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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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- Deanery of Molecular, Genetic and Population Health Sciences - Senior Research Fellow
- Centre for Genomic and Experimental Medicine
- Edinburgh Neuroscience
Person: Academic: Research Active