Atrial Fibrillation Genetic Risk Differentiates Cardioembolic Stroke from other Stroke Subtypes
Authors: Pulit Sara L. , Weng Lu-Chen , McArdle Patrick F , Trinquart Ludovic , Choi Seung Hoan , Mitchell Braxton D. , Rosand Jonathan , de Bakker Paul I W , Benjamin Emelia J , Ellinor Patrick T , Kittner Steven J , Lubitz Steven A , Anderson Christopher D ,   on behalf of the Atrial Fibrillation Genetics Consortium and the International Stroke Genetics Consortium, Christophersen Ingrid E. , Rienstra Michiel , Roselli Carolina , Yin Xiaoyan , Geelhoed Bastiaan , Barnard John , Lin Honghuang , Arking Dan E. , Smith Albert V. , Albert Christine M. , Chaffin Mark , Tucker Nathan R. , Li Molong , Klarin Derek , Bihlmeyer Nathan A , Low Siew-Kee , Weeke Peter E. , Müller-Nurasyid Martina , Smith J. Gustav , Brody Jennifer A. , Niemeijer Maartje N. , Dörr Marcus , Trompet Stella , Huffman Jennifer , Gustafsson Stefan , Schurmann Claudia , Kleber Marcus E. , Lyytikäinen Leo-Pekka , Seppälä Ilkka , Malik Rainer , Horimoto Andrea R. V. R. , Perez Marco , Sinisalo Juha , Aeschbacher Stefanie , Thériault Sébastien , Yao Jie , Radmanesh Farid , Weiss Stefan , Teumer Alexander , Choi Seung Hoan , Weng Lu-Chen , Clauss Sebastian , Deo Rajat , Rader Daniel J. , Shah Svati , Siland Joylene E. , Kubo Michiaki , Smith Jonathan D. , Van Wagoner David R. , Bis Joshua C. , Perz Siegfried , Psaty Bruce M. , Ridker Paul M. , Magnani Jared W. , Harris Tamara B. , Launer Lenore J. , Shoemaker M. Benjamin , Padmanabhan Sandosh , Haessler Jeffrey , Bartz Traci M. , Waldenberger Melanie , Lichtner Peter , Arendt Marina , Krieger Jose E. , Kähönen Mika , Risch Lorenz , Mansur Alfredo J. , Peters Annette , Smith Blair H. , Lind Lars , Scott Stuart A. , Lu Yingchang , Bottinger Erwin B. , Hernesniemi Jussi , Lindgren Cecilia M. , Wong Jorge A , Huang Jie , Eskola Markku , Morris Andrew P. , Ford Ian , Reiner Alex P. , Delgado Graciela , Chen Lin Y. , Chen Yii-Der Ida , Sandhu Roopinder K. , Li Man , Boerwinkle Eric , Eisele Lewin , Lannfelt Lars , Rost Natalia , Orho-Melander arju , Hamsten Anders , Heeringa Jan , Denny Joshua C. , Kriebel Jennifer , Darbar Dawood , Newton-Cheh Christopher , Shaffer Christian , Macfarlane Peter W. , Heilmann Stefanie , Almgren Peter , Huang Paul L. , Sotoodehnia Nona , Soliman Elsayed Z. , Uitterlinden Andre G. , Hofman Albert , Franco Oscar H. , Völker Uwe , Jöckel Karl-Heinz , Sinner Moritz F. , Lin Henry J. , Guo Xiuqing , Dichgans Martin , Ingelsson Erik , Kooperberg Charles , Melander Olle , Loos Ruth J. F. , Laurikka Jari , Conen David , Rosand Jonathan , Harst Pim van der , Lokki Marja-Liisa , Kathiresan Sekar , Pereira Alexandre , Jukema J. Wouter , Hayward Caroline , Rotter Jerome I. , März Winfried , Lehtimäki Terho , Stricker Bruno H. , Chung Mina K. , Felix Stephan B. , Gudnason Vilmundur , Alonso Alvaro , Roden Dan M. , Sun Albert , Anderson Christopher D. , Kääb Stefan , Hopewell Jemma C. , Debette Stephanie , Chauhan Ganesh , Yang Qiong , Worrall Bradford B. , Paré Guillaume , Kamatani Yoichiro , Hagemeijer Yanick P. , Verweij Niek , Taylor Kent D. , Campbell Archie , Magnusson Patrik K. , Porteous David , Hocking Lynne J. , Vlachopoulou Efthymia , Pedersen Nancy L. , Nikus Kjell , Chasman Daniel I. , Heckbert Susan R. , Benjamin Emelia J. , Tanaka Toshihiro , Lunetta Kathryn L. , Lubitz Steven A. , Ellinor Patrick T. , Smoller Sylvia , Sorkin John , Wang Xingwu , Selim Magdy , Pikula Aleksandra , Wolf Philip , Debette Stephanie , Seshadri Sudha , Bakker Paul de , Pulit Sara L. , Chasman Daniel , Rexrode Kathryn , Chen Ida , Rotter Jerome , Luke May , Sale Michelle , Lee Tsong-Hai , Chang Ku-Chou , Elkind Mitchell , Goldstein Larry , James Michael Luke , Breteler Monique , O’Donnell Chris , Leys Didier , Carty Cara , Kidwell Chelsea , Olesen Jes , Sharma Pankaj , Rich Stephen , Tatlisumak Turgot , Happola Olli , Bijlenga Philippe , Soriano Carolina , Giralt Eva , Roquer Jaume , Jimenez-Conde Jordi , Cotlarcius Ioana , Hardy John , Korostynski Michal , Boncoraglio Giorgio , Ballabio Elena , Parati Eugenio , Mateusz Adamski , Urbanik Andrzej , Dziedzic Tomasz , Jagiella Jeremiasz , Gasowski Jerzy , Wnuk Marcin , Olszanecki Rafael , Pera Joanna , Slowik Agnieszka , Juchniewicz Karol Jozef , Levi Christopher , Nyquist Paul , Cendes Iscia , Cabral Norberto , Franca Paulo , Goncalves Anderson , Keller Lina , Crisby Milita , Kostulas Konstantinos , Lemmens Robin , Ahmadi Kourosh , Opherk Christian , Duering Marco , Dichgans Martin , Malik Rainer , Gonik Mariya , Staals Julie , Melander Olle , Burri Philippe , Sadr-Nabavi Ariane , Romero Javier , Biffi Alessandro , Anderson Chris , Falcone Guido , Brouwers Bart , Rosand Jonathan , Rost Natalia , Du Rose , Kourkoulis Christina , Battey Thomas , Lubitz Steven , Mueller-Myhsok Bertram , Meschia James , Brott Thomas , Pare Guillaume , Pichler Alexander , Enzinger Christian , Schmidt Helena , Schmidt Reinhold , Seiler Stephan , Blanton Susan , Yamada Yoshiji , Bersano Anna , Rundek Tatjana , Sacco Ralph , Chan Yu-Feng Yvonne , Gschwendtner Andreas , Deng Zhen , Barr Taura , Gwinn Katrina , Corriveau Roderick , Singleton Andrew , Waddy Salina , Launer Lenore , Chen Christopher , Le Kim En , Lee Wei Ling , Tan Eng King , Olugbodi Akintomi , Rothwell Peter , Schilling Sabrina , Mok Vincent , Lebedeva Elena , Jern Christina , Jood Katarina , Olsson Sandra , Kim Helen , Lee Chaeyoung , Kilarski Laura , Markus Hugh , Peycke Jennifer , Bevan Steve , Sheu Wayne , Chiou Hung Yi , Chern Joseph , Giraldo Elias , Taqi Muhammad , Jain Vivek , Lam Olivia , Howard George , Woo Daniel , Kittner Steven , Mitchell Braxton , Cole John , O’Connell Jeff , Milewicz Dianna , Illoh Kachikwu , Worrall Bradford , Stine Colin , Karaszewski Bartosz , Werring David , Sofat Reecha , Smalley June , Lindgren Arne , Hansen Bjorn , Norrving Bo , Smith Gustav , Martin Juan Jose , Thijs Vincent , Klijn Karin , van’t Hof Femke , Algra Ale , Macleod Mary , Perry Rodney , Arnett Donna , Pezzini Alessandro , Padovani Alessandro , Cramer Steve , Fisher Mark , Saleheen Danish , Broderick Joseph , Kissela Brett , Doney Alex , Cathie Sudlow , Rannikmae Kristiina , Silliman Scott , McDonough Caitrin , Walters Matthew , Pedersen Annie , Nakagawa Kazuma , Chang Christy , Dobbins Mark , McArdle Patrick , Chang Yu-Ching , Brown Robert , Brown Devin , Holliday Elizabeth , Kalaria Raj , Maguire Jane , John Attia , Farrall Martin , Giese Anne-Katrin , Fornage Myriam , Majersik Jennifer , Cushman Mary , Keene Keith , Bennett Siiri , Tirschwell David , Psaty Bruce , Reiner Alex , Longstreth Will , Spence David , Montaner Joan , Fernandez-Cadenas Israel , Langefeld Carl , Bushnell Cheryl , Heitsch Laura , Lee Jin-Moo , Sheth Kevin 
Published: December 2017

Objective

We sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.

Methods

We evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.

Results

We observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10−4in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1).

Conclusions

Genetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.