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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Univ Alexandria, Med Res Inst, Clin & Expt Surg Dept, Hadara, Alexandria 21561, Egypt..
Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England..
Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Inst Hlth Sci, POB 5000, FI-90014 Oulu, Finland.;Translat Lab Genet Med TLGM, Agcy Sci, Technol & Res ASTAR, 8A Biomed Grove, Singapore 138648, Singapore..
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2017 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 541, no 7635, 81-+ p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 541, no 7635, 81-+ p.
National Category
Family Medicine Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-319140DOI: 10.1038/nature20784ISI: 000396119500033PubMedID: 28002404OAI: oai:DiVA.org:uu-319140DiVA: diva2:1086250
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2017-03-31Bibliographically approved

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