Journal Article

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

Tarantini, Letizia, Laffan, Michael, Rota, Federica, Bonder, Marc-Jan, Bertazzi, Pier Alberto, Kasela, Silva, Stolk, Lisette, Tan, Sili, Schramm, Katharina, Kato, Norihiro, Kriebel, Jennifer, Gaunt, Tom R., Lindgren, Cecilia M., Siebert, Reiner, Järvelin, Marjo-Riitta, Elliott, Paul, Waldenberger, Melanie, Hampe, Jochen, Afzal, Uzma, Soininen, Pasi, Peters, Annette, Thorand, Barbara, Smith, George Davey, Uitterlinden, Andre G., Wickremasinghe, Ananda Rajitha, Adamo, Marco, Beekman, Marian, Lehne, Benjamin, Krogh, Vittorio, Panico, Salvatore, Wijmenga, Cisca, van der Harst, Pim, Tsai, Pei-Chien, Matullo, Giuseppe, Dehghan, Abbas, Heijmans, Bastiaan T., Gieger, Christian, Yuan, Wei, Ala-Korpela, Mika, Black, S. Lucas, Hashemi, Majid, Guarrera, Simonetta, Spector, Tim D., Pervjakova, Natalia, Meisinger, Christa, Motta, Valeria, Richmond, Rebecca C., Franco, Oscar H., Kooner, Jaspal S., Yang, Youwen, Jha, Sujeet, Drong, Alexander, Chambers, John C., Herder, Christian, Kunze, Sonja, Roden, Michael, Mok, Zuan Yu, Vineis, Paolo, Blancher, Christine, Brosch, Mario, Carstensen-Kirberg, Maren, Sandling, Johanna K., R

2017

Overview

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. Body fat and diabetes risk 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 disturbances 1 , 2 . Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation 3 , 4 , 5 , 6 , a key regulator of gene expression and molecular phenotype 7 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/177 / 692/699/2743/393 / Adipose Tissue - metabolism / Adiposity - genetics / Asian people / Asian People - genetics / Asthma / Blood - metabolism / Body Mass Index / Cardiovascular disease / Cardiovascular diseases / Cohort Studies / Deoxyribonucleic acid / Diabetes / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - genetics / DNA / DNA methylation / DNA Methylation - genetics / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Epigenomics / Europe - ethnology / Female / Gene expression / Gene loci / Genetic aspects / Genetic Markers / Genetic Predisposition to Disease / Genome-wide association studies / Genome-Wide Association Study / Health aspects / Humanities and Social Sciences / Humans / India - ethnology / letter / Male / Metabolism / multidisciplinary / Neutrophils / Obesity / Obesity - blood / Obesity - complications / Obesity - genetics / Overweight - blood / Overweight - complications / Overweight - genetics / Population / Science / Studies / White People - genetics