Genome-wide associations for birth weight and correlations with adult disease
Momoko Horikoshi, Robin N Beaumont, Felix R Day, Nicole M Warrington, Marjolein N Kooijman, Juan Fernandez-Tajes, Bjarke Feenstra, Natalie R van Zuydam, Kyle J Gaulton, Niels Grarup, Jonathan P Bradfield, David P Strachan, Ruifang Li-Gao, Tarunveer S Ahluwalia, Eskil Kreiner, Rico Rueedi, Leo-Pekka Lyytikäinen, Diana L Cousminer, Ying Wu, Elisabeth Thiering, Carol A Wang, Christian T Have, Jouke-Jan Hottenga, Natalia Vilor-Tejedor, Peter K Joshi, Eileen Tai Hui Boh, Ioanna Ntalla, Niina Pitkänen, Anubha Mahajan, Elisabeth M van Leeuwen, Raimo Joro, Vasiliki Lagou, Michael Nodzenski, Louise A Diver, Krina T Zondervan, Mariona Bustamante, Pedro Marques-Vidal, Josep M Mercader, Amanda J Bennett, Nilufer Rahmioglu, Dale R Nyholt, Ronald Ching Wan Ma, Claudia Ha Ting Tam, Wing Hung Tam, CHARGE Consortium Hematology Working Group, Santhi K Ganesh, Frank Ja van Rooij, Samuel E Jones, Po-Ru Loh, Katherine S Ruth, Marcus A Tuke, Jessica Tyrrell, Andrew R Wood, Hanieh Yaghootkar, Denise M Scholtens, Lavinia Paternoster, Inga Prokopenko, Peter Kovacs, Mustafa Atalay, Sara M Willems, Kalliope Panoutsopoulou, Xu Wang, Lisbeth Carstensen, Frank Geller, Katharina E Schraut, Mario Murcia, Catharina Em van Beijsterveldt, Gonneke Willemsen, Emil V R Appel, Cilius E Fonvig, Caecilie Trier, Carla Mt Tiesler, Marie Standl, Zoltán Kutalik, Sílvia Bonas-Guarch, David M Hougaard, Friman Sánchez, David Torrents, Johannes Waage, Mads V Hollegaard, Hugoline G de Haan, Frits R Rosendaal, Carolina Medina-Gomez, Susan M Ring, Gibran Hemani, George McMahon, Neil R Robertson, Christopher J Groves, Claudia Langenberg, Jian'an Luan, Robert A Scott, Jing Hua Zhao, Frank D Mentch, Scott M MacKenzie, Rebecca M Reynolds, Early Growth Genetics (EGG) Consortium, William L Lowe Jr, Anke Tönjes, Michael Stumvoll, Virpi Lindi, Timo A Lakka, Cornelia M van Duijn, Wieland Kiess, Antje Körner, Thorkild Ia Sørensen, Harri Niinikoski, Katja Pahkala, Olli T Raitakari, Eleftheria Zeggini, George V Dedoussis, Yik-Ying Teo, Seang-Mei Saw, Mads Melbye, Harry Campbell, James F Wilson, Martine Vrijheid, Eco Jcn de Geus, Dorret I Boomsma, Haja N Kadarmideen, Jens-Christian Holm, Torben Hansen, Sylvain Sebert, Andrew T Hattersley, Lawrence J Beilin, John P Newnham, Craig E Pennell, Joachim Heinrich, Linda S Adair, Judith B Borja, Karen L Mohlke, Johan G Eriksson, Elisabeth E Widén, Mika Kähönen, Jorma S Viikari, Terho Lehtimäki, Peter Vollenweider, Klaus Bønnelykke, Hans Bisgaard, Dennis O Mook-Kanamori, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Charlotta Pisinger, Oluf Pedersen, Christine Power, Elina Hyppönen, Nicholas J Wareham, Hakon Hakonarson, Eleanor Davies, Brian R Walker, Vincent Wv Jaddoe, Marjo-Riitta Jarvelin, Struan Fa Grant, Allan A Vaag, Debbie A Lawlor, Timothy M Frayling, George Davey Smith, Andrew P Morris, Ken K Ong, Janine F Felix, Nicholas J Timpson, John Rb Perry, David M Evans, Mark I McCarthy, Rachel M Freathy, Momoko Horikoshi, Robin N Beaumont, Felix R Day, Nicole M Warrington, Marjolein N Kooijman, Juan Fernandez-Tajes, Bjarke Feenstra, Natalie R van Zuydam, Kyle J Gaulton, Niels Grarup, Jonathan P Bradfield, David P Strachan, Ruifang Li-Gao, Tarunveer S Ahluwalia, Eskil Kreiner, Rico Rueedi, Leo-Pekka Lyytikäinen, Diana L Cousminer, Ying Wu, Elisabeth Thiering, Carol A Wang, Christian T Have, Jouke-Jan Hottenga, Natalia Vilor-Tejedor, Peter K Joshi, Eileen Tai Hui Boh, Ioanna Ntalla, Niina Pitkänen, Anubha Mahajan, Elisabeth M van Leeuwen, Raimo Joro, Vasiliki Lagou, Michael Nodzenski, Louise A Diver, Krina T Zondervan, Mariona Bustamante, Pedro Marques-Vidal, Josep M Mercader, Amanda J Bennett, Nilufer Rahmioglu, Dale R Nyholt, Ronald Ching Wan Ma, Claudia Ha Ting Tam, Wing Hung Tam, CHARGE Consortium Hematology Working Group, Santhi K Ganesh, Frank Ja van Rooij, Samuel E Jones, Po-Ru Loh, Katherine S Ruth, Marcus A Tuke, Jessica Tyrrell, Andrew R Wood, Hanieh Yaghootkar, Denise M Scholtens, Lavinia Paternoster, Inga Prokopenko, Peter Kovacs, Mustafa Atalay, Sara M Willems, Kalliope Panoutsopoulou, Xu Wang, Lisbeth Carstensen, Frank Geller, Katharina E Schraut, Mario Murcia, Catharina Em van Beijsterveldt, Gonneke Willemsen, Emil V R Appel, Cilius E Fonvig, Caecilie Trier, Carla Mt Tiesler, Marie Standl, Zoltán Kutalik, Sílvia Bonas-Guarch, David M Hougaard, Friman Sánchez, David Torrents, Johannes Waage, Mads V Hollegaard, Hugoline G de Haan, Frits R Rosendaal, Carolina Medina-Gomez, Susan M Ring, Gibran Hemani, George McMahon, Neil R Robertson, Christopher J Groves, Claudia Langenberg, Jian'an Luan, Robert A Scott, Jing Hua Zhao, Frank D Mentch, Scott M MacKenzie, Rebecca M Reynolds, Early Growth Genetics (EGG) Consortium, William L Lowe Jr, Anke Tönjes, Michael Stumvoll, Virpi Lindi, Timo A Lakka, Cornelia M van Duijn, Wieland Kiess, Antje Körner, Thorkild Ia Sørensen, Harri Niinikoski, Katja Pahkala, Olli T Raitakari, Eleftheria Zeggini, George V Dedoussis, Yik-Ying Teo, Seang-Mei Saw, Mads Melbye, Harry Campbell, James F Wilson, Martine Vrijheid, Eco Jcn de Geus, Dorret I Boomsma, Haja N Kadarmideen, Jens-Christian Holm, Torben Hansen, Sylvain Sebert, Andrew T Hattersley, Lawrence J Beilin, John P Newnham, Craig E Pennell, Joachim Heinrich, Linda S Adair, Judith B Borja, Karen L Mohlke, Johan G Eriksson, Elisabeth E Widén, Mika Kähönen, Jorma S Viikari, Terho Lehtimäki, Peter Vollenweider, Klaus Bønnelykke, Hans Bisgaard, Dennis O Mook-Kanamori, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Charlotta Pisinger, Oluf Pedersen, Christine Power, Elina Hyppönen, Nicholas J Wareham, Hakon Hakonarson, Eleanor Davies, Brian R Walker, Vincent Wv Jaddoe, Marjo-Riitta Jarvelin, Struan Fa Grant, Allan A Vaag, Debbie A Lawlor, Timothy M Frayling, George Davey Smith, Andrew P Morris, Ken K Ong, Janine F Felix, Nicholas J Timpson, John Rb Perry, David M Evans, Mark I McCarthy, Rachel M Freathy
Abstract
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
Conflict of interest statement
One of the authors discloses competing financial interests: Krina Zondervan has a scientific collaboration with Bayer HealthCare Ltd. and Population Diagnostics Inc.
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Source: PubMed