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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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  • Michael M Mendelson
  • 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
  • Jude Gibson
  • Paul Redmond
  • Janie Corley
  • 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

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Original languageEnglish
Article numbere1002215
JournalPLOS Medicine
Volume14
Issue number1
DOIs
Publication statusPublished - 17 Jan 2017

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.

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