期刊
PLOS MEDICINE
卷 14, 期 1, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pmed.1002215
关键词
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资金
- National Institutes of Health [N01-HC-25195, HHSN268201500001I]
- NIH National Heart, Lung, and Blood Institute [R01 HL 104135-01]
- National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011000010C, HHSN2682011000011C, HHSN2682011000012C]
- NIH through the American Recovery and Reinvestment Act of (ARRA) [5RC2HL102419]
- Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health
- Directors Challenge Award, National Institutes of Health
- Division of Intramural Research, National Heart, Lung, and Blood Institute
- Center for Information Technology, National Institutes of Health, Bethesda, MD
- Tommy Kaplan Fund, Boston Childrens Hospital
- NIH [P30 DK46200]
- UKs Biotechnology and Biological Sciences Research Council (BBSRC)
- Royal Society
- Chief Scientist Office of the Scottish Government
- Age UK (The Disconnected Mind project)
- Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award)
- Wellcome Trust Institutional Strategic Support Fund
- University of Edinburgh
- Age UK
- University of Queensland
- BBSRC
- Economic and Social Research Council (ESRC)
- Medical Research Council (MRC)
- University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative [MR/K026992/1]
- National Health and Medical Research Council (NHMRC) [613608, APP496667, APP1010374, APP1046880]
- NHMRC [613602, 1083656]
- Australian Research Council (ARC) [FT0991360]
- Medical Research Council [MR/K026992/1] Funding Source: researchfish
- DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS [N01HC025195] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL104135, U01HL072524, ZIAHL006001, R01HL135313] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020541] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG042187] Funding Source: NIH RePORTER
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.
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