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179 results on '"Mendelson, Michael M."'

1. Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease

Author

Agha, Golareh, Mendelson, Michael M, Ward-Caviness, Cavin K, Joehanes, Roby, Huan, TianXiao, Gondalia, Rahul, Salfati, Elias, Brody, Jennifer A, Fiorito, Giovanni, Bressler, Jan, Chen, Brian H, Ligthart, Symen, Guarrera, Simonetta, Colicino, Elena, Just, Allan C, Wahl, Simone, Gieger, Christian, Vandiver, Amy R, Tanaka, Toshiko, Hernandez, Dena G, Pilling, Luke C, Singleton, Andrew B, Sacerdote, Carlotta, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Li, Yun, Zhang, Guosheng, Stewart, James D, Floyd, James S, Wiggins, Kerri L, Rotter, Jerome I, Multhaup, Michael, Bakulski, Kelly, Horvath, Steven, Tsao, Philip S, Absher, Devin M, Vokonas, Pantel, Hirschhorn, Joel, Fallin, M Daniele, Liu, Chunyu, Bandinelli, Stefania, Boerwinkle, Eric, Dehghan, Abbas, Schwartz, Joel D, Psaty, Bruce M, Feinberg, Andrew P, Hou, Lifang, Ferrucci, Luigi, Sotoodehnia, Nona, Matullo, Giuseppe, Peters, Annette, Fornage, Myriam, Assimes, Themistocles L, Whitsel, Eric A, Levy, Daniel, and Baccarelli, Andrea A

Subjects
Human Genome, Heart Disease, Clinical Research, Prevention, Heart Disease - Coronary Heart Disease, Atherosclerosis, Cardiovascular, Genetics, Adult, Aged, Cohort Studies, Coronary Disease, CpG Islands, DNA Methylation, Europe, Female, Genome-Wide Association Study, Humans, Incidence, Leukocytes, Male, Middle Aged, Myocardial Infarction, Population Groups, Prognosis, Prospective Studies, Risk, United States, coronary artery disease, coronary heart disease, epigenetics, genomics, gene expression regulation, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology
Abstract

BackgroundDNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.MethodsNine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.ResultsAmong 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate

Published
2019

2. DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Author

Richard, Melissa A, Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A, Brody, Jennifer A, Irvin, Marguerite R, Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E, Jia, Yucheng, Syme, Catriona, Salfati, Elias L, Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H, Bressler, Jan, Morrison, Alanna C, Liu, Chunyu, Mendelson, Michael M, Uitterlinden, André G, van Meurs, Joyce B, Consortium, BIOS, Heijmans, Bastiaan T, Hoen, Peter AC ’t, van Meurs, Joyce, Isaacs, Aaron, Jansen, Rick, Franke, Lude, Boomsma, Dorret I, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, van Greevenbroek, Marleen MJ, Stehouwer, Coen DA, van der Kallen, Carla JH, Schalkwijk, Casper G, Wijmenga, Cisca, Zhernakova, Alexandra, Tigchelaar, Ettje F, Slagboom, P Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H, van den Berg, Leonard H, van Duijn, Cornelia M, Hofman, Albert, Jhamai, P Mila, Verbiest, Michael, Suchiman, H Eka D, Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, van Galen, Michiel, Bot, Jan, van ’t Hof, Peter, Deelen, Patrick, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Zhernakova, Dasha V, Luijk, René, Bonder, Marc Jan, van Dijk, Freerk, Arindrarto, Wibowo, Kielbasa, Szymon M, Swertz, Morris A, van Zwet, Erik W, Franco, Oscar H, Zhang, Guosheng, Li, Yun, Stewart, James D, Bis, Joshua C, Psaty, Bruce M, Chen, Yii-Der Ida, Kardia, Sharon LR, Zhao, Wei, Turner, Stephen T, Absher, Devin, Aslibekyan, Stella, Starr, John M, McRae, Allan F, Hou, Lifang, Just, Allan C, Schwartz, Joel D, Vokonas, Pantel S, Menni, Cristina, Spector, Tim D, Shuldiner, Alan, Damcott, Coleen M, Rotter, Jerome I, Palmas, Walter, Liu, Yongmei, and Paus, Tomáš

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Aged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins, BIOS Consortium, DNA methylation, Mendelian randomization, blood pressure, epigenome-wide association study, gene expression, sequence variation, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p  30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Published
2017

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

Author

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, and Deary, Ian J

Subjects
Leukocytes, Humans, Obesity, Body Mass Index, Oligonucleotide Array Sequence Analysis, DNA Methylation, Gene Expression Regulation, Epigenesis, Genetic, Aged, Female, Male, Lipid Metabolism, Coronary Artery Disease, Genome-Wide Association Study, Mendelian Randomization Analysis, Epigenesis, Genetic, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundThe link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.Methods and findingsWe 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.ConclusionsWe 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.

Published
2017

4. Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies

Author

Hedman, Åsa K, Mendelson, Michael M, Marioni, Riccardo E, Gustafsson, Stefan, Joehanes, Roby, Irvin, Marguerite R, Zhi, Degui, Sandling, Johanna K, Yao, Chen, Liu, Chunyu, Liang, Liming, Huan, Tianxiao, McRae, Allan F, Demissie, Serkalem, Shah, Sonia, Starr, John M, Cupples, L Adrienne, Deloukas, Panos, Spector, Timothy D, Sundström, Johan, Krauss, Ronald M, Arnett, Donna K, Deary, Ian J, Lind, Lars, Levy, Daniel, and Ingelsson, Erik

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Atherosclerosis, Heart Disease - Coronary Heart Disease, Cardiovascular, Genetics, Heart Disease, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Aged, Biomarkers, Coronary Disease, CpG Islands, Cross-Sectional Studies, DNA Methylation, Dyslipidemias, Epigenesis, Genetic, Epigenomics, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Lipid Metabolism, Lipids, Male, Metabolomics, Middle Aged, Phenotype, Prognosis, Prospective Studies, Quantitative Trait Loci, Risk Assessment, Risk Factors, United States, cardiovascular diseases, epigenomics, gene expression, lipids, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundGenome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications.Methods and resultsTo identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P

Published
2017

6. Machine Learning for Proteomic Risk Scores in Heart Failure

Author

XU, DONGCHU, primary, CUNNINGHAM, JONATHAN, additional, MARTI-CASTELLOTE, PABLO-MIKI, additional, ZHANG, LUQING, additional, PATEL-MURRAY, NATASHA L., additional, PRESCOTT, MARGARET F., additional, CHUTKOW, WILLIAM, additional, MENDELSON, MICHAEL M., additional, SOLOMON, SCOTT D., additional, and CLAGGETT, BRIAN L., additional

Published
2023
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8. Clinical characteristics of HFrEF patients with rare pathogenic variants in DCM ‐associated genes: a subgroup analysis of the PARADIGM‐HF trial

Author

Barat, Ana, primary, Chen, Chien‐Wei, additional, Patel‐Murray, Natasha, additional, McMurray, John J.V., additional, Packer, Milton, additional, Solomon, Scott D., additional, Desai, Akshay S., additional, Rouleau, Jean L., additional, Zile, Michael R., additional, Attari, Zenab, additional, Zhang, Cong, additional, Xu, Huilei, additional, Hartman, Nicole, additional, Hon, Claudia, additional, Healey, Margaret, additional, Chutkow, William, additional, O'Donnell, Christopher J., additional, Jacob, Jaison, additional, Lefkowitz, Marty, additional, Mendelson, Michael M., additional, Wandel, Simon, additional, Yates, Denise, additional, and Gimpelewicz, Claudio, additional

Published
2023
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10. Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction

Author

Zhang, Luqing, primary, Cunningham, Jonathan W., additional, Claggett, Brian L., additional, Jacob, Jaison, additional, Mendelson, Michael M., additional, Serrano-Fernandez, Pablo, additional, Kaiser, Sergio, additional, Yates, Denise P., additional, Healey, Margaret, additional, Chen, Chien-Wei, additional, Turner, Gordon M., additional, Patel-Murray, Natasha L., additional, Zhao, Faye, additional, Beste, Michael T., additional, Laramie, Jason M., additional, Abraham, William T., additional, Jhund, Pardeep S., additional, Kober, Lars, additional, Packer, Milton, additional, Rouleau, Jean, additional, Zile, Michael R., additional, Prescott, Margaret F., additional, Lefkowitz, Martin, additional, McMurray, John J.V., additional, Solomon, Scott D., additional, and Chutkow, William, additional

Published
2022
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11. Clinical characteristics of heart failure with reduced ejection fraction patients with rare pathogenic variants in dilated cardiomyopathy‐associated genes: A subgroup analysis of the PARADIGM‐HF trial.

Author

Barat, Ana, Chen, Chien‐Wei, Patel‐Murray, Natasha, McMurray, John J.V., Packer, Milton, Solomon, Scott D., Desai, Akshay S., Rouleau, Jean L., Zile, Michael R., Attari, Zenab, Zhang, Cong, Xu, Huilei, Hartman, Nicole, Hon, Claudia, Healey, Margaret, Chutkow, William, O'Donnell, Christopher J., Jacob, Jaison, Lefkowitz, Marty, and Mendelson, Michael M.

Subjects
HEART failure, VENTRICULAR ejection fraction, CLINICAL trials, SUBGROUP analysis (Experimental design), GENES, DILATED cardiomyopathy
Abstract

Aims: To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. Methods and results: This was a post hoc analysis of the Phase 3 PARADIGM‐HF trial. Forty‐four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss‐of‐function (pLoF) variants, which were prioritized using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM‐associated gene tiers. Clinical features were compared between carriers and non‐carriers. Of the 1412 HFrEF participants with whole‐exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier‐1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier‐1 variants only and 12.6% (29/229) had tier‐1, ‐2 or ‐3 variants. Compared to non‐carriers, tier‐1 carriers were younger (4 years; adjusted p‐value [padj] = 4 × 10−3), leaner (27.8 kg/m2 vs. 29.4 kg/m2; padj = 3.2 × 10−3), had lower ejection fraction (27.3% vs. 29.8%; padj = 5.8 × 10−3), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj = 4 × 10−4). Conclusion: Deleterious pLoF variants in genes with definitive/strong association with DCM were identified in ∼5% of HFrEF patients from a PARADIGM‐HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology. [ABSTRACT FROM AUTHOR]

Published
2023
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12. Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction

Author

Zhang, Luqing, Cunningham, Jonathan W., Claggett, Brian L., Jacob, Jaison, Mendelson, Michael M., Serrano-Fernandez, Pablo, Kaiser, Sergio, Yates, Denise P., Healey, Margaret, Chen, Chien-Wei, Turner, Gordon M., Patel-Murray, Natasha L., Zhao, Faye, Beste, Michael T., Laramie, Jason M., Abraham, William T., Jhund, Pardeep S., Kober, Lars, Packer, Milton, Rouleau, Jean, Zile, Michael R., Prescott, Margaret F., Lefkowitz, Martin, McMurray, John J. V., Solomon, Scott D., Chutkow, William, Zhang, Luqing, Cunningham, Jonathan W., Claggett, Brian L., Jacob, Jaison, Mendelson, Michael M., Serrano-Fernandez, Pablo, Kaiser, Sergio, Yates, Denise P., Healey, Margaret, Chen, Chien-Wei, Turner, Gordon M., Patel-Murray, Natasha L., Zhao, Faye, Beste, Michael T., Laramie, Jason M., Abraham, William T., Jhund, Pardeep S., Kober, Lars, Packer, Milton, Rouleau, Jean, Zile, Michael R., Prescott, Margaret F., Lefkowitz, Martin, McMurray, John J. V., Solomon, Scott D., and Chutkow, William

Published
2022

13. Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies

Author

Hedman, Åsa K., Mendelson, Michael M., Marioni, Riccardo E., Gustafsson, Stefan, Joehanes, Roby, Irvin, Marguerite R., Zhi, Degui, Sandling, Johanna K., Yao, Chen, Liu, Chunyu, Liang, Liming, Huan, Tianxiao, McRae, Allan F., Demissie, Serkalem, Shah, Sonia, Starr, John M., Cupples, L. Adrienne, Deloukas, Panos, Spector, Timothy D., Sundström, Johan, Krauss, Ronald M., Arnett, Donna K., Deary, Ian J., Lind, Lars, Levy, Daniel, and Ingelsson, Erik

Published
2017
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14. Transgelin: a new gene involved in LDL endocytosis identified by a genome-wide CRISPR-Cas9 screen

Author

Lucero, Diego, primary, Dikilitas, Ozan, additional, Mendelson, Michael M., additional, Aligabi, Zahra, additional, Islam, Promotto, additional, Neufeld, Edward B., additional, Bansal, Aruna T., additional, Freeman, Lita A., additional, Vaisman, Boris, additional, Tang, Jingrong, additional, Combs, Christian A., additional, Li, Yuesheng, additional, Voros, Szilard, additional, Kullo, Iftikhar J., additional, and Remaley, Alan T., additional

Published
2022
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16. Transgelin: A New Gene Involved in LDL Endocytosis Identified by a Genome-wide CRISPR-Cas9 Screen

Author

Lucero, Diego, primary, Dikilitas, Ozan, additional, Mendelson, Michael M., additional, Islam, Promotto, additional, Neufeld, Edward B., additional, Bansal, Aruna T., additional, Freeman, Lita A., additional, Vaisman, Boris, additional, Tang, Jingrong, additional, Combs, Christian A., additional, Li, Yuesheng, additional, Voros, Szilard, additional, Kullo, Iftikhar J., additional, and Remaley, Alan T., additional

Published
2020
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17. Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality

Author

Ma, Jiantao, primary, Rebholz, Casey M., additional, Braun, Kim V.E., additional, Reynolds, Lindsay M., additional, Aslibekyan, Stella, additional, Xia, Rui, additional, Biligowda, Niranjan G., additional, Huan, Tianxiao, additional, Liu, Chunyu, additional, Mendelson, Michael M., additional, Joehanes, Roby, additional, Hu, Emily A., additional, Vitolins, Mara Z., additional, Wood, Alexis C., additional, Lohman, Kurt, additional, Ochoa-Rosales, Carolina, additional, van Meurs, Joyce, additional, Uitterlinden, Andre, additional, Liu, Yongmei, additional, Elhadad, Mohamed A., additional, Heier, Margit, additional, Waldenberger, Melanie, additional, Peters, Annette, additional, Colicino, Elena, additional, Whitsel, Eric A., additional, Baldassari, Antoine, additional, Gharib, Sina A., additional, Sotoodehnia, Nona, additional, Brody, Jennifer A., additional, Sitlani, Colleen M., additional, Tanaka, Toshiko, additional, Hill, W. David, additional, Corley, Janie, additional, Deary, Ian J., additional, Zhang, Yan, additional, Schöttker, Ben, additional, Brenner, Hermann, additional, Walker, Maura E., additional, Ye, Shumao, additional, Nguyen, Steve, additional, Pankow, Jim, additional, Demerath, Ellen W., additional, Zheng, Yinan, additional, Hou, Lifang, additional, Liang, Liming, additional, Lichtenstein, Alice H., additional, Hu, Frank B., additional, Fornage, Myriam, additional, Voortman, Trudy, additional, and Levy, Daniel, additional

Published
2020
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18. A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease

Author

Ma, Jiantao, Nano, Jana, Ding, Jingzhong, Zheng, Yinan, Hennein, Rachel, Liu, Chunyu, Speliotes, Elizabeth K., Huan, Tianxiao, Song, Ci, Mendelson, Michael M., Joehanes, Roby, Long, Michelle T., Liang, Liming, Smith, Jennifer A., Reynolds, Lindsay M., Ghanbari, Mohsen, Muka, Taulant, van Meurs, Joyce B. J., Alferink, Louise J. M., Franco, Oscar H., Dehghan, Abbas, Ratliff, Scott, Zhao, Wei, Bielak, Lawrence, Kardia, Sharon L. R., Peyser, Patricia A., Ning, Hongyan, VanWagner, Lisa B., Lloyd-Jones, Donald M., Carr, John Jeffrey, Greenland, Philip, Lichtenstein, Alice H., Hu, Frank B., Liu, Yongmei, Hou, Lifang, Murad, Sarwa Darwish, Levy, Daniel, Ma, Jiantao, Nano, Jana, Ding, Jingzhong, Zheng, Yinan, Hennein, Rachel, Liu, Chunyu, Speliotes, Elizabeth K., Huan, Tianxiao, Song, Ci, Mendelson, Michael M., Joehanes, Roby, Long, Michelle T., Liang, Liming, Smith, Jennifer A., Reynolds, Lindsay M., Ghanbari, Mohsen, Muka, Taulant, van Meurs, Joyce B. J., Alferink, Louise J. M., Franco, Oscar H., Dehghan, Abbas, Ratliff, Scott, Zhao, Wei, Bielak, Lawrence, Kardia, Sharon L. R., Peyser, Patricia A., Ning, Hongyan, VanWagner, Lisa B., Lloyd-Jones, Donald M., Carr, John Jeffrey, Greenland, Philip, Lichtenstein, Alice H., Hu, Frank B., Liu, Yongmei, Hou, Lifang, Murad, Sarwa Darwish, and Levy, Daniel

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 x 10(-6)) with replication at Bonferroni-corrected P < 8.6 x 10(-4). Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 x 10(-4)). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

Published
2019
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21. Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study

Author

Cardona, Alexia, primary, Day, Felix R., additional, Perry, John R.B., additional, Loh, Marie, additional, Chu, Audrey Y., additional, Lehne, Benjamin, additional, Paul, Dirk S., additional, Lotta, Luca A., additional, Stewart, Isobel D., additional, Kerrison, Nicola D., additional, Scott, Robert A., additional, Khaw, Kay-Tee, additional, Forouhi, Nita G., additional, Langenberg, Claudia, additional, Liu, Chunyu, additional, Mendelson, Michael M., additional, Levy, Daniel, additional, Beck, Stephan, additional, Leslie, R. David, additional, Dupuis, Josée, additional, Meigs, James B., additional, Kooner, Jaspal S., additional, Pihlajamäki, Jussi, additional, Vaag, Allan, additional, Perfilyev, Alexander, additional, Ling, Charlotte, additional, Hivert, Marie-France, additional, Chambers, John C., additional, Wareham, Nicholas J., additional, and Ong, Ken K., additional

Published
2019
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22. Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals

Author

Mandaviya, Pooja R, primary, Joehanes, Roby, additional, Brody, Jennifer, additional, Castillo-Fernandez, Juan E, additional, Dekkers, Koen F, additional, Do, Anh N, additional, Graff, Mariaelisa, additional, Hänninen, Ismo K, additional, Tanaka, Toshiko, additional, de Jonge, Ester AL, additional, Kiefte-de Jong, Jessica C, additional, Absher, Devin M, additional, Aslibekyan, Stella, additional, de Rijke, Yolanda B, additional, Fornage, Myriam, additional, Hernandez, Dena G, additional, Hurme, Mikko A, additional, Ikram, M Arfan, additional, Jacques, Paul F, additional, Justice, Anne E, additional, Kiel, Douglas P, additional, Lemaitre, Rozenn N, additional, Mendelson, Michael M, additional, Mikkilä, Vera, additional, Moore, Ann Z, additional, Pallister, Tess, additional, Raitakari, Olli T, additional, Schalkwijk, Casper G, additional, Sha, Jin, additional, Slagboom, Eline PE, additional, Smith, Caren E, additional, Stehouwer, Coen DA, additional, Tsai, Pei-Chien, additional, Uitterlinden, André G, additional, van der Kallen, Carla JH, additional, van Heemst, Diana, additional, Arnett, Donna K, additional, Bandinelli, Stefania, additional, Bell, Jordana T, additional, Heijmans, Bastiaan T, additional, Lehtimäki, Terho, additional, Levy, Daniel, additional, North, Kari E, additional, Sotoodehnia, Nona, additional, van Greevenbroek, Marleen MJ, additional, van Meurs, Joyce BJ, additional, and Heil, Sandra G, additional

Published
2019
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23. A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease

Author

Ma, Jiantao, primary, Nano, Jana, additional, Ding, Jingzhong, additional, Zheng, Yinan, additional, Hennein, Rachel, additional, Liu, Chunyu, additional, Speliotes, Elizabeth K., additional, Huan, Tianxiao, additional, Song, Ci, additional, Mendelson, Michael M., additional, Joehanes, Roby, additional, Long, Michelle T., additional, Liang, Liming, additional, Smith, Jennifer A., additional, Reynolds, Lindsay M., additional, Ghanbari, Mohsen, additional, Muka, Taulant, additional, van Meurs, Joyce B.J., additional, Alferink, Louise J.M., additional, Franco, Oscar H., additional, Dehghan, Abbas, additional, Ratliff, Scott, additional, Zhao, Wei, additional, Bielak, Lawrence, additional, Kardia, Sharon L.R., additional, Peyser, Patricia A., additional, Ning, Hongyan, additional, VanWagner, Lisa B., additional, Lloyd-Jones, Donald M., additional, Carr, John Jeffrey, additional, Greenland, Philip, additional, Lichtenstein, Alice H., additional, Hu, Frank B., additional, Liu, Yongmei, additional, Hou, Lifang, additional, Darwish Murad, Sarwa, additional, and Levy, Daniel, additional

Published
2019
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24. Hepatotoxicity of Statins as Determined by Serum Alanine Aminotransferase in a Pediatric Cohort With Dyslipidemia

Author

Desai, Nirav K., primary, Mendelson, Michael M., additional, Baker, Annette, additional, Ryan, Heather H., additional, Griggs, Suzanne, additional, Boghani, Meera, additional, Yellen, Elizabeth, additional, Buckley, Lucy, additional, Gillman, Matthew W., additional, Zachariah, Justin P., additional, Graham, Dionne, additional, Jonas, Maureen M., additional, and de Ferranti, Sarah D., additional

Published
2019
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26. Epigenetics

Author

Weinrauch, Larry A., primary, Gerhard-Herman, Marie D., additional, and Mendelson, Michael M., additional

Published
2018
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27. DNA Methylation Signatures of Depressive Symptoms in Middle-aged and Elderly Persons

Author

Story Jovanova, Olivera, primary, Nedeljkovic, Ivana, additional, Spieler, Derek, additional, Walker, Rosie M., additional, Liu, Chunyu, additional, Luciano, Michelle, additional, Bressler, Jan, additional, Brody, Jennifer, additional, Drake, Amanda J., additional, Evans, Kathryn L., additional, Gondalia, Rahul, additional, Kunze, Sonja, additional, Kuhnel, Brigitte, additional, Lahti, Jari, additional, Lemaitre, Rozenn N., additional, Marioni, Riccardo E., additional, Swenson, Brenton, additional, Himali, Jayandra Jung, additional, Wu, Hongsheng, additional, Li, Yun, additional, McRae, Allan F., additional, Russ, Tom C., additional, Stewart, James, additional, Wang, Zhiying, additional, Zhang, Guosheng, additional, Ladwig, Karl-Heinz, additional, Uitterlinden, Andre G., additional, Guo, Xiuqing, additional, Peters, Annette, additional, Räikkönen, Katri, additional, Starr, John M., additional, Waldenberger, Melanie, additional, Wray, Naomi R., additional, Whitsel, Eric A., additional, Sotoodehnia, Nona, additional, Seshadri, Sudha, additional, Porteous, David J., additional, van Meurs, Joyce, additional, Mosley, Thomas H., additional, McIntosh, Andrew M., additional, Mendelson, Michael M., additional, Levy, Daniel, additional, Hou, Lifang, additional, Eriksson, Johan G., additional, Fornage, Myriam, additional, Deary, Ian J., additional, Baccarelli, Andrea, additional, Tiemeier, Henning, additional, and Amin, Najaf, additional

Published
2018
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29. Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α

Author

Aslibekyan, Stella, primary, Agha, Golareh, additional, Colicino, Elena, additional, Do, Anh N., additional, Lahti, Jari, additional, Ligthart, Symen, additional, Marioni, Riccardo E., additional, Marzi, Carola, additional, Mendelson, Michael M., additional, Tanaka, Toshiko, additional, Wielscher, Matthias, additional, Absher, Devin M., additional, Ferrucci, Luigi, additional, Franco, Oscar H., additional, Gieger, Christian, additional, Grallert, Harald, additional, Hernandez, Dena, additional, Huan, Tianxiao, additional, Iurato, Stella, additional, Joehanes, Roby, additional, Just, Allan C., additional, Kunze, Sonja, additional, Lin, Honghuang, additional, Liu, Chunyu, additional, Meigs, James B., additional, van Meurs, Joyce B. J., additional, Moore, Ann Zenobia, additional, Peters, Annette, additional, Prokisch, Holger, additional, Räikkönen, Katri, additional, Rathmann, Wolfgang, additional, Roden, Michael, additional, Schramm, Katharina, additional, Schwartz, Joel D., additional, Starr, John M., additional, Uitterlinden, André G., additional, Vokonas, Pantel, additional, Waldenberger, Melanie, additional, Yao, Chen, additional, Zhi, Degui, additional, Baccarelli, Andrea A., additional, Bandinelli, Stefania, additional, Deary, Ian J., additional, Dehghan, Abbas, additional, Eriksson, Johan, additional, Herder, Christian, additional, Jarvelin, Marjo-Riitta, additional, Levy, Daniel, additional, and Arnett, Donna K., additional

Published
2018
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32. Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease : A Mendelian Randomization Approach

Author

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, Lrvin, 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, Coriey, 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, Lan J., 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, Lrvin, 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, Coriey, 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, and Deary, Lan J.

Abstract

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.

Published
2017
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33. DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Author

Richard, Melissa A., Richard, Melissa A., Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A., Brody, Jennifer A., Irvin, Marguerite R., Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E., Jia, Yucheng, Syme, Catriona, Salfati, Elias L., Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H., Bressler, Jan, Morrison, Alanna C., Liu, Chunyu, Mendelson, Michael M., Uitterlinden, Andre G., van Meurs, Joyce B., Franco, Oscar H., Zhang, Guosheng, Li, Yun, Stewart, James D., Bis, Joshua C., Psaty, Bruce M., Chen, Yii-Der Ida, Kardia, Sharon L. R., Zhao, Wei, Turner, Stephen T., Absher, Devin, Aslibekyan, Stella, Starr, John M., Mcrae, Allan F., Hou, Lifang, Just, Allan C., Schwartz, Joel D., Vokonas, Pantel S., Menni, Cristina, Spector, Tim D., Shuldiner, Alan, Damcott, Coleen M., Rotter, Jerome I., BIOS Consortium, van Greevenbroek, Marleen, Stehouwer, Coen, van der Kallen, Carla, Schalkwijk, Casper, Fornage, Myriam, Richard, Melissa A., Richard, Melissa A., Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A., Brody, Jennifer A., Irvin, Marguerite R., Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E., Jia, Yucheng, Syme, Catriona, Salfati, Elias L., Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H., Bressler, Jan, Morrison, Alanna C., Liu, Chunyu, Mendelson, Michael M., Uitterlinden, Andre G., van Meurs, Joyce B., Franco, Oscar H., Zhang, Guosheng, Li, Yun, Stewart, James D., Bis, Joshua C., Psaty, Bruce M., Chen, Yii-Der Ida, Kardia, Sharon L. R., Zhao, Wei, Turner, Stephen T., Absher, Devin, Aslibekyan, Stella, Starr, John M., Mcrae, Allan F., Hou, Lifang, Just, Allan C., Schwartz, Joel D., Vokonas, Pantel S., Menni, Cristina, Spector, Tim D., Shuldiner, Alan, Damcott, Coleen M., Rotter, Jerome I., BIOS Consortium, van Greevenbroek, Marleen, Stehouwer, Coen, van der Kallen, Carla, Schalkwijk, Casper, and Fornage, Myriam

Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p <1.0 x 10(-7); replication: N = 7,182, p <1.6 x 10(-3)). The replicated methylation sites are heritable (h(2) > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Published
2017

34. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Author

Ligthart, Symen, Marzi, Carola, Aslibekyan, Stella, Mendelson, Michael M, Conneely, Karen N, Tanaka, Toshiko, Colicino, Elena, Waite, Lindsay L, Joehanes, Roby, Guan, Weihua, Brody, Jennifer A, Elks, Cathy, Marioni, Riccardo, Jhun, Min A, Agha, Golareh, Bressler, Jan, Ward-Caviness, Cavin K, Chen, Brian H, Huan, Tianxiao, Bakulski, Kelly, Salfati, Elias L, WHI-EMPC Investigators, Fiorito, Giovanni, CHARGE epigenetics of Coronary Heart Disease, Wahl, Simone, Schramm, Katharina, Sha, Jin, Hernandez, Dena G, Just, Allan C, Smith, Jennifer A, Sotoodehnia, Nona, Pilling, Luke C, Pankow, James S, Tsao, Phil S, Liu, Chunyu, Zhao, Wei, Guarrera, Simonetta, Michopoulos, Vasiliki J, Smith, Alicia K, Peters, Marjolein J, Melzer, David, Vokonas, Pantel, Fornage, Myriam, Prokisch, Holger, Bis, Joshua C, Chu, Audrey Y, Herder, Christian, Grallert, Harald, Yao, Chen, Shah, Sonia, McRae, Allan F, Lin, Honghuang, Horvath, Steve, Fallin, Daniele, Hofman, Albert, Wareham, Nicholas J, Wiggins, Kerri L, Feinberg, Andrew P, Starr, John M, Visscher, Peter M, Murabito, Joanne M, Kardia, Sharon LR, Absher, Devin M, Binder, Elisabeth B, Singleton, Andrew B, Bandinelli, Stefania, Peters, Annette, Waldenberger, Melanie, Matullo, Giuseppe, Schwartz, Joel D, Demerath, Ellen W, Uitterlinden, André G, van Meurs, Joyce BJ, Franco, Oscar H, Chen, Yii-Der Ida, Levy, Daniel, Turner, Stephen T, Deary, Ian J, Ressler, Kerry J, Dupuis, Josée, Ferrucci, Luigi, Ong, Ken K, Assimes, Themistocles L, Boerwinkle, Eric, Koenig, Wolfgang, Arnett, Donna K, Baccarelli, Andrea A, Benjamin, Emelia J, Dehghan, Abbas, Wareham, Nicholas [0000-0003-1422-2993], Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository

Subjects
Male, Inflammation, DNA methylation, Quantitative Trait Loci, Diabetes, Gene Expression, Genetic Variation, White People, Epigenesis, Genetic, C-reactive protein, Black or African American, Coronary heart disease, Epigenome-wide association study, Humans, CpG Islands, Female, Nucleotide Motifs, Body mass index, Genome-Wide Association Study
Abstract

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P –7) in the discovery panel of European ancestry and replicated (P –4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P –5), ten (17%) CpG sites were associated with a nearby genetic variant (P –3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P –5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

Published
2016

36. Transcriptome-wide association study of inflammatory biologic age

Author

Lin, Honghuang, primary, Lunetta, Kathryn L., additional, Zhao, Qiang, additional, Rong, Jian, additional, Benjamin, Emelia J., additional, Mendelson, Michael M., additional, Joehanes, Roby, additional, Levy, Daniel, additional, Larson, Martin G., additional, and Murabito, Joanne M., additional

Published
2017
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38. Abstract P097: Soluble TNF Receptor II Levels are Associated With Leukocyte DNA Methylation in the Major Histocompatibility Complex Region in the Framingham Heart Study

Author

Mendelson, Michael M, primary, Joehanes, Roby, additional, Liu, Chunyu, additional, Huan, Tianxiao, additional, Yao, Chen, additional, Murabito, Joanne M, additional, Dupuis, Josee, additional, Levy, Daniel, additional, Benjamin, Emelia J, additional, and Lin, Honghuang, additional

Published
2017
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39. Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study

Author

Lin, Honghuang, primary, Yin, Xiaoyan, additional, Xie, Zhijun, additional, Lunetta, Kathryn L., additional, Lubitz, Steven A., additional, Larson, Martin G., additional, Ko, Darae, additional, Magnani, Jared W., additional, Mendelson, Michael M., additional, Liu, Chunyu, additional, McManus, David D., additional, Levy, Daniel, additional, Ellinor, Patrick T., additional, and Benjamin, Emelia J., additional

Published
2017
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40. Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations

Author

Shah, Sonia, Bonder, Marc J, Marioni, Riccardo E, Zhu, Zhihong, McRae, Allan F, Zhernakova, Alexandra, Harris, Sarah E, Liewald, David, Henders, Anjali K, Mendelson, Michael M, Liu, Chunyu, Joehanes, Roby, Liang, Liming, Levy, Daniel, Martin, Nicholas G, Starr, John M, Wijmenga, Cisca, Wray, Naomi R, Yang, Jian, Montgomery, Grant W, Franke, Lude, Deary, Ian J, Visscher, Peter M, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Adult, Adolescent, Genotype, WEIGHT-LOSS, GENOTYPE IMPUTATION, Article, Body Mass Index, Cohort Studies, HEIGHT, Genetics, WIDE ASSOCIATION, Humans, Genetics(clinical), Obesity, POPULATION, Netherlands, Analysis of Variance, Models, Genetic, DNA Methylation, Middle Aged, Body Height, BODY-MASS INDEX, GENOME, Phenotype, Scotland, CARDIOVASCULAR-DISEASE, Genome-Wide Association Study
Abstract

We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n similar to 350,000) and height (n similar to 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the Life Lines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 140/0 of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for Life Lines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BM! methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction.

Published
2015
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41. A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease.

Author

Hennein, Rachel, Tianxiao Huan, Joehanes, Roby, Levy, Daniel, Ci Song, Mendelson, Michael M., Jiantao Ma, Chunyu Liu, Long, Michelle T., Liming Liang, Smith, Jennifer A., Ratliff, Scott, Wei Zhao, Bielak, Lawrence, Kardia, Sharon L. R., Peyser, Patricia A., Alferink, Louise J. M., Murad, Sarwa Darwish, Hongyan Ning, and Lloyd-Jones, Donald M.

Subjects
FATTY liver, DNA methylation, FAT, EPIGENOMICS, FALSE discovery rate, TYPE 2 diabetes, ULTRASONIC imaging
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups. [ABSTRACT FROM AUTHOR]

Published
2019
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42. Association of Maternal Prepregnancy Weight with Offspring Adiposity Throughout Adulthood over 37 Years of Follow-up.

Author

Schoppa, Isabelle, Lyass, Asya, Heard‐Costa, Nancy, de Ferranti, Sarah D., Fox, Caroline, Gillman, Matthew W., D'Agostino, Ralph, Levy, Daniel, Mendelson, Michael M., Heard-Costa, Nancy, and D'Agostino, Ralph Sr

Subjects
OBESITY, WEIGHT gain in pregnancy, BODY mass index, PHYSICAL activity, METABOLIC disorders, ADIPOSE tissues, COMPARATIVE studies, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, RESEARCH, RESEARCH funding, EVALUATION research
Abstract

Objective: This study aimed to determine the relation of maternal prepregnancy weight with offspring BMI across adulthood from almost 40 years of follow-up.Methods: BMI was measured in Framingham Heart Study Offspring cohort participants between 1971 and 2008. The association of maternal prepregnancy weight category (ascertained via direct measure and questionnaire) with serial offspring BMI, overweight, obesity, and change in BMI over time was tested, adjusted for age, sex, and a BMI genetic risk score; secondary models additionally adjusted for physical activity, dietary factors, smoking, education, and familial relatedness.Results: Among 863 participants at initial assessment (83 exposed and 780 controls), mean (SD) age was 33 (10) years, 53% were female, and mean BMI was 24.5 (4.1) kg/m2 . Exposed offspring BMI was higher at every examination cycle, ranging from 1.5 (0.5) to 3.0 (0.5) kg/m2 (P < 0.001), with larger differences at later assessments. The rate of increase in offspring BMI over time was higher in exposed offspring before the age of 50 years (β [SE] = 0.07 [0.02] kg/m2 per year; P = 0.004) but not after the age of 50 years (-0.05 [0.04] kg/m2 per year; P = 0.2).Conclusions: Maternal prepregnancy weight is associated with greater offspring BMI throughout adulthood, with more rapid weight acceleration in early and midadulthood. [ABSTRACT FROM AUTHOR]

Published
2019
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43. Adolescent Dyslipidemia and Standardized Lifestyle Modification

Author

Zachariah, Justin P., primary, Chan, James, additional, Mendelson, Michael M., additional, Regh, Todd, additional, Griggs, Suzanne, additional, Johnson, Philip K., additional, Desai, Nirav, additional, Gillman, Mathew, additional, Graham, Dionne, additional, and de Ferranti, Sarah D., additional

Published
2016
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44. Epigenetic Signatures of Cigarette Smoking

Author

Joehanes, Roby, primary, Just, Allan C., additional, Marioni, Riccardo E., additional, Pilling, Luke C., additional, Reynolds, Lindsay M., additional, Mandaviya, Pooja R., additional, Guan, Weihua, additional, Xu, Tao, additional, Elks, Cathy E., additional, Aslibekyan, Stella, additional, Moreno-Macias, Hortensia, additional, Smith, Jennifer A., additional, Brody, Jennifer A., additional, Dhingra, Radhika, additional, Yousefi, Paul, additional, Pankow, James S., additional, Kunze, Sonja, additional, Shah, Sonia H., additional, McRae, Allan F., additional, Lohman, Kurt, additional, Sha, Jin, additional, Absher, Devin M., additional, Ferrucci, Luigi, additional, Zhao, Wei, additional, Demerath, Ellen W., additional, Bressler, Jan, additional, Grove, Megan L., additional, Huan, Tianxiao, additional, Liu, Chunyu, additional, Mendelson, Michael M., additional, Yao, Chen, additional, Kiel, Douglas P., additional, Peters, Annette, additional, Wang-Sattler, Rui, additional, Visscher, Peter M., additional, Wray, Naomi R., additional, Starr, John M., additional, Ding, Jingzhong, additional, Rodriguez, Carlos J., additional, Wareham, Nicholas J., additional, Irvin, Marguerite R., additional, Zhi, Degui, additional, Barrdahl, Myrto, additional, Vineis, Paolo, additional, Ambatipudi, Srikant, additional, Uitterlinden, André G., additional, Hofman, Albert, additional, Schwartz, Joel, additional, Colicino, Elena, additional, Hou, Lifang, additional, Vokonas, Pantel S., additional, Hernandez, Dena G., additional, Singleton, Andrew B., additional, Bandinelli, Stefania, additional, Turner, Stephen T., additional, Ware, Erin B., additional, Smith, Alicia K., additional, Klengel, Torsten, additional, Binder, Elisabeth B., additional, Psaty, Bruce M., additional, Taylor, Kent D., additional, Gharib, Sina A., additional, Swenson, Brenton R., additional, Liang, Liming, additional, DeMeo, Dawn L., additional, O’Connor, George T., additional, Herceg, Zdenko, additional, Ressler, Kerry J., additional, Conneely, Karen N., additional, Sotoodehnia, Nona, additional, Kardia, Sharon L. R., additional, Melzer, David, additional, Baccarelli, Andrea A., additional, van Meurs, Joyce B. J., additional, Romieu, Isabelle, additional, Arnett, Donna K., additional, Ong, Ken K., additional, Liu, Yongmei, additional, Waldenberger, Melanie, additional, Deary, Ian J., additional, Fornage, Myriam, additional, Levy, Daniel, additional, and London, Stephanie J., additional

Published
2016
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