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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, SimoneUNSPECIFIEDUNSPECIFIED
Drong, AlexanderUNSPECIFIEDUNSPECIFIED
Lehne, BenjaminUNSPECIFIEDUNSPECIFIED
Loh, MarieUNSPECIFIEDUNSPECIFIED
Scott, William R.UNSPECIFIEDUNSPECIFIED
Kunze, SonjaUNSPECIFIEDUNSPECIFIED
Tsai, Pei-ChienUNSPECIFIEDUNSPECIFIED
Ried, Janina S.UNSPECIFIEDUNSPECIFIED
Zhang, WeihuaUNSPECIFIEDUNSPECIFIED
Yang, YouwenUNSPECIFIEDUNSPECIFIED
Tan, SiliUNSPECIFIEDUNSPECIFIED
Fiorito, GiovanniUNSPECIFIEDUNSPECIFIED
Franke, LudeUNSPECIFIEDUNSPECIFIED
Guarrera, SimonettaUNSPECIFIEDUNSPECIFIED
Kasela, SilvaUNSPECIFIEDUNSPECIFIED
Kriebel, JenniferUNSPECIFIEDUNSPECIFIED
Richmond, Rebecca C.UNSPECIFIEDUNSPECIFIED
Adamo, MarcoUNSPECIFIEDUNSPECIFIED
Afzal, UzmaUNSPECIFIEDUNSPECIFIED
Ala-Korpela, MikaUNSPECIFIEDUNSPECIFIED
Albetti, BenedettaUNSPECIFIEDUNSPECIFIED
Ammerpohl, OleUNSPECIFIEDUNSPECIFIED
Apperley, Jane F.UNSPECIFIEDUNSPECIFIED
Beekman, MarianUNSPECIFIEDUNSPECIFIED
Bertazzi, Pier AlbertoUNSPECIFIEDUNSPECIFIED
Black, S. LucasUNSPECIFIEDUNSPECIFIED
Blancher, ChristineUNSPECIFIEDUNSPECIFIED
Bonder, Marc-JanUNSPECIFIEDUNSPECIFIED
Brosch, MarioUNSPECIFIEDUNSPECIFIED
Carstensen-Kirberg, MarenUNSPECIFIEDUNSPECIFIED
de Craen, Anton J. M.UNSPECIFIEDUNSPECIFIED
de Lusignan, SimonS.Lusignan@surrey.ac.ukUNSPECIFIED
Dehghan, AbbasUNSPECIFIEDUNSPECIFIED
Elkalaawy, MohamedUNSPECIFIEDUNSPECIFIED
Fischer, KristaUNSPECIFIEDUNSPECIFIED
Franco, Oscar H.UNSPECIFIEDUNSPECIFIED
Gaunt, Tom R.UNSPECIFIEDUNSPECIFIED
Hampe, JochenUNSPECIFIEDUNSPECIFIED
Hashemi, MajidUNSPECIFIEDUNSPECIFIED
Isaacs, AaronUNSPECIFIEDUNSPECIFIED
Jenkinson, AndrewUNSPECIFIEDUNSPECIFIED
Jha, SujeetUNSPECIFIEDUNSPECIFIED
Kato, NorihiroUNSPECIFIEDUNSPECIFIED
Krogh, VittorioUNSPECIFIEDUNSPECIFIED
Laffan, MichaelUNSPECIFIEDUNSPECIFIED
Meisinger, ChristaUNSPECIFIEDUNSPECIFIED
Meitinger, ThomasUNSPECIFIEDUNSPECIFIED
Mok, Zuan YuUNSPECIFIEDUNSPECIFIED
Motta, ValeriaUNSPECIFIEDUNSPECIFIED
Ng, Hong KiatUNSPECIFIEDUNSPECIFIED
Nikolakopoulou, ZacharoulaUNSPECIFIEDUNSPECIFIED
Nteliopoulos, GeorgiosUNSPECIFIEDUNSPECIFIED
Panico, SalvatoreUNSPECIFIEDUNSPECIFIED
Pervjakova, NataliaUNSPECIFIEDUNSPECIFIED
Prokisch, HolgerUNSPECIFIEDUNSPECIFIED
Rathmann, WolfgangUNSPECIFIEDUNSPECIFIED
Roden, MichaelUNSPECIFIEDUNSPECIFIED
Rota, FedericaUNSPECIFIEDUNSPECIFIED
Rozario, Michelle AnnUNSPECIFIEDUNSPECIFIED
Sandling, Johanna K.UNSPECIFIEDUNSPECIFIED
Schafmayer, ClemensUNSPECIFIEDUNSPECIFIED
Schramm, KatharinaUNSPECIFIEDUNSPECIFIED
Siebert, ReinerUNSPECIFIEDUNSPECIFIED
Slagboom, P. ElineUNSPECIFIEDUNSPECIFIED
Soininen, PasiUNSPECIFIEDUNSPECIFIED
Stolk, LisetteUNSPECIFIEDUNSPECIFIED
Strauch, KonstantinUNSPECIFIEDUNSPECIFIED
Tai, E-ShyongUNSPECIFIEDUNSPECIFIED
Tarantini, LetiziaUNSPECIFIEDUNSPECIFIED
Thorand, BarbaraUNSPECIFIEDUNSPECIFIED
Tigchelaar, Ettje F.UNSPECIFIEDUNSPECIFIED
Tumino, RosarioUNSPECIFIEDUNSPECIFIED
Uitterlinden, Andre G.UNSPECIFIEDUNSPECIFIED
van Duijn, CorneliaUNSPECIFIEDUNSPECIFIED
van Meurs, Joyce B. J.UNSPECIFIEDUNSPECIFIED
Vineis, PaoloUNSPECIFIEDUNSPECIFIED
Wickremasinghe, Ananda RajithaUNSPECIFIEDUNSPECIFIED
Wijmenga, CiscaUNSPECIFIEDUNSPECIFIED
Yang, Tsun-PoUNSPECIFIEDUNSPECIFIED
Yuan, WeiUNSPECIFIEDUNSPECIFIED
Zhernakova, AlexandraUNSPECIFIEDUNSPECIFIED
Batterham, Rachel L.UNSPECIFIEDUNSPECIFIED
Smith, George DaveyUNSPECIFIEDUNSPECIFIED
Deloukas, PanosUNSPECIFIEDUNSPECIFIED
Heijmans, Bastiaan T.UNSPECIFIEDUNSPECIFIED
Herder, ChristianUNSPECIFIEDUNSPECIFIED
Hofman, AlbertUNSPECIFIEDUNSPECIFIED
Lindgren, Cecilia M.UNSPECIFIEDUNSPECIFIED
Milani, LiliUNSPECIFIEDUNSPECIFIED
van der Harst, PimUNSPECIFIEDUNSPECIFIED
Peters, AnnetteUNSPECIFIEDUNSPECIFIED
Illig, ThomasUNSPECIFIEDUNSPECIFIED
Relton, Caroline L.UNSPECIFIEDUNSPECIFIED
Waldenberger, MelanieUNSPECIFIEDUNSPECIFIED
Järvelin, Marjo-RiittaUNSPECIFIEDUNSPECIFIED
Bollati, ValentinaUNSPECIFIEDUNSPECIFIED
Soong, RichieUNSPECIFIEDUNSPECIFIED
Spector, Tim D.UNSPECIFIEDUNSPECIFIED
Scott, JamesUNSPECIFIEDUNSPECIFIED
McCarthy, Mark I.UNSPECIFIEDUNSPECIFIED
Elliott, PaulUNSPECIFIEDUNSPECIFIED
Bell, Jordana T.UNSPECIFIEDUNSPECIFIED
Matullo, GiuseppeUNSPECIFIEDUNSPECIFIED
Gieger, ChristianUNSPECIFIEDUNSPECIFIED
Kooner, Jaspal S.UNSPECIFIEDUNSPECIFIED
Grallert, HaraldUNSPECIFIEDUNSPECIFIED
Chambers, John C.UNSPECIFIEDUNSPECIFIED
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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