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

Authors:
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

Nature 2017 01 21;541(7635):81-86. Epub 2016 Dec 21.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.

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. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. 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, range P = 9.2 × 10 to 6.0 × 10; 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, range P = 5.5 × 10 to 6.1 × 10, 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). 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.

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http://dx.doi.org/10.1038/nature20784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570525PMC
January 2017
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