Person: Joehanes, Roby
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Publication Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach
(Public Library of Science, 2017) 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.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.
Publication Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes
(Public Library of Science, 2017) Mandaviya, Pooja R.; Joehanes, Roby; Aïssi, Dylan; Kühnel, Brigitte; Marioni, Riccardo E.; Truong, Vinh; Stolk, Lisette; Beekman, Marian; Bonder, Marc Jan; Franke, Lude; Gieger, Christian; Huan, Tianxiao; Ikram, M. Arfan; Kunze, Sonja; Liang, Liming; Lindemans, Jan; Liu, Chunyu; McRae, Allan F.; Mendelson, Michael M.; Müller-Nurasyid, Martina; Peters, Annette; Slagboom, P. Eline; Starr, John M.; Trégouët, David-Alexandre; Uitterlinden, André G.; van Greevenbroek, Marleen M. J.; van Heemst, Diana; van Iterson, Maarten; Wells, Philip S.; Yao, Chen; Deary, Ian J.; Gagnon, France; Heijmans, Bastiaan T.; Levy, Daniel; Morange, Pierre-Emmanuel; Waldenberger, Melanie; Heil, Sandra G.; van Meurs, Joyce B. J.Background: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. Methods: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. Results: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. Conclusions: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.