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

TitleAssociation of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach.
Publication TypeJournal Article
Year of Publication2017
AuthorsMendelson, 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
JournalPLoS Med
Volume14
Issue1
Paginatione1002215
Date Published2017 Jan
ISSN1549-1676
KeywordsAged, Body Mass Index, Coronary Artery Disease, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Leukocytes, Lipid Metabolism, Male, Mendelian Randomization Analysis, Obesity, Oligonucleotide Array Sequence Analysis
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.

DOI10.1371/journal.pmed.1002215
Alternate JournalPLoS Med
PubMed ID28095459
PubMed Central IDPMC5240936
Grant ListR01 HL104135 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201000011C / HL / NHLBI NIH HHS / United States
R01 AG042187 / AG / NIA NIH HHS / United States
P30 DK046200 / DK / NIDDK NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201000010C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
U01 HL072524 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
DP2 CA196375 / CA / NCI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
R01 HL135313 / HL / NHLBI NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States

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