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

• Published in: PLoS medicine Vol. 14; no. 1; p. e1002215
• Main Authors: Mendelson, Michael M, Marioni, Riccardo E, Joehanes, Roby, Liu, Chunyu, Hedman, Åsa K, Aslibekyan, Stella, Demerath, Ellen W, Guan, Weihua, Zhi, Degui, Yao, Chen, Huan, Tianxiao, Willinger, Christine, Chen, Brian, Courchesne, Paul, Multhaup, Michael, Irvin, Marguerite R, Cohain, Ariella, Schadt, Eric E, Grove, Megan L, Bressler, Jan, North, Kari, Sundström, Johan, Gustafsson, Stefan, Shah, Sonia, McRae, Allan F, Harris, Sarah E, Gibson, Jude, Redmond, Paul, Corley, Janie, Murphy, Lee, Starr, John M, Kleinbrink, Erica, Lipovich, Leonard, Visscher, Peter M, Wray, Naomi R, Krauss, Ronald M, Fallin, Daniele, Feinberg, Andrew, Absher, Devin M, Fornage, Myriam, Pankow, James S, Lind, Lars, Fox, Caroline, Ingelsson, Erik, Arnett, Donna K, Boerwinkle, Eric, Liang, Liming, Levy, Daniel, Deary, Ian J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17-01-2017; Public Library of Science (PLoS)
• Subjects: Aged; Aging; Biology and life sciences; Body Mass Index; Brain research; Cardiovascular disease; Cardiovascular diseases; Colleges & universities; Consortia; Coronary Artery Disease - etiology; Coronary Artery Disease - genetics; Deoxyribonucleic acid; Diagnosis; DNA; DNA Methylation; Epidemiology; Epigenesis, Genetic; Female; Gene expression; Gene Expression Regulation; Genetic aspects; Genetics; Genome-Wide Association Study - methods; Genomics; Health aspects; Heart; Hospitals; Humans; Investigations; Laboratories; Leukocytes - metabolism; Lipid Metabolism - genetics; Male; Medicine; Medicine and Health Sciences; Mendelian Randomization Analysis; Metabolic diseases; Methylation; Obesity - complications; Oligonucleotide Array Sequence Analysis; Population; Public health; Science; Edinburgh Scotland; Queensland Australia; Alabama; United States > US; Maryland; Massachusetts
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1002215

The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.
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.
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.