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

Wahl, Simone, Drong, Alexander, Lehne, Benjamin, Loh, Marie, Scott, William R., Kunze, Sonja, Tsai, Pei-Chien, Ried, Janina S., Zhang, Weihua, Yang, Youwen , Tan, Sili, Fiorito, Giovanni, Franke, Lude, Guarrera, Simonetta, Kasela, Silva, Kriebel, Jennifer, Richmond, Rebecca C., Adamo, Marco, Afzal, Uzma, Ala-Korpela, Mika, Albetti, Benedetta, Ammerpohl, Ole, Apperley, Jane F., Beekman, Marian, Bertazzi, Pier Alberto, Black, S. Lucas, Blancher, Christine, Bonder, Marc-Jan, Brosch, Mario, Carstensen-Kirberg, Maren, de Craen, Anton J. M., de Lusignan, Simon, Dehghan, Abbas, Elkalaawy, Mohamed, Fischer, Krista, Franco, Oscar H., Gaunt, Tom R., Hampe, Jochen, Hashemi, Majid, Isaacs, Aaron, Jenkinson, Andrew, Jha, Sujeet, Kato, Norihiro, Krogh, Vittorio, Laffan, Michael, Meisinger, Christa, Meitinger, Thomas, Mok, Zuan Yu, Motta, Valeria, Ng, Hong Kiat, Nikolakopoulou, Zacharoula, Nteliopoulos, Georgios, Panico, Salvatore, Pervjakova, Natalia, Prokisch, Holger, Rathmann, Wolfgang, Roden, Michael, Rota, Federica, Rozario, Michelle Ann, Sandling, Johanna K., Schafmayer, Clemens, Schramm, Katharina, Siebert, Reiner, Slagboom, P. Eline, Soininen, Pasi, Stolk, Lisette, Strauch, Konstantin, Tai, E-Shyong, Tarantini, Letizia, Thorand, Barbara, Tigchelaar, Ettje F., Tumino, Rosario, Uitterlinden, Andre G., van Duijn, Cornelia, van Meurs, Joyce B. J., Vineis, Paolo, Wickremasinghe, Ananda Rajitha, Wijmenga, Cisca, Yang, Tsun-Po, Yuan, Wei, Zhernakova, Alexandra, Batterham, Rachel L., Smith, George Davey, Deloukas, Panos, Heijmans, Bastiaan T., Herder, Christian, Hofman, Albert, Lindgren, Cecilia M., Milani, Lili, van der Harst, Pim, Peters, Annette, Illig, Thomas, Relton, Caroline L., Waldenberger, Melanie, Järvelin, Marjo-Riitta, Bollati, Valentina, Soong, Richie, Spector, Tim D., Scott, James, McCarthy, Mark I., Elliott, Paul, Bell, Jordana T., Matullo, Giuseppe, Gieger, Christian, Kooner, Jaspal S., Grallert, Harald and Chambers, John C. (2016) Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity Nature, 541 (7635). pp. 81-86.

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Abstract

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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Wahl, Simone
Drong, Alexander
Lehne, Benjamin
Loh, Marie
Scott, William R.
Kunze, Sonja
Tsai, Pei-Chien
Ried, Janina S.
Zhang, Weihua
Yang, Youwen
Tan, Sili
Fiorito, Giovanni
Franke, Lude
Guarrera, Simonetta
Kasela, Silva
Kriebel, Jennifer
Richmond, Rebecca C.
Adamo, Marco
Afzal, Uzma
Ala-Korpela, Mika
Albetti, Benedetta
Ammerpohl, Ole
Apperley, Jane F.
Beekman, Marian
Bertazzi, Pier Alberto
Black, S. Lucas
Blancher, Christine
Bonder, Marc-Jan
Brosch, Mario
Carstensen-Kirberg, Maren
de Craen, Anton J. M.
de Lusignan, SimonS.Lusignan@surrey.ac.uk
Dehghan, Abbas
Elkalaawy, Mohamed
Fischer, Krista
Franco, Oscar H.
Gaunt, Tom R.
Hampe, Jochen
Hashemi, Majid
Isaacs, Aaron
Jenkinson, Andrew
Jha, Sujeet
Kato, Norihiro
Krogh, Vittorio
Laffan, Michael
Meisinger, Christa
Meitinger, Thomas
Mok, Zuan Yu
Motta, Valeria
Ng, Hong Kiat
Nikolakopoulou, Zacharoula
Nteliopoulos, Georgios
Panico, Salvatore
Pervjakova, Natalia
Prokisch, Holger
Rathmann, Wolfgang
Roden, Michael
Rota, Federica
Rozario, Michelle Ann
Sandling, Johanna K.
Schafmayer, Clemens
Schramm, Katharina
Siebert, Reiner
Slagboom, P. Eline
Soininen, Pasi
Stolk, Lisette
Strauch, Konstantin
Tai, E-Shyong
Tarantini, Letizia
Thorand, Barbara
Tigchelaar, Ettje F.
Tumino, Rosario
Uitterlinden, Andre G.
van Duijn, Cornelia
van Meurs, Joyce B. J.
Vineis, Paolo
Wickremasinghe, Ananda Rajitha
Wijmenga, Cisca
Yang, Tsun-Po
Yuan, Wei
Zhernakova, Alexandra
Batterham, Rachel L.
Smith, George Davey
Deloukas, Panos
Heijmans, Bastiaan T.
Herder, Christian
Hofman, Albert
Lindgren, Cecilia M.
Milani, Lili
van der Harst, Pim
Peters, Annette
Illig, Thomas
Relton, Caroline L.
Waldenberger, Melanie
Järvelin, Marjo-Riitta
Bollati, Valentina
Soong, Richie
Spector, Tim D.
Scott, James
McCarthy, Mark I.
Elliott, Paul
Bell, Jordana T.
Matullo, Giuseppe
Gieger, Christian
Kooner, Jaspal S.
Grallert, Harald
Chambers, John C.
Date : 21 December 2016
Identification Number : 10.1038/nature20784
Copyright Disclaimer : © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved
Depositing User : Jane Hindle
Date Deposited : 22 Sep 2017 12:49
Last Modified : 10 Jan 2018 15:02
URI: http://epubs.surrey.ac.uk/id/eprint/842382

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