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PLoS Med. 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.

Author information

1
Framingham Heart Study, Framingham, Massachusetts, United States of America.
2
Boston University School of Medicine, Boston, Massachusetts, United States of America.
3
Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
4
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
5
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
6
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
7
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
8
Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts, United States of America.
9
Department of Biostatistics, Boston University, Boston, Massachusetts, United States of America.
10
Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
11
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
12
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
13
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
14
Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
15
Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
16
Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
17
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
18
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
19
Cardiovascular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
20
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
21
Wellcome Trust Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom.
22
Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
23
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom.
24
Center for Molecular Medicine and Genetics and Department of Neurology, Wayne State University, Detroit, Michigan, United States of America.
25
Children's Hospital Oakland Research Institute, Oakland, California, United States of America.
26
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
27
Brown Foundation Institute of Molecular Medicine, University of Texas, Houston, Texas, United States of America.
28
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
29
College of Public Health, University of Kentucky, Lexington, Kentucky, United States of America.
30
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
31
Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, Massachusetts, United States of America.

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.

PMID:
28095459
PMCID:
PMC5240936
DOI:
10.1371/journal.pmed.1002215
[Indexed for MEDLINE]
Free PMC Article

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