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

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.