Genome-wide associations for birth weight and correlations with adult disease.

Authors:
Dr Anubha Mahajan, PhD
Dr Anubha Mahajan, PhD
Wellcome Trust Centre for Human Genetics, University of Oxford
UK
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 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 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 William L Lowe 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

Nature 2016 10 28;538(7624):248-252. Epub 2016 Sep 28.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK.

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). 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 (R = -0.22, P = 5.5 × 10), T2D (R = -0.27, P = 1.1 × 10) and coronary artery disease (R = -0.30, P = 6.5 × 10). 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). 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.

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http://dx.doi.org/10.1038/nature19806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164934PMC
October 2016
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