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., Marioni, Riccardo E., Joehanes, Roby, Liu, Chunyu, Hedman, Åsa K., Aslibekyan, Stella, Demerath, Ellen W., Guan, Weihua, Zhi, Degui, Yao, Chen, Huan, Tianxiao, Willinger, Christine, Chen, Brian, Courchesne, Paul, Multhaup, Michael, Irvin, Marguerite R., Cohain, Ariella, Schadt, Eric E., Grove, Megan L., Bressler, Jan, North, Kari, Sundstrom, Johan, Gustafsson, Stefan, Shah, Sonia, McRae, Allan F., Harris, Sarah E., Gibson, Jude, Redmond, Paul, Corley, Janie, Murphy, Lee, Starr, John M., Kleinbrink, Erica, Lipovich, Leonard, Visscher, Peter M., Wray, Naomi R., Krauss, Ronald M., Fallin, Daniele, Feinberg, Andrew, Absher, Devin M., Fornage, Myriam, Pankow, James S., Lind, Lars, Fox, Caroline, Ingelsson, Erik, Arnett, Donna K., Boerwinkle, Eric, Liang, Liming, Levy, Daniel and Deary, Ian J. (2017) Association of body mass index with DNA methylation and gene expression in blood cells and relations to cardiometabolic disease: a Mendelian randomization approach. PLoS Medicine, 14 1: e1002215. doi:10.1371/journal.pmed.1002215

Author Mendelson, Michael M.
Marioni, Riccardo E.
Joehanes, Roby
Liu, Chunyu
Hedman, Åsa K.
Aslibekyan, Stella
Demerath, Ellen W.
Guan, Weihua
Zhi, Degui
Yao, Chen
Huan, Tianxiao
Willinger, Christine
Chen, Brian
Courchesne, Paul
Multhaup, Michael
Irvin, Marguerite R.
Cohain, Ariella
Schadt, Eric E.
Grove, Megan L.
Bressler, Jan
North, Kari
Sundstrom, Johan
Gustafsson, Stefan
Shah, Sonia
McRae, Allan F.
Harris, Sarah E.
Gibson, Jude
Redmond, Paul
Corley, Janie
Murphy, Lee
Starr, John M.
Kleinbrink, Erica
Lipovich, Leonard
Visscher, Peter M.
Wray, Naomi R.
Krauss, Ronald M.
Fallin, Daniele
Feinberg, Andrew
Absher, Devin M.
Fornage, Myriam
Pankow, James S.
Lind, Lars
Fox, Caroline
Ingelsson, Erik
Arnett, Donna K.
Boerwinkle, Eric
Liang, Liming
Levy, Daniel
Deary, Ian J.
Title Association of body mass index with DNA methylation and gene expression in blood cells and relations to cardiometabolic disease: a Mendelian randomization approach
Journal name PLoS Medicine   Check publisher's open access policy
ISSN 1549-1676
Publication date 2017-01-17
Sub-type Article (original research)
DOI 10.1371/journal.pmed.1002215
Open Access Status DOI
Volume 14
Issue 1
Start page e1002215
Total pages 30
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Subject 2700 Medicine
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.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID MR/K026992/1
P30 DK020541
R01 AG042187
R01 HL135313
Institutional Status UQ
Additional Notes Article number e1002215

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
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