Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

Steven A. Lubitz, Kathryn L. Lunetta, Honghuang Lin, Dan E. Arking, Stella Trompet, Guo Li, Bouwe P. Krijthe, Daniel I. Chasman, John Barnard, Marcus E. Kleber, Marcus Dörr, Kouichi Ozaki, Albert V. Smith, Martina Müller-Nurasyid, Stefan Walter, Sunil K. Agarwal, Joshua C. Bis, Jennifer A. Brody, Lin Y. Chen, Brendan M. EverettIan Ford, Oscar H. Franco, Tamara B. Harris, Albert Hofman, Stefan Kääb, Saagar Mahida, Sekar Kathiresan, Michiaki Kubo, Lenore J. Launer, Peter W. Macfarlane, Jared W. Magnani, Barbara McKnight, David D. McManus, Annette Peters, Bruce M. Psaty, Lynda M. Rose, Jerome I. Rotter, Guenther Silbernagel, Jonathan D. Smith, Nona Sotoodehnia, David J. Stott, Kent D. Taylor, Andreas Tomaschitz, Tatsuhiko Tsunoda, Andre G. Uitterlinden, David R. Van Wagoner, Uwe Völker, Henry Völzke, Joanne M. Murabito, Moritz F. Sinner, Vilmundur Gudnason, Stephan B. Felix, Winfried März, Mina Chung, Christine M. Albert, Bruno H. Stricker, Toshihiro Tanaka, Susan R. Heckbert, J. Wouter Jukema, Alvaro Alonso, Emelia J. Benjamin, Patrick T. Ellinor

研究成果: Article

81 引用 (Scopus)

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Objectives This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. Background AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. Methods We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). Results We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. Conclusions The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

元の言語English
ページ(範囲)1200-1210
ページ数11
ジャーナルJournal of the American College of Cardiology
63
発行部数12
DOI
出版物ステータスPublished - 01-04-2014

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Genetic Markers
Atrial Fibrillation
Chromosomes
Genetic Predisposition to Disease

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

これを引用

Lubitz, S. A., Lunetta, K. L., Lin, H., Arking, D. E., Trompet, S., Li, G., ... Ellinor, P. T. (2014). Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. Journal of the American College of Cardiology, 63(12), 1200-1210. https://doi.org/10.1016/j.jacc.2013.12.015
Lubitz, Steven A. ; Lunetta, Kathryn L. ; Lin, Honghuang ; Arking, Dan E. ; Trompet, Stella ; Li, Guo ; Krijthe, Bouwe P. ; Chasman, Daniel I. ; Barnard, John ; Kleber, Marcus E. ; Dörr, Marcus ; Ozaki, Kouichi ; Smith, Albert V. ; Müller-Nurasyid, Martina ; Walter, Stefan ; Agarwal, Sunil K. ; Bis, Joshua C. ; Brody, Jennifer A. ; Chen, Lin Y. ; Everett, Brendan M. ; Ford, Ian ; Franco, Oscar H. ; Harris, Tamara B. ; Hofman, Albert ; Kääb, Stefan ; Mahida, Saagar ; Kathiresan, Sekar ; Kubo, Michiaki ; Launer, Lenore J. ; Macfarlane, Peter W. ; Magnani, Jared W. ; McKnight, Barbara ; McManus, David D. ; Peters, Annette ; Psaty, Bruce M. ; Rose, Lynda M. ; Rotter, Jerome I. ; Silbernagel, Guenther ; Smith, Jonathan D. ; Sotoodehnia, Nona ; Stott, David J. ; Taylor, Kent D. ; Tomaschitz, Andreas ; Tsunoda, Tatsuhiko ; Uitterlinden, Andre G. ; Van Wagoner, David R. ; Völker, Uwe ; Völzke, Henry ; Murabito, Joanne M. ; Sinner, Moritz F. ; Gudnason, Vilmundur ; Felix, Stephan B. ; März, Winfried ; Chung, Mina ; Albert, Christine M. ; Stricker, Bruno H. ; Tanaka, Toshihiro ; Heckbert, Susan R. ; Jukema, J. Wouter ; Alonso, Alvaro ; Benjamin, Emelia J. ; Ellinor, Patrick T. / Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. :: Journal of the American College of Cardiology. 2014 ; 巻 63, 番号 12. pp. 1200-1210.
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title = "Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese",
abstract = "Objectives This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. Background AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. Methods We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). Results We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. Conclusions The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.",
author = "Lubitz, {Steven A.} and Lunetta, {Kathryn L.} and Honghuang Lin and Arking, {Dan E.} and Stella Trompet and Guo Li and Krijthe, {Bouwe P.} and Chasman, {Daniel I.} and John Barnard and Kleber, {Marcus E.} and Marcus D{\"o}rr and Kouichi Ozaki and Smith, {Albert V.} and Martina M{\"u}ller-Nurasyid and Stefan Walter and Agarwal, {Sunil K.} and Bis, {Joshua C.} and Brody, {Jennifer A.} and Chen, {Lin Y.} and Everett, {Brendan M.} and Ian Ford and Franco, {Oscar H.} and Harris, {Tamara B.} and Albert Hofman and Stefan K{\"a}{\"a}b and Saagar Mahida and Sekar Kathiresan and Michiaki Kubo and Launer, {Lenore J.} and Macfarlane, {Peter W.} and Magnani, {Jared W.} and Barbara McKnight and McManus, {David D.} and Annette Peters and Psaty, {Bruce M.} and Rose, {Lynda M.} and Rotter, {Jerome I.} and Guenther Silbernagel and Smith, {Jonathan D.} and Nona Sotoodehnia and Stott, {David J.} and Taylor, {Kent D.} and Andreas Tomaschitz and Tatsuhiko Tsunoda and Uitterlinden, {Andre G.} and {Van Wagoner}, {David R.} and Uwe V{\"o}lker and Henry V{\"o}lzke and Murabito, {Joanne M.} and Sinner, {Moritz F.} and Vilmundur Gudnason and Felix, {Stephan B.} and Winfried M{\"a}rz and Mina Chung and Albert, {Christine M.} and Stricker, {Bruno H.} and Toshihiro Tanaka and Heckbert, {Susan R.} and Jukema, {J. Wouter} and Alvaro Alonso and Benjamin, {Emelia J.} and Ellinor, {Patrick T.}",
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pages = "1200--1210",
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Lubitz, SA, Lunetta, KL, Lin, H, Arking, DE, Trompet, S, Li, G, Krijthe, BP, Chasman, DI, Barnard, J, Kleber, ME, Dörr, M, Ozaki, K, Smith, AV, Müller-Nurasyid, M, Walter, S, Agarwal, SK, Bis, JC, Brody, JA, Chen, LY, Everett, BM, Ford, I, Franco, OH, Harris, TB, Hofman, A, Kääb, S, Mahida, S, Kathiresan, S, Kubo, M, Launer, LJ, Macfarlane, PW, Magnani, JW, McKnight, B, McManus, DD, Peters, A, Psaty, BM, Rose, LM, Rotter, JI, Silbernagel, G, Smith, JD, Sotoodehnia, N, Stott, DJ, Taylor, KD, Tomaschitz, A, Tsunoda, T, Uitterlinden, AG, Van Wagoner, DR, Völker, U, Völzke, H, Murabito, JM, Sinner, MF, Gudnason, V, Felix, SB, März, W, Chung, M, Albert, CM, Stricker, BH, Tanaka, T, Heckbert, SR, Jukema, JW, Alonso, A, Benjamin, EJ & Ellinor, PT 2014, 'Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese', Journal of the American College of Cardiology, 巻. 63, 番号 12, pp. 1200-1210. https://doi.org/10.1016/j.jacc.2013.12.015

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. / Lubitz, Steven A.; Lunetta, Kathryn L.; Lin, Honghuang; Arking, Dan E.; Trompet, Stella; Li, Guo; Krijthe, Bouwe P.; Chasman, Daniel I.; Barnard, John; Kleber, Marcus E.; Dörr, Marcus; Ozaki, Kouichi; Smith, Albert V.; Müller-Nurasyid, Martina; Walter, Stefan; Agarwal, Sunil K.; Bis, Joshua C.; Brody, Jennifer A.; Chen, Lin Y.; Everett, Brendan M.; Ford, Ian; Franco, Oscar H.; Harris, Tamara B.; Hofman, Albert; Kääb, Stefan; Mahida, Saagar; Kathiresan, Sekar; Kubo, Michiaki; Launer, Lenore J.; Macfarlane, Peter W.; Magnani, Jared W.; McKnight, Barbara; McManus, David D.; Peters, Annette; Psaty, Bruce M.; Rose, Lynda M.; Rotter, Jerome I.; Silbernagel, Guenther; Smith, Jonathan D.; Sotoodehnia, Nona; Stott, David J.; Taylor, Kent D.; Tomaschitz, Andreas; Tsunoda, Tatsuhiko; Uitterlinden, Andre G.; Van Wagoner, David R.; Völker, Uwe; Völzke, Henry; Murabito, Joanne M.; Sinner, Moritz F.; Gudnason, Vilmundur; Felix, Stephan B.; März, Winfried; Chung, Mina; Albert, Christine M.; Stricker, Bruno H.; Tanaka, Toshihiro; Heckbert, Susan R.; Jukema, J. Wouter; Alonso, Alvaro; Benjamin, Emelia J.; Ellinor, Patrick T.

:: Journal of the American College of Cardiology, 巻 63, 番号 12, 01.04.2014, p. 1200-1210.

研究成果: Article

TY - JOUR

T1 - Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

AU - Lubitz, Steven A.

AU - Lunetta, Kathryn L.

AU - Lin, Honghuang

AU - Arking, Dan E.

AU - Trompet, Stella

AU - Li, Guo

AU - Krijthe, Bouwe P.

AU - Chasman, Daniel I.

AU - Barnard, John

AU - Kleber, Marcus E.

AU - Dörr, Marcus

AU - Ozaki, Kouichi

AU - Smith, Albert V.

AU - Müller-Nurasyid, Martina

AU - Walter, Stefan

AU - Agarwal, Sunil K.

AU - Bis, Joshua C.

AU - Brody, Jennifer A.

AU - Chen, Lin Y.

AU - Everett, Brendan M.

AU - Ford, Ian

AU - Franco, Oscar H.

AU - Harris, Tamara B.

AU - Hofman, Albert

AU - Kääb, Stefan

AU - Mahida, Saagar

AU - Kathiresan, Sekar

AU - Kubo, Michiaki

AU - Launer, Lenore J.

AU - Macfarlane, Peter W.

AU - Magnani, Jared W.

AU - McKnight, Barbara

AU - McManus, David D.

AU - Peters, Annette

AU - Psaty, Bruce M.

AU - Rose, Lynda M.

AU - Rotter, Jerome I.

AU - Silbernagel, Guenther

AU - Smith, Jonathan D.

AU - Sotoodehnia, Nona

AU - Stott, David J.

AU - Taylor, Kent D.

AU - Tomaschitz, Andreas

AU - Tsunoda, Tatsuhiko

AU - Uitterlinden, Andre G.

AU - Van Wagoner, David R.

AU - Völker, Uwe

AU - Völzke, Henry

AU - Murabito, Joanne M.

AU - Sinner, Moritz F.

AU - Gudnason, Vilmundur

AU - Felix, Stephan B.

AU - März, Winfried

AU - Chung, Mina

AU - Albert, Christine M.

AU - Stricker, Bruno H.

AU - Tanaka, Toshihiro

AU - Heckbert, Susan R.

AU - Jukema, J. Wouter

AU - Alonso, Alvaro

AU - Benjamin, Emelia J.

AU - Ellinor, Patrick T.

PY - 2014/4/1

Y1 - 2014/4/1

N2 - Objectives This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. Background AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. Methods We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). Results We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. Conclusions The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

AB - Objectives This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. Background AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. Methods We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). Results We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. Conclusions The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

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UR - http://www.scopus.com/inward/citedby.url?scp=84896908605&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2013.12.015

DO - 10.1016/j.jacc.2013.12.015

M3 - Article

C2 - 24486271

AN - SCOPUS:84896908605

VL - 63

SP - 1200

EP - 1210

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 12

ER -