Hofman, Albert ; Felix, Janine F. ; Jaddoe, Vincent W. V. ; Hansen, Torben ; Pisinger, Charlotta ; Vaag, Allan A. ; Pedersen, Oluf ; Uitterlinden, Andre G. ; Jarvelin, Marjo-Riitta ; Power, Christine ; Hypponen, Elina ; Scholtens, Denise M. ; Lowe, William L. ; Smith, George Davey ; Timpson, Nicholas J. ; Morris, Andrew P. ; Wareham, Nicholas J. ; Hakonarson, Hakon ; Grant, Struan F. A. ; Frayling, Timothy M. ; Lawlor, Debbie A. ; Njolstad, Pal R. ; Johansson, Stefan ; Ong, Ken K. ; McCarthy, Mark I. ; Perry, John R. B. ; Evans, David M. ; Freathy, Rachel M.
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.
Horikoshi, Momoko ; Yaghootkar, Hanieh ; Mook-Kanamori, Dennis O. ; Sovio, Ulla ; Taal, H. Rob ; Hennig, Branwen J. ; Bradfield, Jonathan P. ; St Pourcain, Beate ; Evans, David M. ; Charoen, Pimphen ; Kaakinen, Marika ; Cousminer, Diana L. ; Lehtimaki, Terho ; Kreiner-Moller, Eskil ; Warrington, Nicole M. ; Bustamante, Mariona ; Feenstra, Bjarke ; Berry, Diane J. ; Thiering, Elisabeth ; Pfab, Thiemo ; Barton, Sheila J. ; Shields, Beverley M. ; Kerkhof, Marjan ; van Leeuwen, Elisabeth M. ; Fulford, Anthony J. ; Kutalik, Zoltan ; Zhao, Jing Hua ; den Hoed, Marcel ; Mahajan, Anubha ; Lindi, Virpi ; Goh, Liang-Kee ; Hottenga, Jouke-Jan ; Wu, Ying ; Raitakari, Olli T. ; Harder, Marie N. ; Meirhaeghe, Aline ; Ntalla, Ioanna ; Salem, Rany M. ; Jameson, Karen A. ; Zhou, Kaixin ; Monies, Dorota M. ; Lagou, Vasiliki ; Kirin, Mirna ; Heikkinen, Jani ; Adair, Linda S. ; Alkuraya, Fowzan S. ; Al-Odaib, Ali ; Amouyel, Philippe ; Andersson, Ehm Astrid ; Bennett, Amanda J. ; Blakemore, Alexandra I. F. ; Buxton, Jessica L. ; Dallongeville, Jean ; Das, Shikta ; de Geus, Eco J. C. ; Estivill, Xavier ; Flexeder, Claudia ; Froguel, Philippe ; Geller, Frank ; Godfrey, Keith M. ; Gottrand, Frederic ; Groves, Christopher J. ; Hansen, Torben ; Hirschhorn, Joel N. ; Hofman, Albert ; Hollegaard, Mads V. ; Hougaard, David M. ; Hyppoenen, Elina ; Inskip, Hazel M. ; Isaacs, Aaron ; Jorgensen, Torben ; Kanaka-Gantenbein, Christina ; Kemp, John P. ; Kiess, Wieland ; Kilpelainen, Tuomas O. ; Klopp, Norman ; Knight, Bridget A. ; Kuzawa, Christopher W. ; McMahon, George ; Newnham, John P. ; Niinikoski, Harri ; Oostra, Ben A. ; Pedersen, Louise ; Postma, Dirkje S. ; Ring, Susan M. ; Rivadeneira, Fernando ; Robertson, Neil R. ; Sebert, Sylvain ; Simell, Olli ; Slowinski, Torsten ; Tiesler, Carla M. T. ; Toenjes, Anke ; Vaag, Allan ; Viikari, Jorma S. ; Vink, Jacqueline M. ; Vissing, Nadja Hawwa ; Wareham, Nicholas J. ; Willemsen, Gonneke ; Witte, Daniel R. ; Zhang, Haitao ; Zhao, Jianhua ; Wilson, James F. ; Stumvoll, Michael ; Prentice, Andrew M. ; Meyer, Brian F. ; Pearson, Ewan R. ; Boreham, Colin A. G. ; Cooper, Cyrus ; Gillman, Matthew W. ; Dedoussis, George V. ; Moreno, Luis A. ; Pedersen, Oluf ; Saarinen, Maiju ; Mohlke, Karen L. ; Boomsma, Dorret I. ; Saw, Seang-Mei ; Lakka, Timo A. ; Koerner, Antje ; Loos, Ruth J. F. ; Ong, Ken K. ; Vollenweider, Peter ; van Duijn, Cornelia M. ; Koppelman, Gerard H. ; Hattersley, Andrew T. ; Holloway, John W. ; Hocher, Berthold ; Heinrich, Joachim ; Power, Chris ; Melbye, Mads ; Guxens, Monica ; Pennell, Craig E. ; Bonnelykke, Klaus ; Bisgaard, Hans ; Eriksson, Johan G. ; Widen, Elisabeth ; Hakonarson, Hakon ; Uitterlinden, Andre G. ; Pouta, Anneli ; Lawlor, Debbie A. ; Smith, George Davey ; Frayling, Timothy M. ; McCarthy, Mark I. ; Grant, Struan F. A. ; Jaddoe, Vincent W. V. ; Jarvelin, Marjo-Riitta ; Timpson, Nicholas J. ; Prokopenko, Inga ; Freathy, Rachel M.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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