GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

著者: Nora Franceschini, Claudia Giambartolomei, Paul S. de Vries, Chris Finan, Joshua C. Bis, Rachael P. Huntley, Ruth C. Lovering, Salman M. Tajuddin, Thomas W. Winkler, Misa Graff, Maryam Kavousi, Caroline Dale, Albert V. Smith, Edith Hofer, Elisabeth M. van Leeuwen, Ilja M. Nolte, Lingyi Lu, Markus Scholz, Muralidharan Sargurupremraj, Niina Pitkänen, Oscar Franzén, Peter K. Joshi, Raymond Noordam, Riccardo E. Marioni, Shih‐Jen Hwang, Solomon K. Musani, Ulf Schminke, Walter Palmas, Aaron Isaacs, Adolfo Correa, Alan B. Zonderman, Albert Hofman, Alexander Teumer, Amanda J. Cox, André G. Uitterlinden, Andrew Wong, Andries J. Smit, Anne B. Newman, Annie Britton, Arno Ruusalepp, Bengt Sennblad, Bo Hedblad, Bogdan Paşaniuc, Brenda W.J.H. Penninx, Carl D. Langefeld, Christina L. Wassel, Christophe Tzourio, Cristiano Fava, Damiano Baldassarre, Daniel H. O’Leary, Daniel Teupser, Diana Kuh, Elena Tremoli, Elmo Mannarino, Enzo Grossi, E BOERWINKLE, Eric E. Schadt, Erik Ingelsson, Fabrizio Veglia, Fernando Rivadeneira, Frank Beutner, Ganesh Chauhan, Gerardo Heiss, Harold Snieder, Harry Campbell, Henry Völzke, Hugh S. Markus, Ian J. Deary, J. Wouter Jukema, Jacqueline de Graaf, Jacqueline Price, Janne Pott, Jemma C. Hopewell, Jingjing Liang, Joachim Thiery, Jorgen Engmann, Karl Gertow, Kenneth Rice, Kent D. Taylor, Klodian Dhana, Lambertus A. Kiemeney, Lars Lind, Laura M. Raffield, Lenore J. Launer, Lesca M. Holdt, Marcus Dörr, Martin Dichgans, Matthew Traylor, Matthias Sitzer, Meena Kumari, Mika Kivimäki, Mike A. Nalls, Olle Melander, Olli T. Raitakari, Oscar H. Franco, Oscar L. Rueda‐Ochoa, Panos Roussos, Peter H. Whincup, Philippe Amouyel, Philippe Giral, Pramod Anugu, Quenna Wong, Rainer Malik, Rainer Rauramaa, Ralph Burkhardt, Rebecca Hardy, R. Schmidt, Renée de Mutsert, Richard Morris, Rona J. Strawbridge, S. Goya Wannamethee, Sara Hägg, Sonia Shah, Stela McLachlan, Stella Trompet, Sudha Seshadri, Sudhir Kurl, Susan R. Heckbert, Susan M. Ring, Tamara B. Harris, Terho Lehtimäki, Tessel E. Galesloot, Tina Shah, Ulf dé Fairé, Vincent Plagnol, Wayne D. Rosamond, Wendy S. Post, Xiaofeng Zhu, Xiaoling Zhang, Xiuqing Guo, Yasaman Saba, Yukinori Okada, Aniket Mishra, Loes C.A. Rutten‐Jacobs, Anne-Katrin Giese, Sander W. van der Laan, Sólveig Grétarsdóttir, Christopher D. Anderson, Michael Chong, Hieab H.H. Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M. Bartz, Oscar Benavente, Steve Bevan, Giorgio B. Boncoraglio, Robert D. Brown, Adam S. Butterworth, Caty Carrera, Cara L. Carty, Daniel I. Chasman, Wei‐Min Chen, John W. Cole, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, P. Bakker, Anita L. DeStefano, Marcel den Hoed, Qing Duan, Stefan T. Engelter, Guido J. Falcone, Rebecca F. Gottesman, Raji P. Grewal, Stefan Gustafsson, Jeffrey Haessler, Tamara B. Harris, Ahamad Hassan, Aki S. Havulinna, Elizabeth G. Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I. Hyacinth, M. Arfan Ikram, Marguerite R. Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A. Johnson, J. Wouter Jukema, Masahiro Kanai, Keith L. Keene, Brett Kissela, Dawn Kleindorfer, Charles Kooperberg, Michiaki Kubo, Leslie Lange, Carl D. Langefeld, Claudia Langenberg, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M. Lewis, Wei‐Yu Lin, Arne Lindgren, Erik Lorentzen, Patrik K. E. Magnusson, Jane Maguire, Ani Manichaikul, Patrick F. McArdle, James F. Meschia, Thomas H. Mosley, Toshiharu Ninomiya, Martin O’Donnell, Sara L. Pulit, Kristiina Rannikmäe, Alex P. Reiner, Kathryn M. Rexrode, Stephen S. Rich, Paul M. Ridker, Natalia S. Rost, Peter M. Rothwell, Tatjana Rundek, Ralph L. Sacco, Saori Sakaue, Michèle M. Sale, Veikko Salomaa, Bishwa R. Sapkota, R. Schmidt, Carsten Oliver Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie Sudlow, Christian Tanislav, Turgut Tatlisumak, Vincent Thijs, Guðmar Þorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, James Walters, Nicholas J. Wareham, Sylvia Wassertheil‐Smoller, Kerri L. Wiggins, Qiong Yang, Salim Yusuf, Tomi Pastinen, Arno Ruusalepp, Eric E. Schadt, Simon Koplev, Veronica Codoni, Mete Civelek, Nick Smith, David‐Alexandre Trégouët, Ingrid E. Christophersen, Carolina Roselli, Steven A. Lubitz, Patrick T. Ellinor, E Shyong Tai, Jaspal S. Kooner, Norihiro Kato, Jiang He, Pim van der Harst, Paul Elliott, John C. Chambers, Fumihiko Takeuchi, Andrew D. Johnson, Dharambir K. Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernández‐Cadenas, W.T. Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Paré, Danish Saleheen, Kari Stefansson, Bradford B. Worrall, Steven J. Kittner, Joanna M. M. Howson, Yoichiro Kamatani, Abbas Dehghan, Adrie Seldenrijk, Alanna C. Morrison, Anders Hamsten, Bruce M. Psaty, Cornelia M. van Duijn, Debbie A. Lawlor, Dennis O. Mook‐Kanamori, Donald W. Bowden, Helena Schmidt, James F. Wilson, James G. Wilson, Jerome I. Rotter, Joanna M. Wardlaw, John Deanfield, Julian Halcox, Leo‐Pekka Lyytikäinen, Markus Loeffler, Michele K. Evans, Stéphanie Debette, Steve E. Humphries, Uwe Völker, Vilmundur Guðnason, Aroon D. Hingorani, Johan Björkegren, Juan P. Casas, Christopher J. O’Donnell - Nature Communications 2018 被引用: 178

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.