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. 2017 Jan 17;14(1):e1002215.
doi: 10.1371/journal.pmed.1002215. eCollection 2017 Jan.

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

Michael M Mendelson  1   2   3   4 , Riccardo E Marioni  5   6   7 , Roby Joehanes  1   4   8 , Chunyu Liu  1   4   9 , Åsa K Hedman  10 , Stella Aslibekyan  11 , Ellen W Demerath  12 , Weihua Guan  13 , Degui Zhi  14 , Chen Yao  1   4 , Tianxiao Huan  1   4 , Christine Willinger  1   4 , Brian Chen  4 , Paul Courchesne  1   4 , Michael Multhaup  15 , Marguerite R Irvin  11 , Ariella Cohain  16 , Eric E Schadt  16 , Megan L Grove  17 , Jan Bressler  17 , Kari North  18 , Johan Sundström  19 , Stefan Gustafsson  10 , Sonia Shah  7   20 , Allan F McRae  7   20 , Sarah E Harris  5   6 , Jude Gibson  21 , Paul Redmond  22 , Janie Corley  22 , Lee Murphy  21 , John M Starr  5   23 , Erica Kleinbrink  24 , Leonard Lipovich  24 , Peter M Visscher  5   7   20 , Naomi R Wray  7   20 , Ronald M Krauss  25 , Daniele Fallin  15 , Andrew Feinberg  15 , Devin M Absher  26 , Myriam Fornage  17   27 , James S Pankow  12 , Lars Lind  19 , Caroline Fox  1   4 , Erik Ingelsson  10   28 , Donna K Arnett  29 , Eric Boerwinkle  17   30 , Liming Liang  31 , Daniel Levy  1   4 , Ian J Deary  5   22
Affiliations

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

Michael M Mendelson et al. PLoS Med. .

Abstract

Background: The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.

Methods and findings: We 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.

Conclusions: We 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.

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Conflict of interest statement

JS is an advisory board member for Itrim. CF is now an employee of Merck, but was not an employee when the work was conducted. EI is a scientific advisor and consultant for Precision Wellness, Inc. and scientific advisor for Cellink for work unrelated to this paper. IJD has research grants from Age UK and the UK Medical Research Council.

Figures

Fig 1
Fig 1. Series of analyses conducted for the epigenome-wide association study of body mass index.
ARIC, Atherosclerosis Risk in Communities; BMI, body mass index; DHS, DNase I hypersensitive site; FHS, Framingham Heart Study; GO, Gene Ontology; GOLDN, Genetics of Lipid Lowering Drugs and Diet Network; GWAS, genome-wide association study; LBC, Lothian Birth Cohorts; MR, Mendelian randomization; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; TSS, transcription start site.
Fig 2
Fig 2. Histogram of the proportion of obese individuals (BMI ≥ 30 kg/m2) in the PIVUS cohort across deciles of the additive weighted composite methylation measure of the 77 nonredundant replicated CpGs (|r| < 0.7) from the BMI epigenome-wide association study.
BMI, body mass index; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors.
Fig 3
Fig 3. Annotated genes of replicated differentially methylated CpGs identified in the BMI epigenome-wide association study.
Genes are grouped by association with gene expression, association of gene expression with BMI, and Mendelian randomization analyses for causal support. Duplicate gene names within the same group are not shown. Figure does not include 18 intergenic CpGs without a gene annotation. BMI, body mass index; EWAS, epigenome-wide association study.
See this image and copyright information in PMC

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