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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
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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 × 10-7, 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.
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“Analyses of causal variants at GWAS loci focused originally on coding regions, but it has become clear that for many common diseases regulatory variation explains most of the risk burden [21].”
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Metadata
- Authors
- Wahl, S., Drong, A., Lehne, B., Loh, M., Scott, W. R., Kunze, S., Tsai, P.-C., Ried, J. S., Zhang, W., Yang, Y., Tan, S., Fiorito, G., Franke, L., Guarrera, S., Kasela, S., Kriebel, J., Richmond, R. C., Adamo, M., Afzal, U., Ala-Korpela, M., Albetti, B., Ammerpohl, O., Apperley, J. F., Beekman, M., Bertazzi, P. A., Black, S. L., Blancher, C., Bonder, M.-J., Brosch, M., Carstensen-Kirberg, M., de Craen, A. J. M., de Lusignan, S., Dehghan, A., Elkalaawy, M., Fischer, K., Franco, O. H., Gaunt, T. R., Hampe, J., Hashemi, M., Isaacs, A., Jenkinson, A., Jha, S., Kato, N., Krogh, V., Laffan, M., Meisinger, C., Meitinger, T., Mok, Z. Y., Motta, V., Ng, H. K., Nikolakopoulou, Z., Nteliopoulos, G., Panico, S., Pervjakova, N., Prokisch, H., Rathmann, W., Roden, M., Rota, F., Rozario, M. A., Sandling, J. K., Schafmayer, C., Schramm, K., Siebert, R., Slagboom, P. E., Soininen, P., Stolk, L., Strauch, K., Tai, E.-S., Tarantini, L., Thorand, B., Tigchelaar, E. F., Tumino, R., Uitterlinden, A. G., van Duijn, C., van Meurs, J. B. J., Vineis, P., Wickremasinghe, A. R., Wijmenga, C., Yang, T.-P., Yuan, W., Zhernakova, A., Batterham, R. L., Smith, G. D., Deloukas, P., Heijmans, B. T., Herder, C., Hofman, A., Lindgren, C. M., Milani, L., van der Harst, P., Peters, A., Illig, T., Relton, C. L., Waldenberger, M., Järvelin, M.-R., Bollati, V., Soong, R., Spector, T. D., Scott, J., McCarthy, M. I., Elliott, P., Bell, J. T., Matullo, G., Gieger, C., Kooner, J. S., Grallert, H., & Chambers, J. C.
- Affiliations
- Helmholtz Munich (DE)
- Centre for Human Genetics (GB)
- MRC Centre for Environment and Health (GB)
- Agency for Science, Technology and Research (SG)
- King's College London (GB)
- Ealing Hospital NHS Trust (GB)
- National University of Singapore (SG)
- Italian institute for Genomic Medicine (IT)
- University Medical Center Groningen (NL)
- University of Tartu (EE)
- University of Bristol (GB)
- University College Hospital (GB)
- University of Milan (IT)
- University Hospital Schleswig-Holstein (DE)
- Imperial College London (GB)
- Leiden University Medical Center (NL)
- Technische Universität Dresden (DE)
- Erasmus MC (NL)
- Max Healthcare (IN)
- National Center for Global Health and Medicine (JP)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Federico II University Hospital (IT)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Düsseldorf University Hospital (DE)
- Uppsala University (SE)
- Universität Ulm (DE)
- University of Eastern Finland (FI)
- University of Kelaniya (LK)
- Wellcome Sanger Institute (GB)
- Institute of Cancer Research (GB)
- Queen Mary University of London (GB)
- Broad Institute (US)
- Oulu University Hospital (FI)
- Imperial College Healthcare NHS Trust (GB)
- Corresponding author
- Kooner, Jaspal S.
- Grallert, Harald
- Chambers, John C.
- ORCID
- Loh, Marie
- Scott, William R.
- Kunze, Sonja
- Tsai, Pei-Chien
- Zhang, Weihua
- Yang, Youwen
- Fiorito, Giovanni
- Franke, Lude
- Guarrera, Simonetta
- Kasela, Silva
- Kriebel, Jennifer
- Richmond, Rebecca C.
- Afzal, Uzma
- Ammerpohl, Ole
- Apperley, Jane F.
- Beekman, Marian
- Bertazzi, Pier Alberto
- Black, S. Lucas
- Blancher, Christine
- Bonder, Marc-Jan
- Brosch, Mario
- Dehghan, Abbas
- Elkalaawy, Mohamed
- Fischer, Krista
- Franco, Oscar H.
- Gaunt, Tom R.
- Hampe, Jochen
- Isaacs, Aaron
- Jha, Sujeet
- Krogh, Vittorio
- Laffan, Michael
- Meisinger, Christa
- Meitinger, Thomas
- Nteliopoulos, Georgios
- Panico, Salvatore
- Prokisch, Holger
- Rathmann, Wolfgang
- Roden, Michael
- Rota, Federica
- Sandling, Johanna K.
- Schafmayer, Clemens
- Schramm, Katharina
- Siebert, Reiner
- Slagboom, P. Eline
- Strauch, Konstantin
- Tai, E-Shyong
- Tarantini, Letizia
- Thorand, Barbara
- Tumino, Rosario
- Vineis, Paolo
- Wijmenga, Cisca
- Yang, Tsun-Po
- Zhernakova, Alexandra
- Batterham, Rachel L.
- Smith, George Davey
- Deloukas, Panos
- Heijmans, Bastiaan T.
- Herder, Christian
- Lindgren, Cecilia M.
- Milani, Lili
- Peters, Annette
- Illig, Thomas
- Relton, Caroline L.
- 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.
- Venue
- Nature
- Published
- 2016-12-21
- Volume
- 541
- Issue
- 7635
- Pages
- 81-86
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5570525
- OpenAlex
- W2561301122
- Cited by
- 945
- References
- 39
- Citations by year
- 2026: 45 · 2025: 66 · 2024: 75 · 2023: 87 · 2022: 110 · 2021: 146 · 2020: 113 · 2019: 126 · 2018: 93 · 2017: 79 · 2016: 3
- FWCI
- 52.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- Explore Bristol Research (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Bristol Research (University of Bristol) (acceptedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- Wellcome Trust (084723)
- National Institute for Health and Care Research (NF-SI-0611-10136, NF-SI-0611-10275, NF-SI-0611-10099, RP-2015-06-005, RP-PG-0407-10371, NF-SI-0514-10027, ACF-2009-18-005)
- British Heart Foundation (PG/14/56/30976, RG/14/5/30893)
- European Commission (305280)
- University of Bristol
- German-Israeli Foundation for Scientific Research and Development
- Eesti Teadusagentuur
- Tartu Ülikool (SP1GVARENG)
- Directorate for Biological Sciences
- Medical Research Council (MR/L01341X/1, MR/K002414/1, MC_PC_15018, MR/N015355/1, MC_G0802523)
- Biotechnology and Biological Sciences Research Council (BB/I025263/1)
- Economic and Social Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- DNA methylation, body mass index, obesity, type 2 diabetes, adipose tissue, blood DNA methylation, methylation risk score, inflammation, gene expression signatures, epigenetic biomarkers
- MeSH terms
- Adipose Tissue, Blood, Diabetes Mellitus, Type 2, Europe, Female, Genetic Markers, Humans, India, Male, Obesity, Cohort Studies, Body Mass Index, DNA Methylation, Genetic Predisposition to Disease, Epigenesis, Genetic, White People, Asian People, Adiposity, Overweight, Genome-Wide Association Study, Epigenomics
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