%0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Eric Boerwinkle %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Protein-Lysine 6-Oxidase %K Quantitative Trait Loci %K Risk Factors %X

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

%B Nat Commun %V 9 %P 5141 %8 2018 Dec 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30510157?dopt=Abstract %R 10.1038/s41467-018-07340-5 %0 Journal Article %J PLoS Med %D 2017 %T Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach. %A Mendelson, Michael M %A Marioni, Riccardo E %A Joehanes, Roby %A Liu, Chunyu %A Hedman, Åsa K %A Aslibekyan, Stella %A Demerath, Ellen W %A Guan, Weihua %A Zhi, Degui %A Yao, Chen %A Huan, Tianxiao %A Willinger, Christine %A Chen, Brian %A Courchesne, Paul %A Multhaup, Michael %A Irvin, Marguerite R %A Cohain, Ariella %A Schadt, Eric E %A Grove, Megan L %A Bressler, Jan %A North, Kari %A Sundström, Johan %A Gustafsson, Stefan %A Shah, Sonia %A McRae, Allan F %A Harris, Sarah E %A Gibson, Jude %A Redmond, Paul %A Corley, Janie %A Murphy, Lee %A Starr, John M %A Kleinbrink, Erica %A Lipovich, Leonard %A Visscher, Peter M %A Wray, Naomi R %A Krauss, Ronald M %A Fallin, Daniele %A Feinberg, Andrew %A Absher, Devin M %A Fornage, Myriam %A Pankow, James S %A Lind, Lars %A Fox, Caroline %A Ingelsson, Erik %A Arnett, Donna K %A Eric Boerwinkle %A Liang, Liming %A Levy, Daniel %A Deary, Ian J %K Aged %K Body Mass Index %K Coronary Artery Disease %K DNA Methylation %K Epigenesis, Genetic %K Female %K Gene Expression Regulation %K Genome-Wide Association Study %K Humans %K Leukocytes %K Lipid Metabolism %K Male %K Mendelian Randomization Analysis %K Obesity %K Oligonucleotide Array Sequence Analysis %X

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.

%B PLoS Med %V 14 %P e1002215 %8 2017 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28095459?dopt=Abstract %R 10.1371/journal.pmed.1002215