TY - JOUR AB - Approximately 1.5 billion people worldwide are overweight oraffected by obesity, and are at risk of developing type 2 diabetes,cardiovascular disease and related metabolic and inflammatorydisturbances1,2. Although the mechanisms linking adiposity toassociated clinical conditions are poorly understood, recent studiessuggest that adiposity may influence DNA methylation3–6, a keyregulator of gene expression and molecular phenotype7. Here weuse epigenome-wide association to show that body mass index(BMI; a key measure of adiposity) is associated with widespreadchanges 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). Geneticassociation analyses demonstrate that the alterations in DNAmethylation are predominantly the consequence of adiposity,rather than the cause. We find that methylation loci are enrichedfor functional genomic features in multiple tissues (P<0.05), andshow that sentinel methylation markers identify gene expressionsignatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to6.1×10−35, n=1,785 samples). The methylation loci identify genesinvolved in lipid and lipoprotein metabolism, substrate transportand inflammatory pathways. Finally, we show that the disturbancesin DNA methylation predict future development of type 2 diabetes(relative risk per 1 standard deviation increase in methylation riskscore: 2.3 (2.07–2.56); P=1.1×10−54). Our results provide newinsights into the biologic pathways influenced by adiposity, and mayenable development of new strategies for prediction and preventionof type 2 diabetes and other adverse clinical consequences of obesity AU - Wahl,S AU - Drong,A AU - Lehne,B AU - Loh,M AU - Scott,WR AU - Kunze,S AU - Tsai,P-C AU - Ried,JS AU - Zhang,W AU - Yang,Y AU - Tan,S AU - Fiorito,G AU - Franke,L AU - Guarrera,S AU - Kasela,S AU - Kriebel,J AU - Richmond,RC AU - Adamo,M AU - Afzal,U AU - Ala-Korpela,M AU - Albetti,B AU - Ammerpohl,O AU - Apperley,JF AU - Beekman,M AU - Bertazzi,PA AU - Black,SL AU - Blancher,C AU - Bonder,M-J AU - Brosch,M AU - Carstensen-Kirberg,M AU - de,Craen AJM AU - de,Lusignan S AU - Dehghan,A AU - Elkalaawy,M AU - Fischer,K AU - Franco,OH AU - Gaunt,TR AU - Hampe,J AU - Hashemi,M AU - Isaacs,A AU - Jenkinson,A AU - Jha,S AU - Kato,N AU - Krogh,V AU - Laffan,M AU - Meisinger,C AU - Meitinger,T AU - Mok,ZY AU - Motta,V AU - Ng,HK AU - Nikolakopoulou,Z AU - Nteliopoulos,G AU - Panico,S AU - Pervjakova,N AU - Prokisch,H AU - Rathmann,W AU - Roden,M AU - Rota,F AU - Rozario,MA AU - Sandling,JK AU - Schafmayer,C AU - Schramm,K AU - Siebert,R AU - Slagboom,PE AU - Soininen,P AU - Stolk,L AU - Strauch,K AU - Tai,E-S AU - Tarantini,L AU - Thorand,B AU - Tigchelaar,EF AU - Tumino,R AU - Uitterlinden,AG AU - van,Duijn C AU - van,Meurs JBJ AU - Vineis,P AU - Wickremasinghe,AR AU - Wijmenga,C AU - Yang,T-P AU - Yuan,W AU - Zhernakova,A AU - Batterham,RL AU - Smith,GD AU - Deloukas,P AU - Heijmans,BT AU - Herder,C AU - Hofman,A AU - Lindgren,CM AU - Milani,L AU - van,der Harst P AU - Peters,A AU - Illig,T AU - Relton,CL AU - Waldenberger,M AU - Jaervelin,M-R AU - Bollati,V AU - Soong,R AU - Spector,TD AU - Scott,J AU - McCarthy,MI AU - Elliott,P AU - Bell,JT AU - Matullo,G AU - Gieger,C AU - Kooner,JS AU - Grallert,H AU - Chambers,JC DO - 10.1038/nature20784 EP - 81 PY - 2016/// SN - 0028-0836 SP - 81 TI - Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity T2 - Nature UR - http://dx.doi.org/10.1038/nature20784 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000396119500033&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202 UR - http://hdl.handle.net/10044/1/49547 VL - 541 ER -