Dataset Information

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

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.

SUBMITTER: Mendelson MM

PROVIDER: S-EPMC5240936 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Mendelson Michael M MM Marioni Riccardo E RE Joehanes Roby R Liu Chunyu C Hedman Åsa K ÅK Aslibekyan Stella S Demerath Ellen W EW Guan Weihua W Zhi Degui D Yao Chen C Huan Tianxiao T Willinger Christine C Chen Brian B Courchesne Paul P Multhaup Michael M Irvin Marguerite R MR Cohain Ariella A Schadt Eric E EE Grove Megan L ML Bressler Jan J North Kari K Sundström Johan J Gustafsson Stefan S Shah Sonia S McRae Allan F AF Harris Sarah E SE Gibson Jude J Redmond Paul P Corley Janie J Murphy Lee L Starr John M JM Kleinbrink Erica E Lipovich Leonard L Visscher Peter M PM Wray Naomi R NR Krauss Ronald M RM Fallin Daniele D Feinberg Andrew A Absher Devin M DM Fornage Myriam M Pankow James S JS Lind Lars L Fox Caroline C Ingelsson Erik E Arnett Donna K DK Boerwinkle Eric E Liang Liming L Levy Daniel D Deary Ian J IJ

PLoS medicine 20170117 1

<h4>Background</h4>The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.<h4>Methods and findings</h4>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 ...[more]

PMID: 28095459

Similar Datasets

Project description:ImportanceHigher body mass index (BMI) is a risk factor for cardiometabolic disease; however, the underlying causal associations remain unclear.ObjectivesTo use UK Biobank data to report causal estimates of the association between BMI and cardiometabolic disease outcomes and traits, such as pulse rate, using mendelian randomization.Design, setting, and participantsCross-sectional baseline data from a population-based cohort study including 119 859 UK Biobank participants with complete phenotypic (medical and sociodemographic) and genetic data. Participants attended 1 of 22 assessment centers across the United Kingdom between 2006 and 2010. The present study was conducted from May 1 to July 11, 2016.Main outcomes and measuresPrevalence of hypertension, coronary heart disease, and type 2 diabetes were determined at assessment, based on self-report. Blood pressure was measured clinically. Participants self-reported sociodemographic information pertaining to relevant confounders. A polygenic risk score comprising 93 single-nucleotide polymorphisms associated with BMI from previous genome-wide association studies was constructed, and the genetic risk score was applied to derive causal estimates using a mendelian randomization approach.ResultsOf the 119 859 individuals included in the study, 56 816 (47.4%) were men; mean (SD) age was 56.87 (7.93) years. Mendelian randomization analysis showed significant positive associations between genetically instrumented higher BMI and risk of hypertension (odds ratio [OR] per 1-SD higher BMI, 1.64; 95% CI, 1.48-1.83; P = 1.1 × 10-19), coronary heart disease (OR, 1.35; 95% CI, 1.09-1.69; P = .007) and type 2 diabetes (OR, 2.53; 95% CI, 2.04-3.13; P = 1.5 × 10-17), as well as systolic blood pressure (β = 1.65 mm Hg; 95% CI, 0.78-2.52 mm Hg; P = 2.0 × 10-04) and diastolic blood pressure (β = 1.37 mm Hg; 95% CI, 0.88-1.85 mm Hg; P = 3.6 × 10-08). These associations were independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history.Conclusions and relevanceThe results of this study add to the burgeoning evidence of an association between higher BMI and increased risk of cardiometabolic diseases. This finding has relevance for public health policies in many countries with increasing obesity levels.

Dataset Information

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

Background

Methods and findings

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets