Genome-Wide Associations for Birth Weight and Correlations with Adult Disease

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Citation

Horikoshi, Momoko; Beaumont, Robin N.; Day, Felix R.; Warrington, Nicole M.; Kooijman, Marjolein N.; Fernandez-Tajes, Juan; Feenstra, Bjarke; van Zuydam, Natalie R.; Gaulton, Kyle J.; & Grarup, Niels, et al. (2016). Genome-Wide Associations for Birth Weight and Correlations with Adult Disease. Nature, 538(7624), 248-252. PMCID: PMC5164934

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 x 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 x 10-13), T2D (Rg = -0.27, P = 1.1 x 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 x 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 x 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.

URL

http://dx.doi.org/10.1038/nature19806

Reference Type

Journal Article

Year Published

2016

Journal Title

Nature

Author(s)

Horikoshi, Momoko
Beaumont, Robin N.
Day, Felix R.
Warrington, Nicole M.
Kooijman, Marjolein N.
Fernandez-Tajes, Juan
Feenstra, Bjarke
van Zuydam, Natalie R.
Gaulton, Kyle J.
Grarup, Niels
Bradfield, Jonathan P.
Strachan, David P.
Li-Gao, Ruifang
Ahluwalia, Tarunveer S.
Kreiner, Eskil
Rueedi, Rico
Lyytikainen, Leo-Pekka
Cousminer, Diana L.
Wu, Ying
Thiering, Elisabeth
Wang, Carol A.
Have, Christian Theil
Hottenga, Jouke-Jan
Vilor-Tejedor, Natalia
Joshi, Peter K.
Boh, Eileen Tai Hui
Ntalla, Ioanna
Pitkanen, Niina
Mahajan, Anubha
van Leeuwen, Elisabeth M.
Joro, Raimo
Lagou, Vasiliki
Nodzenski, Michael
Diver, Louise A.
Zondervan, Krina T.
Bustamante, Mariona
Marques-Vidal, Pedro
Mercader, Josep M.
Bennett, Amanda J.
Rahmioglu, Nilufer
Nyholt, Dale R.
Ma, Ronald C. W.
Tam, Claudia H. T.
Tam, Wing Hung
CHARGE Consortium Hematology Working Group,
Ganesh, Santhi K.
van Rooij, Frank J. A.
Jones, Samuel E.
Loh, Po-Ru
Ruth, Katherine S.
Tuke, Marcus A.
Tyrrell, Jessica
Wood, Andrew R.
Yaghootkar, Hanieh
Scholtens, Denise M.
Paternoster, Lavinia
Prokopenko, Inga
Kovacs, Peter
Atalay, Mustafa
Willems, Sara M.
Panoutsopoulou, Kalliope
Wang, Xu
Carstensen, Lisbeth
Geller, Frank
Schraut, Katharina E.
Murcia, Mario
van Beijsterveldt, Catharina E. M.
Willemsen, Gonneke
Appel, Emil V. R.
Fonvig, Cilius E.
Trier, Caecilie
Tiesler, Carla M. T.
Standl, Marie
Kutalik, Zoltan
Bonas-Guarch, Silvia
Hougaard, David M.
Sanchez, Friman
Torrents, David
Waage, Johannes
Hollegaard, Mads V.
de Haan, Hugoline G.
Rosendaal, Frits R.
Medina-Gomez, Carolina
Ring, Susan M.
Hemani, Gibran
McMahon, George
Robertson, Neil R.
Groves, Christopher J.
Langenberg, Claudia
Luan, Jian'an
Scott, Robert A.
Zhao, Jing Hua
Mentch, Frank D.
MacKenzie, Scott M.
Reynolds, Rebecca M.
Early Growth Genetics (EGG) Consortium,
Lowe, William L.
Tonjes, Anke
Stumvoll, Michael
Lindi, Virpi
Lakka, Timo A.
van Duijn, Cornelia M.
Kiess, Wieland
Korner, Antje
Sorensen, Thorkild I. A.
Niinikoski, Harri
Pahkala, Katja
Raitakari, Olli T.
Zeggini, Eleftheria
Dedoussis, George
Teo, Yik Ying
Saw, Seang-Mei
Melbye, Mads
Campbell, Harry
Wilson, James F.
Vrijheid, Martine
de Geus, Eco J. C.
Boomsma, Dorret I.
Kadarmideen, Haja N.
Holm, Jens-Christian
Hansen, Torben
Sebert, Sylvain
Hattersley, Andrew T.
Beilin, Lawrence J.
Newnham, John P.
Pennell, Craig E.
Heinrich, Joachim
Adair, Linda S.
Borja, Judith B.
Mohlke, Karen L.
Eriksson, Johan G.
Widen, Elisabeth
Kahonen, Mika
Viikari, Jorma S.
Lehtimaki, Terho
Vollenweider, Peter
Bonnelykke, Klaus
Bisgaard, Hans
Mook-Kanamori, Dennis O.
Hofman, Albert
Rivadeneira, Fernando
Uitterlinden, Andre G.
Pisinger, Charlotta
Pedersen, Oluf
Power, Chris
Hypponen, Elina
Wareham, Nicholas J.
Hakonarson, Hakon
Davies, Eleanor
Walker, Brian R.
Jaddoe, Vincent W. V.
Jarvelin, Marjo-Riitta
Grant, Struan F. A.
Vaag, Allan A.
Lawlor, Debbie A.
Frayling, Timothy M.
Smith, George Davey
Morris, Andrew P.
Ong, Ken K.
Felix, Janine F.
Timpson, Nicholas J.
Perry, John R. B.
Evans, David M.
McCarthy, Mark I.
Freathy, Rachel M.

PMCID

PMC5164934

ORCiD

Adair - 0000-0002-3670-8073