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 H Chen; Paul  Courchesne; Michael L Multhaup; Marguerite R Irvin; Ariella Cohain; Eric E. Schadt; Megan L. Grove; Jan Bressler; Kari E. North; Johan Sundstrom; 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 P Feinberg; Devin M Absher; Myriam Fornage; James S. Pankow; Lars Lind; Caroline S. 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 H Chen, Paul Courchesne, Michael L Multhaup, Marguerite R Irvin, Ariella Cohain, Eric E. Schadt, Megan L. Grove, Jan BresslerKari E. North, Johan Sundstrom, 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 P Feinberg, Devin M Absher, Myriam Fornage, James S. Pankow, Lars Lind, Caroline S. Fox, Erik Ingelsson, Donna K Arnett, Eric Boerwinkle, Liming Liang, Daniel Levy, Ian J. Deary

Research output: Contribution to journal › Article › peer-review

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) withand differential methylation offor 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 included conducted Mendelian randomization analyses to supportinvestigate 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 for of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to Ssterol Rregulatory Eelement Bbinding Ttranscription Ffactor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the methylation findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci werewas 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
Article number	e1002215
Number of pages	30
Journal	PLoS Medicine
Volume	14
Issue number	1
DOIs	https://doi.org/10.1371/journal.pmed.1002215
Publication status	Published - 17 Jan 2017

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MendelsonEtalPM2017AssociationOfBodyMassIndexFinal published version, 3.64 MBLicence: Creative Commons: CC0 - "No Rights Reserved"

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
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Riccardo Marioni
- Centre for Genomic and Experimental Medicine
- Edinburgh Neuroscience
- School of Genetics and Cancer - Personal Chair of Molecular Epidemiology of Ageing
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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. H., Courchesne, P., Multhaup, M. L., 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

@article{754cc177bc2040b4a23334576774138e,

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) withand differential methylation offor 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 included conducted Mendelian randomization analyses to supportinvestigate 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 for of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to Ssterol Rregulatory Eelement Bbinding Ttranscription Ffactor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the methylation findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci werewas 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 Chen, {Brian H} and Paul Courchesne and Multhaup, {Michael L} and Irvin, {Marguerite R} and Ariella Cohain and Schadt, {Eric E.} and Grove, {Megan L.} and Jan Bressler and North, {Kari E.} and Johan Sundstrom 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 Feinberg, {Andrew P} and Absher, {Devin M} and Myriam Fornage and Pankow, {James S.} and Lars Lind and Fox, {Caroline S.} and Erik Ingelsson and Arnett, {Donna K} and Eric Boerwinkle and Liming Liang and Daniel Levy and Deary, {Ian J.}",

year = "2017",

month = jan,

day = "17",

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

language = "English",

volume = "14",

journal = "PLoS Medicine",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "1",

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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, BH, Courchesne, P, Multhaup, ML, Irvin, MR, Cohain, A, Schadt, EE, Grove, ML, Bressler, J, North, KE, Sundstrom, 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, AP, Absher, DM, Fornage, M, Pankow, JS, Lind, L, Fox, CS, 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

TY - JOUR

T1 - Association of body mass index with DNA methylation and gene expression in blood cells and relations to cardiometabolic disease: 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 H

AU - Courchesne, Paul

AU - Multhaup, Michael L

AU - Irvin, Marguerite R

AU - Cohain, Ariella

AU - Schadt, Eric E.

AU - Grove, Megan L.

AU - Bressler, Jan

AU - North, Kari E.

AU - Sundstrom, 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 P

AU - Absher, Devin M

AU - Fornage, Myriam

AU - Pankow, James S.

AU - Lind, Lars

AU - Fox, Caroline S.

AU - Ingelsson, Erik

AU - Arnett, Donna K

AU - Boerwinkle, Eric

AU - Liang, Liming

AU - Levy, Daniel

AU - Deary, Ian J.

PY - 2017/1/17

Y1 - 2017/1/17

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) withand differential methylation offor 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 included conducted Mendelian randomization analyses to supportinvestigate 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 for of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to Ssterol Rregulatory Eelement Bbinding Ttranscription Ffactor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the methylation findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci werewas 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) withand differential methylation offor 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 included conducted Mendelian randomization analyses to supportinvestigate 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 for of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to Ssterol Rregulatory Eelement Bbinding Ttranscription Ffactor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the methylation findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci werewas 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.

U2 - 10.1371/journal.pmed.1002215

DO - 10.1371/journal.pmed.1002215

M3 - Article

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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RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

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