title: Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study.
abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little is known about the molecular mechanisms associated with AF arrhythmogenesis. DNA methylation is an important epigenetic mechanism that regulates gene expression and downstream biological processes. We hypothesize that DNA methylation might play an important role in the susceptibility to develop AF. A total of 2,639 participants from the Offspring Cohort of Framingham Heart Study were enrolled in the current study. These participants included 183 participants with prevalent AF and 220 with incident AF during up to 9 years follow up. Genome-wide methylation was profiled using the Illumina Infinium HumanMethylation450 BeadChip on blood-derived DNA collected during the eighth examination cycle (2005-2008). Two CpG sites were significantly associated with prevalent AF, and five CpGs were associated with incident AF after correction for multiple testing (FDR < 0.05). Fourteen previously reported genome-wide significant AF-related SNP were each associated with at least one CpG site; the most significant association was rs6490029 at the CUX2 locus and cg10833066 (P = 9.5 × 10-279). In summary, we performed genome-wide methylation profiling in a community-based cohort and identified seven methylation signatures associated with AF. Our study suggests that DNA methylation might play an important role in AF arrhythmogenesis.
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yin
authors.affiliation: Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.|TCM Clinical Basis Institute, Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Xie
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.|The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Department of Mathematics and Statistics, Boston University, Boston, MA, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Darae
authors.initials: D
authors.lastname: Ko
authors.affiliation: Division of Cardiology, Department of Medicine, UPMC Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Magnani
authors.affiliation: Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.|Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Mendelson
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Medicine and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: McManus
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.|The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.affiliation: National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.|Section of Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.|Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000453:epidemiology / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D015994:Incidence; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D012372:ROC Curve