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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 2542 |
| Tidsskrift | Nature Communications |
| Vol/bind | 11 |
| Udgave nummer | 1 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 1 dec. 2020 |
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. / 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 M, Fabiola; Foco, Luisa; Gögele, Martin; Hicks, Andrew A.; Cook, James P.; Lind, Lars; Lindgren, Cecilia M.; Sundström, Johan; Nelson, Christopher P.; Riaz, Muhammad B.; Samani, Nilesh J.; Sinagra, Gianfranco; Ulivi, Sheila; Kähönen, 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; Thériault, Sébastien; Hutri-Kähönen, Nina; Lehtimäki, Terho; Lyytikäinen, 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 V.; Bottinger, Erwin P.; Loos, Ruth J.F.; Nadkarni, Girish N.; Preuss, Michael H.; Correa, Adolfo; Mei, Hao; Wilson, James; Meitinger, Thomas; Müller-Nurasyid, Martina; Peters, Annette; Waldenberger, Melanie; Mangino, Massimo; Spector, Timothy D.; Rienstra, Michiel; van de Vegte, Yordi J.; van der Harst, Pim; Verweij, Niek; Kääb, Stefan; Schramm, Katharina; Sinner, Moritz F.; Strauch, Konstantin; Cutler, Michael J.; Fatkin, Diane; London, Barry; Olesen, Morten; Roden, Dan M.; Benjamin Shoemaker, M.; Gustav Smith, J.; 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; Wouter Jukema, J.; Macfarlane, Peter W.; Trompet, Stella; Dörr, Marcus; Felix, Stephan B.; Völker, Uwe; Weiss, Stefan; Havulinna, Aki S.; Jula, Antti; Sääksjärvi, Katri; Salomaa, Veikko; Guo, Xiuqing; Heckbert, Susan R.; Lin, Henry J.; Rotter, Jerome I.; Taylor, Kent D.; Yao, Jie; de Mutsert, Renée; Maan, Arie C.; Mook-Kanamori, Dennis O.; Noordam, Raymond; Cucca, Francesco; Ding, Jun; Lakatta, Edward G.; Qian, Yong; Tarasov, Kirill V.; Levy, Daniel; Lin, Honghuang; Newton-Cheh, Christopher H.; Lunetta, Kathryn L.; Murray, Alison D.; Porteous, David J.; Smith, Blair H.; Stricker, Bruno H.; Uitterlinden, André; 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; Abdullah Said, M.; Yldau van der Ende, M.; 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.
I: Nature Communications, Bind 11, Nr. 1, 2542, 01.12.2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
TY - JOUR
T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
AU - Ntalla, Ioanna
AU - Weng, Lu Chen
AU - Cartwright, James H.
AU - Hall, Amelia Weber
AU - Sveinbjornsson, Gardar
AU - Tucker, Nathan R.
AU - Choi, Seung Hoan
AU - Chaffin, Mark D.
AU - Roselli, Carolina
AU - Barnes, Michael R.
AU - Mifsud, Borbala
AU - Warren, Helen R.
AU - Hayward, Caroline
AU - Marten, Jonathan
AU - Cranley, James J.
AU - Concas, Maria Pina
AU - Gasparini, Paolo
AU - Boutin, Thibaud
AU - Kolcic, Ivana
AU - Polasek, Ozren
AU - Rudan, Igor
AU - Araujo, Nathalia M.
AU - Lima-Costa, Maria Fernanda
AU - Ribeiro, Antonio Luiz P.
AU - Souza, Renan P.
AU - Tarazona-Santos, Eduardo
AU - Giedraitis, Vilmantas
AU - Ingelsson, Erik
AU - Mahajan, Anubha
AU - Morris, Andrew P.
AU - Del Greco M, Fabiola
AU - Foco, Luisa
AU - Gögele, Martin
AU - Hicks, Andrew A.
AU - Cook, James P.
AU - Lind, Lars
AU - Lindgren, Cecilia M.
AU - Sundström, Johan
AU - Nelson, Christopher P.
AU - Riaz, Muhammad B.
AU - Samani, Nilesh J.
AU - Sinagra, Gianfranco
AU - Ulivi, Sheila
AU - Kähönen, Mika
AU - Mishra, Pashupati P.
AU - Mononen, Nina
AU - Nikus, Kjell
AU - Caulfield, Mark J.
AU - Dominiczak, Anna
AU - Padmanabhan, Sandosh
AU - Montasser, May E.
AU - O’Connell, Jeff R.
AU - Ryan, Kathleen
AU - Shuldiner, Alan R.
AU - Aeschbacher, Stefanie
AU - Conen, David
AU - Risch, Lorenz
AU - Thériault, Sébastien
AU - Hutri-Kähönen, Nina
AU - Lehtimäki, Terho
AU - Lyytikäinen, Leo Pekka
AU - Raitakari, Olli T.
AU - Barnes, Catriona L.K.
AU - Campbell, Harry
AU - Joshi, Peter K.
AU - Wilson, James F.
AU - Isaacs, Aaron
AU - Kors, Jan A.
AU - van Duijn, Cornelia M.
AU - Huang, Paul L.
AU - Gudnason, Vilmundur
AU - Harris, Tamara B.
AU - Launer, Lenore J.
AU - Smith, Albert V.
AU - Bottinger, Erwin P.
AU - Loos, Ruth J.F.
AU - Nadkarni, Girish N.
AU - Preuss, Michael H.
AU - Correa, Adolfo
AU - Mei, Hao
AU - Wilson, James
AU - Meitinger, Thomas
AU - Müller-Nurasyid, Martina
AU - Peters, Annette
AU - Waldenberger, Melanie
AU - Mangino, Massimo
AU - Spector, Timothy D.
AU - Rienstra, Michiel
AU - van de Vegte, Yordi J.
AU - van der Harst, Pim
AU - Verweij, Niek
AU - Kääb, Stefan
AU - Schramm, Katharina
AU - Sinner, Moritz F.
AU - Strauch, Konstantin
AU - Cutler, Michael J.
AU - Fatkin, Diane
AU - London, Barry
AU - Olesen, Morten
AU - Roden, Dan M.
AU - Benjamin Shoemaker, M.
AU - Gustav Smith, J.
AU - Biggs, Mary L.
AU - Bis, Joshua C.
AU - Brody, Jennifer A.
AU - Psaty, Bruce M.
AU - Rice, Kenneth
AU - Sotoodehnia, Nona
AU - De Grandi, Alessandro
AU - Fuchsberger, Christian
AU - Pattaro, Cristian
AU - Pramstaller, Peter P.
AU - Ford, Ian
AU - Wouter Jukema, J.
AU - Macfarlane, Peter W.
AU - Trompet, Stella
AU - Dörr, Marcus
AU - Felix, Stephan B.
AU - Völker, Uwe
AU - Weiss, Stefan
AU - Havulinna, Aki S.
AU - Jula, Antti
AU - Sääksjärvi, Katri
AU - Salomaa, Veikko
AU - Guo, Xiuqing
AU - Heckbert, Susan R.
AU - Lin, Henry J.
AU - Rotter, Jerome I.
AU - Taylor, Kent D.
AU - Yao, Jie
AU - de Mutsert, Renée
AU - Maan, Arie C.
AU - Mook-Kanamori, Dennis O.
AU - Noordam, Raymond
AU - Cucca, Francesco
AU - Ding, Jun
AU - Lakatta, Edward G.
AU - Qian, Yong
AU - Tarasov, Kirill V.
AU - Levy, Daniel
AU - Lin, Honghuang
AU - Newton-Cheh, Christopher H.
AU - Lunetta, Kathryn L.
AU - Murray, Alison D.
AU - Porteous, David J.
AU - Smith, Blair H.
AU - Stricker, Bruno H.
AU - Uitterlinden, André
AU - van den Berg, Marten E.
AU - Haessler, Jeffrey
AU - Jackson, Rebecca D.
AU - Kooperberg, Charles
AU - Peters, Ulrike
AU - Reiner, Alexander P.
AU - Whitsel, Eric A.
AU - Alonso, Alvaro
AU - Arking, Dan E.
AU - Boerwinkle, Eric
AU - Ehret, Georg B.
AU - Soliman, Elsayed Z.
AU - Avery, Christy L.
AU - Gogarten, Stephanie M.
AU - Kerr, Kathleen F.
AU - Laurie, Cathy C.
AU - Seyerle, Amanda A.
AU - Stilp, Adrienne
AU - Assa, Solmaz
AU - Abdullah Said, M.
AU - Yldau van der Ende, M.
AU - Lambiase, Pier D.
AU - Orini, Michele
AU - Ramirez, Julia
AU - Van Duijvenboden, Stefan
AU - Arnar, David O.
AU - Gudbjartsson, Daniel F.
AU - Holm, Hilma
AU - Sulem, Patrick
AU - Thorleifsson, Gudmar
AU - Thorolfsdottir, Rosa B.
AU - Thorsteinsdottir, Unnur
AU - Benjamin, Emelia J.
AU - Tinker, Andrew
AU - Stefansson, Kari
AU - Ellinor, Patrick T.
AU - Jamshidi, Yalda
AU - Lubitz, Steven A.
AU - Munroe, Patricia B.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085157192&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-15706-x
DO - 10.1038/s41467-020-15706-x
M3 - Journal article
C2 - 32439900
AN - SCOPUS:85085157192
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2542
ER -