Author: ["Simone Wahl","Alexander Drong","Benjamin Lehne","Marie Loh","William R. Scott","Sonja Kunze","Pei-Chien Tsai","Janina S. Ried","Weihua Zhang","Youwen Yang","Sili Tan","Giovanni Fiorito","Lude Franke","Simonetta Guarrera","Silva Kasela","Jennifer Kriebel","Rebecca C. Richmond","Marco Adamo","Uzma Afzal","Mika Ala-Korpela","Benedetta Albetti","Ole Ammerpohl","Jane F. Apperley","Marian Beekman","Pier Alberto Bertazzi","S. Lucas Black","Christine Blancher","Marc-Jan Bonder","Mario Brosch","Maren Carstensen-Kirberg","Anton J. M. de Craen","Simon de Lusignan","Abbas Dehghan","Mohamed Elkalaawy","Krista Fischer","Oscar H. Franco","Tom R. Gaunt","Jochen Hampe","Majid Hashemi","Aaron Isaacs","Andrew Jenkinson","Sujeet Jha","Norihiro Kato","Vittorio Krogh","Michael Laffan","Christa Meisinger","Thomas Meitinger","Zuan Yu Mok","Valeria Motta","Hong Kiat Ng","Zacharoula Nikolakopoulou","Georgios Nteliopoulos","Salvatore Panico","Natalia Pervjakova","Holger Prokisch","Wolfgang Rathmann","Michael Roden","Federica Rota","Michelle Ann Rozario","Johanna K. Sandling","Clemens Schafmayer","Katharina Schramm","Reiner Siebert","P. Eline Slagboom","Pasi Soininen","Lisette Stolk","Konstantin Strauch","E-Shyong Tai","Letizia Tarantini","Barbara Thorand","Ettje F. Tigchelaar","Rosario Tumino","Andre G. Uitterlinden","Cornelia van Duijn","Joyce B. J. van Meurs","Paolo Vineis","Ananda Rajitha Wickremasinghe","Cisca Wijmenga","Tsun-Po Yang","Wei Yuan","Alexandra Zhernakova","Rachel L. Batterham","George Davey Smith","Panos Deloukas","Bastiaan T. Heijmans","Christian Herder","Albert Hofman","Cecilia M. Lindgren","Lili Milani","Pim van der Harst","Annette Peters","Thomas Illig","Caroline L. Relton","Melanie Waldenberger","Marjo-Riitta Järvelin","Valentina Bollati","Richie Soong","Tim D. Spector","James Scott","Mark I. McCarthy","Paul Elliott","Jordana T. Bell","Giuseppe Matullo","Christian Gieger","Jaspal S. Kooner","Harald Grallert","John C. Chambers"]
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Abstract
A large-scale epigenome-wide association study identifies changes in DNA methylation associated with body mass index in blood and adipose tissue, and correlates DNA methylation sites with high risk of incident type 2 diabetes. Obesity is a major risk factor for type 2 diabetes and related metabolic disorders. Genetic association studies have identified genomic loci associated with obesity, and recent studies have also suggested associations with DNA methylation. These authors report an epigenome-wide association study for body mass index (BMI), identifying an association with DNA methylation at 187 loci in blood and adipose tissue. They find that these methylation changes are secondary to adiposity and are also associated with an increased risk of developing type 2 diabetes, independent of conventional risk factors. Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances1,2. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation3,4,5,6, a key regulator of gene expression and molecular phenotype7. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10−7, range P = 9.2 × 10−8 to 6.0 × 10−46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to 6.1 × 10−35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07–2.56); P = 1.1 × 10−54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.