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.
  
  
  RESULTS
  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.
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Boston University School of Medicine, Boston, Massachusetts, United States of America.|Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Mendelson
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.|Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Riccardo E
authors.initials: RE
authors.lastname: Marioni
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.|Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.|Department of Biostatistics, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Åsa K
authors.identifier: http://orcid.org/0000-0001-5413-204X
authors.initials: ÅK
authors.lastname: Hedman
authors.affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Ellen W
authors.initials: EW
authors.lastname: Demerath
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.affiliation: Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Chen
authors.identifier: http://orcid.org/0000-0002-3944-7788
authors.initials: C
authors.lastname: Yao
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Tianxiao
authors.identifier: http://orcid.org/0000-0001-5840-9413
authors.initials: T
authors.lastname: Huan
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Willinger
authors.affiliation: Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Brian
authors.identifier: http://orcid.org/0000-0001-9065-3301
authors.initials: B
authors.lastname: Chen
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Courchesne
authors.affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Multhaup
authors.affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ariella
authors.identifier: http://orcid.org/0000-0003-2375-0683
authors.initials: A
authors.lastname: Cohain
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Megan L
authors.identifier: http://orcid.org/0000-0001-6764-2508
authors.initials: ML
authors.lastname: Grove
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Jan
authors.initials: J
authors.lastname: Bressler
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kari
authors.initials: K
authors.lastname: North
authors.affiliation: Cardiovascular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Sundström
authors.affiliation: Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gustafsson
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Wellcome Trust Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jude
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Redmond
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Janie
authors.initials: J
authors.lastname: Corley
authors.affiliation: Wellcome Trust Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Lee
authors.identifier: http://orcid.org/0000-0001-6467-7449
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Center for Molecular Medicine and Genetics and Department of Neurology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Erica
authors.identifier: http://orcid.org/0000-0002-8565-207X
authors.initials: E
authors.lastname: Kleinbrink
authors.affiliation: Center for Molecular Medicine and Genetics and Department of Neurology, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Leonard
authors.identifier: http://orcid.org/0000-0002-0531-3570
authors.initials: L
authors.lastname: Lipovich
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.|Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California, United States of America.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Daniele
authors.identifier: http://orcid.org/0000-0002-9948-3908
authors.initials: D
authors.lastname: Fallin
authors.affiliation: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feinberg
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
authors.forename: Devin M
authors.identifier: http://orcid.org/0000-0003-4405-1646
authors.initials: DM
authors.lastname: Absher
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.|Brown Foundation Institute of Molecular Medicine, University of Texas, Houston, Texas, United States of America.
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Cardiovascular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fox
authors.affiliation: Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: College of Public Health, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Departments of Epidemiology and Biostatistics, School of Public Health, Harvard University, Boston, Massachusetts, United States of America.
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts, United States of America.|Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
mesh_terms: D000368:Aged; D015992:Body Mass Index; D003324:Coronary Artery Disease / Q000209:etiology / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D057182:Mendelian Randomization Analysis; D009765:Obesity / Q000150:complications; D020411:Oligonucleotide Array Sequence Analysis