Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

Summary

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.

Key Points

• 1Methylation at eighty-three identified CpGs correlates with body mass index
• 2Novel loci linked to lipid metabolism and cardiometabolic disease are presented
• 3The study involved over seven thousand participants across multiple cohorts
• 4Cross-sectional data limits causal interpretation of findings
• 5Genetic analyses support links between methylation and adiposity traits

Related articles

• Disentangling vegetation diversity from climate-energy and habitat heterogeneity for explaining animal geographic patterns

  This study investigates the relationships between vegetation diversity and animal geographic patterns, testing whether vegetation diversity can explain animal richness beyond the effects of climate-energy and habitat heterogeneity.

• Characteristics of Cells in Microanatomy and Embryology

  This document provides an extensive outline on the characteristics of cells, including their size, shape, number of nuclei, location of nuclei, and arrangement. It serves as a lecture guide for students studying microanatomy and embryology.

• MICROANATOMY & EMBRYOLOGY: NUCLEUS, CELL DIVISION, AND CELL CYCLE

  This document outlines key concepts in microanatomy and embryology, focusing on the structure and function of the cell nucleus, cell division processes including mitosis and meiosis, and apoptosis.

• Development of the Skin

  This document outlines the microanatomy and embryology of skin development, including the formation of skin layers, appendages, and glands throughout gestation. It serves as a comprehensive guide for students studying the integumentary system.

• Embryology of Muscle: Microanatomy & Embryology

  This document outlines the embryological development of various muscle types, including striated skeletal, cardiac, and smooth muscle, highlighting their origins, development process, and associated anatomy.