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

被引：222

作者：

Mendelson, Michael M. ^{[1
,2
,3
,4
]}

Marioni, Riccardo E. ^{[5
,6
,7
]}

Joehanes, Roby ^{[1
,4
,8
]}

Liu, Chunyu ^{[1
,4
,9
]}

Hedman, Asa K. ^{[10
]}

Aslibekyan, Stella ^{[11
]}

Demerath, Ellen W. ^{[12
]}

Guan, Weihua ^{[13
]}

Zhi, Degui ^{[14
]}

Yao, Chen ^{[1
,4
]}

Huan, Tianxiao ^{[1
,4
]}

Willinger, Christine ^{[1
,4
]}

Chen, Brian ^{[4
]}

Courchesne, Paul ^{[1
,4
]}

Multhaup, Michael ^{[15
]}

Lrvin, Marguerite R. ^{[11
]}

Cohain, Ariella ^{[16
,17
]}

Schadt, Eric E. ^{[16
,17
]}

Grove, Megan L. ^{[18
]}

Bressler, Jan ^{[18
]}

North, Kari ^{[19
]}

Sundstrom, Johan ^{[20
]}

Gustafsson, Stefan ^{[10
]}

Shah, Sonia ^{[7
,21
]}

McRae, Allan F. ^{[7
,21
]}

Harris, Sarah E. ^{[5
,6
]}

Gibson, Jude ^{[22
]}

Redmond, Paul ^{[23
]}

Coriey, Janie ^{[23
]}

Murphy, Lee ^{[22
]}

Starr, John M. ^{[5
,24
]}

Kleinbrink, Erica ^{[25
,26
]}

Lipovich, Leonard ^{[25
,26
]}

Visscher, Peter M. ^{[5
,7
,21
]}

Wray, Naomi R. ^{[7
,21
]}

Krauss, Ronald M. ^{[27
]}

Fallin, Daniele ^{[15
]}

Feinberg, Andrew ^{[15
]}

Absher, Devin M. ^{[28
]}

Fornage, Myriam ^{[18
,33
]}

Pankow, James S. ^{[12
]}

Lind, Lars ^{[20
]}

Fox, Caroline ^{[1
,4
]}

Ingelsson, Erik ^{[10
,30
]}

Arnett, Donna K. ^{[34
]}

Boerwinkle, Eric ^{[18
,29
]}

Liang, Liming ^{[31
,32
]}

Levy, Daniel ^{[1
,4
]}

Deary, Lan J. ^{[5
,23
]}

机构：

[1] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA

[2] Boston Univ, Sch Med, Boston, MA 02118 USA

[3] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA

[4] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA

[5] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland

[6] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland

[7] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[8] Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA

[9] Boston Univ, Dept Biostat, Boston, MA USA

[10] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden

[11] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA

[12] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[13] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA

[14] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA

[15] Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA

[16] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[17] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[18] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA

[19] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA

[20] Uppsala Univ, Dept Med Sci, Cardiovasc Epidemiol, Uppsala, Sweden

[21] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[22] Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH8 9YL, Midlothian, Scotland

[23] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland

[24] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland

[25] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA

[26] Wayne State Univ, Dept Neurol, Detroit, MI USA

[27] Childrens Hosp Oakland Res Inst, Oakland, CA USA

[28] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[29] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[30] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA

[31] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[32] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[33] Univ Texas Houston, Brown Fdn Inst Mol Med, Houston, TX USA

[34] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA

来源：

PLOS MEDICINE | 2017年 / 14卷 / 01期

基金：

英国医学研究理事会; 美国国家卫生研究院; 英国惠康基金; 澳大利亚研究理事会; 英国生物技术与生命科学研究理事会; 澳大利亚国家健康与医学研究理事会; 英国经济与社会研究理事会;

关键词：

EPIGENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; LIPID-LOWERING DRUGS; GENOME-WIDE; ADIPOSE-TISSUE; INSULIN-RESISTANCE; PROVIDES INSIGHTS; COMMON VARIANTS; LOCI; OBESITY;

D O I：

10.1371/journal.pmed.1002215

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页数：30

共 91 条

[1] BLUEPRINT to decode the epigenetic signature written in blood [J].

Adams, David ;

Altucci, Lucia ;

Antonarakis, Stylianos E. ;

Ballesteros, Juan ;

Beck, Stephan ;

Bird, Adrian ;

Bock, Christoph ;

Boehm, Bernhard ;

Campo, Elias ;

Caricasole, Andrea ;

Dahl, Fredrik ;

Dermitzakis, Emmanouil T. ;

Enver, Tariq ;

Esteller, Manel ;

Estivill, Xavier ;

Ferguson-Smith, Anne ;

Fitzgibbon, Jude ;

Flicek, Paul ;

Giehl, Claudia ;

Graf, Thomas ;

Grosveld, Frank ;

Guigo, Roderic ;

Gut, Ivo ;

Helin, Kristian ;

Jarvius, Jonas ;

Kueppers, Ralf ;

Lehrach, Hans ;

Lengauer, Thomas ;

Lernmark, Ake ;

Leslie, David ;

Loeffler, Markus ;

Macintyre, Elizabeth ;

Mai, Antonello ;

Martens, Joost H. A. ;

Minucci, Saverio ;

Ouwehand, Willem H. ;

Pelicci, Pier Giuseppe ;

Pendeville, Helene ;

Porse, Bo ;

Rakyan, Vardhman ;

Reik, Wolf ;

Schrappe, Martin ;

Schuebeler, Dirk ;

Seifert, Martin ;

Siebert, Reiner ;

Simmons, David ;

Soranzo, Nicole ;

Spicuglia, Salvatore ;

Stratton, Michael ;

Stunnenberg, Hendrik G. .

NATURE BIOTECHNOLOGY, 2012, 30 (03) :224-226

[2] Epigenetic associations of type 2 diabetes and BMI in an Arab population [J].

Al Muftah, Wadha A. ;

Al-Shafai, Mashael ;

Zaghlool, Shaza B. ;

Visconti, Alessia ;

Tsai, Pei-Chien ;

Kumar, Pankaj ;

Spector, Tim ;

Bell, Jordana ;

Falchi, Mario ;

Suhre, Karsten .

CLINICAL EPIGENETICS, 2016, 8

[3] Methylation of SOCS3 is inversely associated with metabolic syndrome in an epigenome-wide association study of obesity [J].

Ali, Omar ;

Cerjak, Diana ;

Kent, Jack W., Jr. ;

James, Roland ;

Blangero, John ;

Carless, Melanie A. ;

Zhang, Yi .

EPIGENETICS, 2016, 11 (09) :699-707

[4] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[5] Epigenome-wide study identifies novel methylation loci associated with body mass index and waist circumference [J].

Aslibekyan, Stella ;

Demerath, Ellen W. ;

Mendelson, Michael ;

Zhi, Degui ;

Guan, Weihua ;

Liang, Liming ;

Sha, Jin ;

Pankow, James S. ;

Liu, Chunyu ;

Irvin, Marguerite R. ;

Fornage, Myriam ;

Hidalgo, Bertha ;

Lin, Li-An ;

Stanton Thibeault, Krista ;

Bressler, Jan ;

Tsai, Michael Y. ;

Grove, Megan L. ;

Hopkins, Paul N. ;

Boerwinkle, Eric ;

Borecki, Ingrid B. ;

Ordovas, Jose M. ;

Levy, Daniel ;

Tiwari, Hemant K. ;

Absher, Devin M. ;

Arnett, Donna K. .

OBESITY, 2015, 23 (07) :1493-1501

[6] Intracellular Pathogen Sensor NOD2 Programs Macrophages to Trigger Notch1 Activation [J].

Bansal, Kushagra ;

Balaji, Kithiganahalli N. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (07) :5823-5835

[7] Genome-Wide Association of Lipid-Lowering Response to Statins in Combined Study Populations [J].

Barber, Mathew J. ;

Mangravite, Lara M. ;

Hyde, Craig L. ;

Chasman, Daniel I. ;

Smith, Joshua D. ;

McCarty, Catherine A. ;

Li, Xiaohui ;

Wilke, Russell A. ;

Rieder, Mark J. ;

Williams, Paul T. ;

Ridker, Paul M. ;

Chatterjee, Aurobindo ;

Rotter, Jerome I. ;

Nickerson, Deborah A. ;

Stephens, Matthew ;

Krauss, Ronald M. .

PLOS ONE, 2010, 5 (03)

[8] Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes [J].

Bellini, Lara ;

Campana, Melanie ;

Mahfouz, Rana ;

Carlier, Aurelie ;

Veret, Julien ;

Magnan, Christophe ;

Hajduch, Eric ;

Le Stunff, Herve .

EXPERT OPINION ON THERAPEUTIC TARGETS, 2015, 19 (08) :1037-1050

[9] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture [J].

Berndt, Sonja I. ;

Gustafsson, Stefan ;

Maegi, Reedik ;

Ganna, Andrea ;

Wheeler, Eleanor ;

Feitosa, Mary F. ;

Justice, Anne E. ;

Monda, Keri L. ;

Croteau-Chonka, Damien C. ;

Day, Felix R. ;

Esko, Tonu ;

Fall, Tove ;

Ferreira, Teresa ;

Gentilini, Davide ;

Jackson, Anne U. ;

Luan, Jian'an ;

Randall, Joshua C. ;

Vedantam, Sailaja ;

Willer, Cristen J. ;

Winkler, Thomas W. ;

Wood, Andrew R. ;

Workalemahu, Tsegaselassie ;

Hu, Yi-Juan ;

Lee, Sang Hong ;

Liang, Liming ;

Lin, Dan-Yu ;

Min, Josine L. ;

Neale, Benjamin M. ;

Thorleifsson, Gudmar ;

Yang, Jian ;

Albrecht, Eva ;

Amin, Najaf ;

Bragg-Gresham, Jennifer L. ;

Cadby, Gemma ;

den Heijer, Martin ;

Eklund, Niina ;

Fischer, Krista ;

Goel, Anuj ;

Hottenga, Jouke-Jan ;

Huffman, Jennifer E. ;

Jarick, Ivonne ;

Johansson, Asa ;

Johnson, Toby ;

Kanoni, Stavroula ;

Kleber, Marcus E. ;

Koenig, Inke R. ;

Kristiansson, Kati ;

Kutalik, Zoltn ;

Lamina, Claudia ;

Lecoeur, Cecile .

NATURE GENETICS, 2013, 45 (05) :501-U69

[10] High density DNA methylation array with single CpG site resolution [J].

Bibikova, Marina ;

Barnes, Bret ;

Tsan, Chan ;

Ho, Vincent ;

Klotzle, Brandy ;

Le, Jennie M. ;

Delano, David ;

Zhang, Lu ;

Schroth, Gary P. ;

Gunderson, Kevin L. ;

Fan, Jian-Bing ;

Shen, Richard .

GENOMICS, 2011, 98 (04) :288-295

← 1 2 3 4 5 6 7 8 9 10 →