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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

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Ntalla , I , Weng , L-C , Cartwright , J H , Hall , A W , Sveinbjornsson , G , Tucker , N R , Choi , S H , Chaffin , M D , Roselli , C , Barnes , M R , Mifsud , B , Warren , H R , Hayward , C , Marten , J , Cranley , J J , Concas , M P , Gasparini , P , Boutin , T , Kolcic , I , Polasek , O , Rudan , I , Araujo , N M , Lima-Costa , M F , Ribeiro , A L P , Souza , R P , Tarazona-Santos , E , Giedraitis , V , Ingelsson , E , Mahajan , A , Morris , A P , Del Greco , F M , Foco , L , Gogele , M , Hicks , A A , Cook , J P , Lind , L , Lindgren , C M , Sundstrom , J , Nelson , C P , Riaz , M B , Samani , N J , Sinagra , G , Ulivi , S , Kahonen , M , Mishra , P P , Mononen , N , Nikus , K , Caulfield , M J , Dominiczak , A , Padmanabhan , S , Montasser , M E , O'Connell , J R , Ryan , K , Shuldiner , A R , Aeschbacher , S , Conen , D , Risch , L , Theriault , S , Hutri-Kahonen , N , Lehtimaki , T , Lyytikainen , L-P , Raitakari , O T , Barnes , C L K , Campbell , H , Joshi , P K , Wilson , J F , Isaacs , A , Kors , J A , van Duijn , C M , Huang , P L , Gudnason , V , Harris , T B , Launer , L J , Smith , A , Bottinger , E P , Loos , R J F , Nadkarni , G N , Preuss , M H , Correa , A , Mei , H , Wilson , J , Meitinger , T , Mueller-Nurasyid , M , Peters , A , Waldenberger , M , Mangino , M , Spector , T D , Rienstra , M , van de Vegte , Y J , van der Harst , P , Verweij , N , Kaab , S , Schramm , K , Sinner , M F , Strauch , K , Cutler , M J , Fatkin , D , London , B , Olesen , M , Roden , D M , Shoemaker , M B , Smith , J G , Biggs , M L , Bis , J C , Brody , J A , Psaty , B M , Rice , K , Sotoodehnia , N , De Grandi , A , Fuchsberger , C , Pattaro , C , Pramstaller , P P , Ford , I , Jukema , J W , Macfarlane , P W , Trompet , S , Doerr , M , Felix , S B , Voelker , U , Weiss , S , Havulinna , A S , Jula , A , Sääksjärvi , K , Salomaa , V , Guo , X , Heckbert , S R , Lin , H J , Rotter , J , Taylor , K D , Yao , J , de Mutsert , R , Maan , A C , Mook-Kanamori , D O , Noordam , R , Cucca , F , Ding , J , Lakatta , E G , Qian , Y , Tarasov , K , Levy , D , Lin , H , Newton-Cheh , C H , Lunetta , K L , Murray , A D , Porteous , D J , Smith , B H , Stricker , B H , Uitterlinden , A , van den Berg , M E , Haessler , J , Jackson , R D , Kooperberg , C , Peters , U , Reiner , A P , Whitsel , E A , Alonso , A , Arking , D E , Boerwinkle , E , Ehret , G B , Soliman , E Z , Avery , C L , Gogarten , S M , Kerr , K F , Laurie , C C , Seyerle , A A , Stilp , A , Assa , S , Said , M A , van der Ende , M Y , Lambiase , P D , Orini , M , Ramirez , J , Van Duijvenboden , S , Arnar , D O , Gudbjartsson , D F , Holm , H , Sulem , P , Thorleifsson , G , Thorolfsdottir , R B , Thorsteinsdottir , U , Benjamin , E J , Tinker , A , Stefansson , K , Ellinor , P T , Jamshidi , Y , Lubitz , S A & Munroe , P B 2020 , ' Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction ' , Nature Communications , vol. 11 , no. 1 , 2542 . https://doi.org/10.1038/s41467-020-15706-x

Title: Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
Author: Ntalla, Ioanna; Weng, Lu-Chen; Cartwright, James H.; Hall, Amelia Weber; Sveinbjornsson, Gardar; Tucker, Nathan R.; Choi, Seung Hoan; Chaffin, Mark D.; Roselli, Carolina; Barnes, Michael R.; Mifsud, Borbala; Warren, Helen R.; Hayward, Caroline; Marten, Jonathan; Cranley, James J.; Concas, Maria Pina; Gasparini, Paolo; Boutin, Thibaud; Kolcic, Ivana; Polasek, Ozren; Rudan, Igor; Araujo, Nathalia M.; Lima-Costa, Maria Fernanda; Ribeiro, Antonio Luiz P.; Souza, Renan P.; Tarazona-Santos, Eduardo; Giedraitis, Vilmantas; Ingelsson, Erik; Mahajan, Anubha; Morris, Andrew P.; Del Greco, Fabiola M.; Foco, Luisa; Gogele, Martin; Hicks, Andrew A.; Cook, James P.; Lind, Lars; Lindgren, Cecilia M.; Sundstrom, Johan; Nelson, Christopher P.; Riaz, Muhammad B.; Samani, Nilesh J.; Sinagra, Gianfranco; Ulivi, Sheila; Kahonen, Mika; Mishra, Pashupati P.; Mononen, Nina; Nikus, Kjell; Caulfield, Mark J.; Dominiczak, Anna; Padmanabhan, Sandosh; Montasser, May E.; O'Connell, Jeff R.; Ryan, Kathleen; Shuldiner, Alan R.; Aeschbacher, Stefanie; Conen, David; Risch, Lorenz; Theriault, Sebastien; Hutri-Kahonen, Nina; Lehtimaki, Terho; Lyytikainen, Leo-Pekka; Raitakari, Olli T.; Barnes, Catriona L. K.; Campbell, Harry; Joshi, Peter K.; Wilson, James F.; Isaacs, Aaron; Kors, Jan A.; van Duijn, Cornelia M.; Huang, Paul L.; Gudnason, Vilmundur; Harris, Tamara B.; Launer, Lenore J.; Smith, Albert; Bottinger, Erwin P.; Loos, Ruth J. F.; Nadkarni, Girish N.; Preuss, Michael H.; Correa, Adolfo; Mei, Hao; Wilson, James; Meitinger, Thomas; Mueller-Nurasyid, Martina; Peters, Annette; Waldenberger, Melanie; Mangino, Massimo; Spector, Timothy D.; Rienstra, Michiel; van de Vegte, Yordi J.; van der Harst, Pim; Verweij, Niek; Kaab, Stefan; Schramm, Katharina; Sinner, Moritz F.; Strauch, Konstantin; Cutler, Michael J.; Fatkin, Diane; London, Barry; Olesen, Morten; Roden, Dan M.; Shoemaker, M. Benjamin; Smith, J. Gustav; Biggs, Mary L.; Bis, Joshua C.; Brody, Jennifer A.; Psaty, Bruce M.; Rice, Kenneth; Sotoodehnia, Nona; De Grandi, Alessandro; Fuchsberger, Christian; Pattaro, Cristian; Pramstaller, Peter P.; Ford, Ian; Jukema, J. Wouter; Macfarlane, Peter W.; Trompet, Stella; Doerr, Marcus; Felix, Stephan B.; Voelker, Uwe; Weiss, Stefan; Havulinna, Aki S.; Jula, Antti; Sääksjärvi, Katri; Salomaa, Veikko; Guo, Xiuqing; Heckbert, Susan R.; Lin, Henry J.; Rotter, Jerome; Taylor, Kent D.; Yao, Jie; de Mutsert, Renee; Maan, Arie C.; Mook-Kanamori, Dennis O.; Noordam, Raymond; Cucca, Francesco; Ding, Jun; Lakatta, Edward G.; Qian, Yong; Tarasov, Kirill; Levy, Daniel; Lin, Honghuang; Newton-Cheh, Christopher H.; Lunetta, Kathryn L.; Murray, Alison D.; Porteous, David J.; Smith, Blair H.; Stricker, Bruno H.; Uitterlinden, Andre; van den Berg, Marten E.; Haessler, Jeffrey; Jackson, Rebecca D.; Kooperberg, Charles; Peters, Ulrike; Reiner, Alexander P.; Whitsel, Eric A.; Alonso, Alvaro; Arking, Dan E.; Boerwinkle, Eric; Ehret, Georg B.; Soliman, Elsayed Z.; Avery, Christy L.; Gogarten, Stephanie M.; Kerr, Kathleen F.; Laurie, Cathy C.; Seyerle, Amanda A.; Stilp, Adrienne; Assa, Solmaz; Said, M. Abdullah; van der Ende, M. Yldau; Lambiase, Pier D.; Orini, Michele; Ramirez, Julia; Van Duijvenboden, Stefan; Arnar, David O.; Gudbjartsson, Daniel F.; Holm, Hilma; Sulem, Patrick; Thorleifsson, Gudmar; Thorolfsdottir, Rosa B.; Thorsteinsdottir, Unnur; Benjamin, Emelia J.; Tinker, Andrew; Stefansson, Kari; Ellinor, Patrick T.; Jamshidi, Yalda; Lubitz, Steven A.; Munroe, Patricia B.
Contributor organization: Medicum
Institute for Molecular Medicine Finland
Complex Disease Genetics
Helsinki Institute of Life Science HiLIFE
University of Helsinki
Date: 2020-05-21
Language: eng
Number of pages: 12
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-020-15706-x
URI: http://hdl.handle.net/10138/316270
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Subject: GENOME-WIDE ASSOCIATION
ATRIAL-FIBRILLATION
MUTATIONS
RISK
DURATION
CARDIOMYOPATHY
CALCINEURIN
BRADYCARDIA
DECREASE
ELEMENTS
1184 Genetics, developmental biology, physiology
3142 Public health care science, environmental and occupational health
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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