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; 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 Fallin; Andrew 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

doi:10.1371/journal.pmed.1002215

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 BresslerKari 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 Fallin, Andrew 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

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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.

Original language	English (US)
Article number	e1002215
Journal	PLoS medicine
Volume	14
Issue number	1
DOIs	https://doi.org/10.1371/journal.pmed.1002215
State	Published - Jan 2017

ASJC Scopus subject areas

General Medicine

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Mendelson, M. M., Marioni, R. E., Joehanes, R., Liu, C., Hedman, Å. K., Aslibekyan, S., Demerath, E. W., Guan, W., Zhi, D., Yao, C., Huan, T., Willinger, C., Chen, B., Courchesne, P., Multhaup, M., Irvin, M. R., Cohain, A., Schadt, E. E., Grove, M. L., ... Deary, I. 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), Article e1002215. https://doi.org/10.1371/journal.pmed.1002215

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, D , Feinberg, A, 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

@article{0f9ef8bc803f4ffc953e29fa54c16d86,

title = "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.",

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 Daniele Fallin and Andrew Feinberg 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.}",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2017, Public Library of Science. All Rights Reserved.",

year = "2017",

month = jan,

doi = "10.1371/journal.pmed.1002215",

language = "English (US)",

volume = "14",

journal = "PLoS medicine",

issn = "1549-1277",

number = "1",

}

TY - JOUR

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

AU - Feinberg, Andrew

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.

N1 - Funding Information: 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. Publisher Copyright: © 2017, Public Library of Science. All Rights Reserved.

PY - 2017/1

Y1 - 2017/1

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

M3 - Article

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AN - SCOPUS:85010976480

SN - 1549-1277

VL - 14

JO - PLoS medicine

JF - PLoS medicine

IS - 1

M1 - e1002215

ER -

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

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