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 disturbances(1,2). Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation(3-6), 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 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 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 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 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 x 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.
Original language | English |
---|---|
Pages (from-to) | 81-86 |
Number of pages | 6 |
Journal | Nature |
Volume | 541 |
Issue number | 81 |
DOIs | |
Publication status | Published - 5-Jan-2017 |
Keywords
- DNA METHYLATION
- MENDELIAN RANDOMIZATION
- BARIATRIC SURGERY
- DISEASE
- OBESITY
- GLUCOSE
- HUMANS
- HEALTH
- TRENDS
- TISSUE
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Epigenome-wide association study of body mass index, and the adverse
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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. / Wahl, Simone; Drong, Alexander W; 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; Jaervelin, 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.
In: Nature, Vol. 541, No. 81, 05.01.2017, p. 81-86.Research output: Contribution to journal › Letter › Academic › peer-review
TY - JOUR
T1 - Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
AU - Wahl, Simone
AU - Drong, Alexander W
AU - Lehne, Benjamin
AU - Loh, Marie
AU - Scott, William R
AU - Kunze, Sonja
AU - Tsai, Pei-Chien
AU - Ried, Janina S.
AU - Zhang, Weihua
AU - Yang, Youwen
AU - Tan, Sili
AU - Fiorito, Giovanni
AU - Franke, Lude
AU - Guarrera, Simonetta
AU - Kasela, Silva
AU - Kriebel, Jennifer
AU - Richmond, Rebecca C
AU - Adamo, Marco
AU - Afzal, Uzma
AU - Ala-Korpela, Mika
AU - Albetti, Benedetta
AU - Ammerpohl, Ole
AU - Apperley, Jane F.
AU - Beekman, Marian
AU - Bertazzi, Pier Alberto
AU - Black, S. Lucas
AU - Blancher, Christine
AU - Bonder, Marc-Jan
AU - Brosch, Mario
AU - Carstensen-Kirberg, Maren
AU - De Craen, Anton J. M.
AU - de Lusignan, Simon
AU - Dehghan, Abbas
AU - Elkalaawy, Mohamed
AU - Fischer, Krista
AU - Franco, Oscar H.
AU - Gaunt, Tom R.
AU - Hampe, Jochen
AU - Hashemi, Majid
AU - Isaacs, Aaron
AU - Jenkinson, Andrew
AU - Jha, Sujeet
AU - Kato, Norihiro
AU - Krogh, Vittorio
AU - Laffan, Michael
AU - Meisinger, Christa
AU - Meitinger, Thomas
AU - Mok, Zuan Yu
AU - Motta, Valeria
AU - Ng, Hong Kiat
AU - Nikolakopoulou, Zacharoula
AU - Nteliopoulos, Georgios
AU - Panico, Salvatore
AU - Pervjakova, Natalia
AU - Prokisch, Holger
AU - Rathmann, Wolfgang
AU - Roden, Michael
AU - Rota, Federica
AU - Rozario, Michelle Ann
AU - Sandling, Johanna K.
AU - Schafmayer, Clemens
AU - Schramm, Katharina
AU - Siebert, Reiner
AU - Slagboom, P. Eline
AU - Soininen, Pasi
AU - Stolk, Lisette
AU - Strauch, Konstantin
AU - Tai, E. Shyong
AU - Tarantini, Letizia
AU - Thorand, Barbara
AU - Tigchelaar, Ettje F.
AU - Tumino, Rosario
AU - Uitterlinden, Andre G.
AU - Van Duijn, Cornelia
AU - van Meurs, Joyce B. J.
AU - Vineis, Paolo
AU - Wickremasinghe, Ananda Rajitha
AU - Wijmenga, Cisca
AU - Yang, Tsun-Po
AU - Yuan, Wei
AU - Zhernakova, Alexandra
AU - Batterham, Rachel L.
AU - Smith, George Davey
AU - Deloukas, Panos
AU - Heijmans, Bastiaan T.
AU - Herder, Christian
AU - Hofman, Albert
AU - Lindgren, Cecilia M.
AU - Milani, Lili
AU - van der Harst, Pim
AU - Peters, Annette
AU - Illig, Thomas
AU - Relton, Caroline L
AU - Waldenberger, Melanie
AU - Jaervelin, Marjo-Riitta
AU - Bollati, Valentina
AU - Soong, Richie
AU - Spector, Tim D.
AU - Scott, James
AU - McCarthy, Mark I.
AU - Elliott, Paul
AU - Bell, Jordana T
AU - Matullo, Giuseppe
AU - Gieger, Christian
AU - Kooner, Jaspal S.
AU - Grallert, Harald
AU - Chambers, John C.
PY - 2017/1/5
Y1 - 2017/1/5
N2 - 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(3-6), 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 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 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 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 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 x 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.
AB - 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(3-6), 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 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 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 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 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 x 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.
KW - DNA METHYLATION
KW - MENDELIAN RANDOMIZATION
KW - BARIATRIC SURGERY
KW - DISEASE
KW - OBESITY
KW - GLUCOSE
KW - HUMANS
KW - HEALTH
KW - TRENDS
KW - TISSUE
U2 - 10.1038/nature20784
DO - 10.1038/nature20784
M3 - Letter
C2 - 28002404
VL - 541
SP - 81
EP - 86
JO - Nature
JF - Nature
SN - 0028-0836
IS - 81
ER -