Nature · 2016

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

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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, Lyytikäinen Leo-Pekka, Cousminer Diana L, Wu Ying, Thiering Elisabeth, Wang Carol A, Have Christian T, Hottenga Jouke-Jan, Vilor-Tejedor Natalia, Joshi Peter K, Boh Eileen Tai Hui, Ntalla Ioanna, Pitkänen 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 Ching Wan, Tam Claudia Ha Ting, Tam Wing Hung, CHARGE Consortium Hematology Working Group, Ganesh Santhi K, van Rooij Frank Ja, 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 Em, Willemsen Gonneke, Appel Emil V R, Fonvig Cilius E, Trier Caecilie, Tiesler Carla Mt, Standl Marie, Kutalik Zoltán, Bonas-Guarch Sílvia, Hougaard David M, Sánchez 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, Tönjes Anke, Stumvoll Michael, Lindi Virpi, Lakka Timo A, van Duijn Cornelia M, Kiess Wieland, Körner Antje, Sørensen Thorkild Ia, Niinikoski Harri, Pahkala Katja, Raitakari Olli T, Zeggini Eleftheria, Dedoussis George V, Teo Yik-Ying, Saw Seang-Mei, Melbye Mads, Campbell Harry, Wilson James F, Vrijheid Martine, de Geus Eco Jcn, 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, Widén Elisabeth E, Kähönen Mika, Viikari Jorma S, Lehtimäki Terho, Vollenweider Peter, Bønnelykke Klaus, Bisgaard Hans, Mook-Kanamori Dennis O, Hofman Albert, Rivadeneira Fernando, Uitterlinden André G, Pisinger Charlotta, Pedersen Oluf, Power Christine, Hyppönen Elina, Wareham Nicholas J, Hakonarson Hakon, Davies Eleanor, Walker Brian R, Jaddoe Vincent Wv, Jarvelin Marjo-Riitta, Grant Struan Fa, Vaag Allan A, Lawlor Debbie A, Frayling Timothy M, Davey Smith George, Morris Andrew P, Ong Ken K, Felix Janine F, Timpson Nicholas J, Perry John Rb, Evans David M, McCarthy Mark I, Freathy Rachel M

Аннотация

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.

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

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