Research Article: Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

Date Published: January 17, 2017

Publisher: Public Library of Science

Author(s): Michael M. Mendelson, Riccardo E. Marioni, Roby Joehanes, Chunyu Liu, Åsa K. Hedman, Stella Aslibekyan, Ellen W. Demerath, Weihua Guan, Degui Zhi, Chen Yao, Tianxiao Huan, Christine Willinger, Brian Chen, Paul Courchesne, Michael Multhaup, Marguerite R. Irvin, Ariella Cohain, Eric E. Schadt, Megan L. Grove, Jan Bressler, Kari North, Johan Sundström, Stefan Gustafsson, Sonia Shah, Allan F. McRae, Sarah E. Harris, Jude Gibson, Paul Redmond, Janie Corley, Lee Murphy, John M. Starr, Erica Kleinbrink, Leonard Lipovich, Peter M. Visscher, Naomi R. Wray, Ronald M. Krauss, Daniele Fallin, Andrew Feinberg, Devin M. Absher, Myriam Fornage, James S. Pankow, Lars Lind, Caroline Fox, Erik Ingelsson, Donna K. Arnett, Eric Boerwinkle, Liming Liang, Daniel Levy, Ian J. Deary, Cathryn Lewis

Abstract: BackgroundThe link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.Methods and FindingsWe conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination.ConclusionsWe present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.

Partial Text: Obesity is highly prevalent in developed nations [1] and contributes to a substantial burden of morbidity and mortality [2,3]. Despite advances in the understanding of genetic variants, lifestyle factors, and gene–environment interactions associated with obesity [4–7], much of the interindividual variation in body weight remains unexplained by measurable lifestyle and genetic factors. DNA methylation, one of the most frequent and well-characterized epigenetic modifications, reflects at the molecular level a wide range of environmental exposures and genetic influences [8]. By stabilizing chromatin structure and altering gene expression, DNA methylation has the potential to affect an individual’s susceptibility to obesity (see review in [9]). Further, changes in the methylation of DNA may occur secondarily to obesity and may consequently influence the development of adiposity-related diseases such as diabetes, dyslipidemia, hypertension, and cardiovascular disease. Large gaps in knowledge remain as to how human epigenetic modifications relate to obesity and its sequelae.

In this analysis of the association of BMI with differential methylation of blood-derived DNA, we provide robust evidence of a connection between replicable epigenetic signaling at 83 CpGs and BMI. We also demonstrate the correlation of BMI-related differential methylation with the altered expression of ten genes in whole blood that are overrepresented in lipid metabolism pathways. Among the 83 replicated BMI-related CpGs, one differentially methylated locus (cg11024682) at the lipid metabolism transcription factor SREBF1 demonstrated evidence of a causal effect on BMI; genetically predicted exposure to differential methylation and expression of SREBF1 was found to be associated with BMI and other adiposity traits, glycemic traits, dyslipidemia, and coronary artery disease. In contrast, we found that a substantial proportion (16 out of 83 [19%]) of the BMI-related differentially methylated CpGs identified in this EWAS are likely a consequence of BMI (i.e., downstream signals).



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