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, 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, 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
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Nature. 2016 Oct 13;538(7624):248-252. doi: 10.1038/nature19806. Epub 2016 Sep 28.
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.
出生体重（BW）已被证明受胎儿和母体因素的影响，在观察性研究中，它与包括2型糖尿病（T2D）和心血管疾病在内的成人代谢性疾病的未来风险可重复相关。这些生命历程关联通常归因于不良早期生活环境的影响。在此，我们对153781名个体的出生体重进行了多血统全基因组关联研究（GWAS）荟萃分析，确定了60个胎儿基因型与出生体重相关的基因座（P < 5×10）。总体而言，出生体重约15%的变异可通过胎儿遗传变异检测来解释。仅通过基因关联分析，我们发现出生体重与收缩压（R = -0.22，P = 5.5×10）、2型糖尿病（R = -0.27，P = 1.1×10）和冠状动脉疾病（R = -0.30，P = 6.5×10）之间存在强烈的负向遗传相关性。此外，利用大型队列数据集，我们证明遗传因素是出生体重与未来心脏代谢风险之间负协方差的主要贡献因素。通路分析表明，与出生体重相关区域内基因的蛋白质产物在包括胰岛素信号传导、葡萄糖稳态、糖原生物合成和染色质重塑等多种过程中富集。在已知的印记区域中与出生体重的关联也有富集（P = 1.9×10）。我们证明早期生长表型与成人心脏代谢疾病之间的生命历程关联部分是共享遗传效应的结果，并确定了这些因果遗传效应所介导的一些通路。
