|Title||Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Mendelson 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|
|Secondary Authors||Deary IJ|
|Date Published||2017 Jan|
|Keywords||Aged, 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|
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.
|Alternate Journal||PLoS Med|
|PubMed Central ID||PMC5240936|
|Grant List||R01 HL104135 / HL / NHLBI NIH HHS / United States |
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
R01 AG042187 / AG / NIA NIH HHS / United States
U01 HL072524 / HL / NHLBI NIH HHS / United States
DP2 CA196375 / CA / NCI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
R01 HL135313 / HL / NHLBI NIH HHS / United States