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 Lyytikaïnen, Diana L. Cousminer, Ying Wu, Elisabeth ThieringCarol 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 C W Ma, Claudia H T Tam, Wing Hung Tam, Santhi K. Ganesh, Frank J A 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 E M Van Beijsterveldt, Gonneke Willemsen, Emil V R Appel, Cilius E. Fonvig, Caecilie Trier, Carla M T Tiesler, Marie Standl, Zoltán Kutalik, Sílvia Bonàs-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, William L. Lowe, Anke Tönjes, Michael Stumvoll, Virpi Lindi, Timo A. Lakka, Cornelia M. Van Duijn, Wieland Kiess, Antje Körner, Thorkild I A 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 J C N 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 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 W V Jaddoe, Marjo Riitta Järvelin, Struan F A 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 R B Perry, David M. Evans, Mark I. McCarthy, Rachel M. Freathy

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Abstract

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide
association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P <5x10-8). Overall, ˜15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg=-0.22, P =5.5x10-13),
T2D (rg=-0.27, P =1.1x10-6) and coronary artery disease (rg=-0.30, P =6.5x10-9) and, in large cohort data sets, 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=1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated.
Original languageEnglish
Pages (from-to)248-252
Number of pages5
JournalNature
Volume538
Issue number7624
DOIs
Publication statusPublished - 2016

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