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, 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 & 29 others 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 Daniele Fallin, Andrew P 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1002215
JournalPLoS Medicine
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2017

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Methylation
DNA Methylation
Random Allocation
Gene expression
Blood Cells
Body Mass Index
Blood
Cells
Gene Expression
Adiposity
Sterols
Mendelian Randomization Analysis
Transcription Factors
Obesity
Microarrays
Lipid Metabolism
Genes
Coronary Artery Disease
Association reactions
Parturition

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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; Sundström, 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 Daniele; Feinberg, Andrew P; 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.

In: PLoS Medicine, Vol. 14, No. 1, e1002215, 01.01.2017.

Research output: Contribution to journalArticle

Mendelson, MM, Marioni, RE, Joehanes, R, Liu, C, Hedman, ÅK, Aslibekyan, S, Demerath, EW, Guan, W, Zhi, D, Yao, C, Huan, T, Willinger, C, Chen, B, Courchesne, P, Multhaup, M, Irvin, MR, Cohain, A, Schadt, EE, Grove, ML, Bressler, J, North, K, Sundström, J, Gustafsson, S, Shah, S, McRae, AF, Harris, SE, Gibson, J, Redmond, P, Corley, J, Murphy, L, Starr, JM, Kleinbrink, E, Lipovich, L, Visscher, PM, Wray, NR, Krauss, RM, Fallin, DD, Feinberg, AP, Absher, DM, Fornage, M, Pankow, JS, Lind, L, Fox, C, Ingelsson, E, Arnett, DK, Boerwinkle, E, Liang, L, Levy, D & Deary, IJ 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, vol. 14, no. 1, e1002215. https://doi.org/10.1371/journal.pmed.1002215
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 ; Sundström, 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 Daniele ; Feinberg, Andrew P ; 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. / Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease : A Mendelian Randomization Approach. In: PLoS Medicine. 2017 ; Vol. 14, No. 1.
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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.",
author = "Mendelson, {Michael M.} and Marioni, {Riccardo E.} and Roby Joehanes and Chunyu Liu and Hedman, {{\AA}sa K.} and Stella Aslibekyan and Demerath, {Ellen W.} and Weihua Guan and Degui Zhi and Chen Yao and Tianxiao Huan and Christine Willinger and Brian Chen and Paul Courchesne and Michael Multhaup and Irvin, {Marguerite R.} and Ariella Cohain and Schadt, {Eric E.} and Grove, {Megan L.} and Jan Bressler and Kari North and Johan Sundstr{\"o}m and Stefan Gustafsson and Sonia Shah and McRae, {Allan F.} and Harris, {Sarah E.} and Jude Gibson and Paul Redmond and Janie Corley and Lee Murphy and Starr, {John M.} and Erica Kleinbrink and Leonard Lipovich and Visscher, {Peter M.} and Wray, {Naomi R.} and Krauss, {Ronald M.} and Fallin, {Daniele Daniele} and Feinberg, {Andrew P} and Absher, {Devin M.} and Myriam Fornage and Pankow, {James S.} and Lars Lind and Caroline Fox and Erik Ingelsson and Arnett, {Donna K.} and Eric Boerwinkle and Liming Liang and Daniel Levy and Deary, {Ian J.}",
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T1 - Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease

T2 - A Mendelian Randomization Approach

AU - Mendelson, Michael M.

AU - Marioni, Riccardo E.

AU - Joehanes, Roby

AU - Liu, Chunyu

AU - Hedman, Åsa K.

AU - Aslibekyan, Stella

AU - Demerath, Ellen W.

AU - Guan, Weihua

AU - Zhi, Degui

AU - Yao, Chen

AU - Huan, Tianxiao

AU - Willinger, Christine

AU - Chen, Brian

AU - Courchesne, Paul

AU - Multhaup, Michael

AU - Irvin, Marguerite R.

AU - Cohain, Ariella

AU - Schadt, Eric E.

AU - Grove, Megan L.

AU - Bressler, Jan

AU - North, Kari

AU - Sundström, Johan

AU - Gustafsson, Stefan

AU - Shah, Sonia

AU - McRae, Allan F.

AU - Harris, Sarah E.

AU - Gibson, Jude

AU - Redmond, Paul

AU - Corley, Janie

AU - Murphy, Lee

AU - Starr, John M.

AU - Kleinbrink, Erica

AU - Lipovich, Leonard

AU - Visscher, Peter M.

AU - Wray, Naomi R.

AU - Krauss, Ronald M.

AU - Fallin, Daniele Daniele

AU - Feinberg, Andrew P

AU - Absher, Devin M.

AU - Fornage, Myriam

AU - Pankow, James S.

AU - Lind, Lars

AU - Fox, Caroline

AU - Ingelsson, Erik

AU - Arnett, Donna K.

AU - Boerwinkle, Eric

AU - Liang, Liming

AU - Levy, Daniel

AU - Deary, Ian J.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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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U2 - 10.1371/journal.pmed.1002215

DO - 10.1371/journal.pmed.1002215

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