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© 2016 Macmillan Publishers Limited, part of Springer Nature.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 disease1. These lifecourse 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.
Author(s): Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J, Feenstra B, Van Zuydam NR, Gaulton KJ, Grarup N, Bradfield JP, Strachan DP, Li-Gao R, Ahluwalia TS, Kreiner E, Rueedi R, Lyytikainen L-P, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Hottenga J-J, Vilor-Tejedor N, Joshi PK, Boh ETH, Ntalla I, Pitkanen N, Mahajan A, Van Leeuwen EM, Joro R, Lagou V, Nodzenski M, Diver LA, Zondervan KT, Bustamante M, Marques-Vidal P, Mercader JM, Bennett AJ, Rahmioglu N, Nyholt DR, Ma RCW, Tam CHT, Tam WH, Ganesh SK, Van Rooij FJA, Jones SE, Loh P-R, Ruth KS, Tuke MA, Tyrrell J, Wood AR, Yaghootkar H, Scholtens DM, Paternoster L, Prokopenko I, Kovacs P, Atalay M, Willems SM, Panoutsopoulou K, Wang X, Carstensen L, Geller F, Schraut KE, Murcia M, Van Beijsterveldt CEM, Willemsen G, Appel EVR, Fonvig CE, Trier C, Tiesler CMT, Standl M, Kutalik Z, Bonas-Guarch S, Hougaard DM, Sanchez F, Torrents D, Waage J, Hollegaard MV, De Haan HG, Rosendaal FR, Medina-Gomez C, Ring SM, Hemani G, McMahon G, Robertson NR, Groves CJ, Langenberg C, Luan J, Scott RA, Zhao JH, Mentch FD, MacKenzie SM, Reynolds RM, Lowe WL, Tonjes A, Stumvoll M, Lindi V, Lakka TA, Van Duijn CM, Kiess W, Korner A, Sorensen TIA, Niinikoski H, Pahkala K, Raitakari OT, Zeggini E, Dedoussis GV, Teo Y-Y, Saw S-M, Melbye M, Campbell H, Wilson JF, Vrijheid M, De Geus EJCN, Boomsma DI, Kadarmideen HN, Holm J-C, Hansen T, Sebert S, Hattersley AT, Beilin LJ, Newnham JP, Pennell CE, Heinrich J, Adair LS, Borja JB, Mohlke KL, Eriksson JG, Widen E, Kahonen M, Viikari JS, Lehtimaki T, Vollenweider P, Bonnelykke K, Bisgaard H, Mook-Kanamori DO, Hofman A, Rivadeneira F, Uitterlinden AG, Pisinger C, Pedersen O, Power C, Hypponen E, Wareham NJ, Hakonarson H, Davies E, Walker BR, Jaddoe VWV, Jarvelin M-R, Grant SFA, Vaag AA, Lawlor DA, Frayling TM, Smith GD, Morris AP, Ong KK, Felix JF, Timpson NJ, Perry JRB, Evans DM, McCarthy MI, Freathy RM
Publication type: Article
Publication status: Published
Print publication date: 13/10/2016
Online publication date: 28/09/2016
Acceptance date: 02/09/2016
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Publishing Group
PubMed id: 27680694
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