Genome-wide association study of PR interval

Arne Pfeufer; Charlotte Van Noord; Kristin D. Marciante; Dan E. Arking; Martin G. Larson; Albert Vernon Smith; Kirill V. Tarasov; Martina Müller; Nona Sotoodehnia; Moritz F. Sinner; Germaine C. Verwoert; Man Li; W. H.Linda Kao; Anna Köttgen; Josef Coresh; Joshua C. Bis; Bruce M. Psaty; Kenneth Rice; Jerome I. Rotter; Fernando Rivadeneira; Albert Hofman; Jan A. Kors; Bruno H.C. Stricker; André G. Uitterlinden; Cornelia M. Van Duijn; Britt M. Beckmann; Wiebke Sauter; Christian Gieger; Steven A. Lubitz; Christopher Newton-Cheh; Thomas J. Wang; Jared W. Magnani; Renate B. Schnabel; Mina K. Chung; John Barnard; Jonathan D. Smith; David R. Van Wagoner; Ramachandran S. Vasan; Thor Aspelund; Gudny Eiriksdottir; Tamara B. Harris; Lenore J. Launer; Samer S. Najjar; Edward Lakatta; David Schlessinger; Manuela Uda; Gonçalo R. Abecasis; Bertram Müller-Myhsok; Georg B. Ehret; Eric Boerwinkle; Aravinda Chakravarti; Elsayed Z. Soliman; Kathryn L. Lunetta; Siegfried Perz; H. Erich Wichmann; Thomas Meitinger; Daniel Levy; Vilmundur Gudnason; Patrick T. Ellinor; Serena Sanna; Stefan Kääb; Jacqueline C.M. Witteman; Alvaro Alonso; Emelia J. Benjamin; Susan R. Heckbert

doi:10.1038/ng.517

Genome-wide association study of PR interval

Arne Pfeufer, Charlotte Van Noord, Kristin D. Marciante, Dan E. Arking, Martin G. Larson, Albert Vernon Smith, Kirill V. Tarasov, Martina Müller, Nona Sotoodehnia, Moritz F. Sinner, Germaine C. Verwoert, Man Li, W. H.Linda Kao, Anna Köttgen, Josef Coresh, Joshua C. Bis, Bruce M. Psaty, Kenneth Rice, Jerome I. Rotter, Fernando RivadeneiraAlbert Hofman, Jan A. Kors, Bruno H.C. Stricker, André G. Uitterlinden, Cornelia M. Van Duijn, Britt M. Beckmann, Wiebke Sauter, Christian Gieger, Steven A. Lubitz, Christopher Newton-Cheh, Thomas J. Wang, Jared W. Magnani, Renate B. Schnabel, Mina K. Chung, John Barnard, Jonathan D. Smith, David R. Van Wagoner, Ramachandran S. Vasan, Thor Aspelund, Gudny Eiriksdottir, Tamara B. Harris, Lenore J. Launer, Samer S. Najjar, Edward Lakatta, David Schlessinger, Manuela Uda, Gonçalo R. Abecasis, Bertram Müller-Myhsok, Georg B. Ehret, Eric Boerwinkle, Aravinda Chakravarti, Elsayed Z. Soliman, Kathryn L. Lunetta, Siegfried Perz, H. Erich Wichmann, Thomas Meitinger, Daniel Levy, Vilmundur Gudnason, Patrick T. Ellinor, Serena Sanna, Stefan Kääb, Jacqueline C.M. Witteman, Alvaro Alonso, Emelia J. Benjamin, Susan R. Heckbert

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324 Scopus citations

Abstract

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Original language	English (US)
Pages (from-to)	153-159
Number of pages	7
Journal	Nature genetics
Volume	42
Issue number	2
DOIs	https://doi.org/10.1038/ng.517
State	Published - Feb 2010

ASJC Scopus subject areas

Genetics

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10.1038/ng.517

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Pfeufer, A., Van Noord, C., Marciante, K. D., Arking, D. E., Larson, M. G., Smith, A. V., Tarasov, K. V., Müller, M., Sotoodehnia, N., Sinner, M. F., Verwoert, G. C., Li, M., Kao, W. H. L., Köttgen, A., Coresh, J., Bis, J. C., Psaty, B. M., Rice, K., Rotter, J. I., ... Heckbert, S. R. (2010). Genome-wide association study of PR interval. Nature genetics, 42(2), 153-159. https://doi.org/10.1038/ng.517

Pfeufer, A, Van Noord, C, Marciante, KD, Arking, DE, Larson, MG, Smith, AV, Tarasov, KV, Müller, M, Sotoodehnia, N, Sinner, MF, Verwoert, GC, Li, M, Kao, WHL, Köttgen, A, Coresh, J, Bis, JC, Psaty, BM, Rice, K, Rotter, JI, Rivadeneira, F, Hofman, A, Kors, JA, Stricker, BHC, Uitterlinden, AG, Van Duijn, CM, Beckmann, BM, Sauter, W, Gieger, C, Lubitz, SA, Newton-Cheh, C, Wang, TJ, Magnani, JW, Schnabel, RB, Chung, MK, Barnard, J, Smith, JD, Van Wagoner, DR, Vasan, RS, Aspelund, T, Eiriksdottir, G, Harris, TB, Launer, LJ, Najjar, SS, Lakatta, E, Schlessinger, D, Uda, M, Abecasis, GR, Müller-Myhsok, B, Ehret, GB, Boerwinkle, E, Chakravarti, A, Soliman, EZ, Lunetta, KL, Perz, S, Wichmann, HE, Meitinger, T, Levy, D, Gudnason, V, Ellinor, PT, Sanna, S, Kääb, S, Witteman, JCM, Alonso, A, Benjamin, EJ & Heckbert, SR 2010, 'Genome-wide association study of PR interval', Nature genetics, vol. 42, no. 2, pp. 153-159. https://doi.org/10.1038/ng.517

@article{f99d76f61ff04514b326e6e1563a674e,

title = "Genome-wide association study of PR interval",

abstract = "The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.",

author = "Arne Pfeufer and {Van Noord}, Charlotte and Marciante, {Kristin D.} and Arking, {Dan E.} and Larson, {Martin G.} and Smith, {Albert Vernon} and Tarasov, {Kirill V.} and Martina M{\"u}ller and Nona Sotoodehnia and Sinner, {Moritz F.} and Verwoert, {Germaine C.} and Man Li and Kao, {W. H.Linda} and Anna K{\"o}ttgen and Josef Coresh and Bis, {Joshua C.} and Psaty, {Bruce M.} and Kenneth Rice and Rotter, {Jerome I.} and Fernando Rivadeneira and Albert Hofman and Kors, {Jan A.} and Stricker, {Bruno H.C.} and Uitterlinden, {Andr{\'e} G.} and {Van Duijn}, {Cornelia M.} and Beckmann, {Britt M.} and Wiebke Sauter and Christian Gieger and Lubitz, {Steven A.} and Christopher Newton-Cheh and Wang, {Thomas J.} and Magnani, {Jared W.} and Schnabel, {Renate B.} and Chung, {Mina K.} and John Barnard and Smith, {Jonathan D.} and {Van Wagoner}, {David R.} and Vasan, {Ramachandran S.} and Thor Aspelund and Gudny Eiriksdottir and Harris, {Tamara B.} and Launer, {Lenore J.} and Najjar, {Samer S.} and Edward Lakatta and David Schlessinger and Manuela Uda and Abecasis, {Gon{\c c}alo R.} and Bertram M{\"u}ller-Myhsok and Ehret, {Georg B.} and Eric Boerwinkle and Aravinda Chakravarti and Soliman, {Elsayed Z.} and Lunetta, {Kathryn L.} and Siegfried Perz and Wichmann, {H. Erich} and Thomas Meitinger and Daniel Levy and Vilmundur Gudnason and Ellinor, {Patrick T.} and Serena Sanna and Stefan K{\"a}{\"a}b and Witteman, {Jacqueline C.M.} and Alvaro Alonso and Benjamin, {Emelia J.} and Heckbert, {Susan R.}",

note = "Funding Information: Diseases in the Elderly, Netherlands Genome Initiative, Stichting Zorgonderzoek Nederland-Medische Wetenschappen (The Netherlands Organisation for Health Research and Development), Netherlands Hartstichting, Netherlands Ministry of Education Culture and Science, Netherlands Ministry of Health Welfare and Sports; the European Commission; Erasmus Medical Center, Erasmus University Rotterdam and the municipality of Rotterdam. SardiNIA: We thank A. Scuteri and M. Orr{\`u} for longstanding, continual support of the project and for phenotype characterization. NIA NO1-AG-1-2109, 263-MA-410953, NIH and NIA Intramural Research Programs, NHGRI and NHLBI. Role of the sponsors: None of the funding organizations had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review or approval of the manuscript. More detailed acknowledgments can be found in the Supplementary Note. Funding Information: We gratefully acknowledge all of the participants in the studies. AGES: US National Institutes of Health (NIH) N01-AG-12100, US National Institute on Aging (NIA) and NIH Intramural Research Programs, Hjartavernd (Icelandic Heart Association), Althingi (Icelandic parliament), US National Heart, Lung, and Blood Institute (NHLBI), US National Eye Institute and US National Institute on Deafness and Other Communication Disorders. ARIC: NHLBI N01-HC-55015, N01-HC-55016, N01-HC-55018 through N01-HC-55022, R01-HL-087641, R01-HL-59367, R01-HL-086694 and R01-HL-054512; US National Human Genome Research Institute (NHGRI) U01-HG004402; NIH HHSN268200625226C; and the Donald W. Reynolds Cardiovascular Clinical Research Center. Infrastructure was supported by NIH UL1-RR025005. CCAF: NHLBI R01-HL090620 and P50-HL077107, and intramural funding from the Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic. CHS: NHLBI N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01-HL-080295, R01-HL-087652 and R01-HL-088456; US National Center for Research Resources M01-RR-00425; National Institute of Diabetes and Digestive and Kidney Diseases DK063491; US National Institute of Neurological Disorders and Stroke; and the Cedars-Sinai Board of Governors. FHS: NIH N01-HC-25195, HL-076784, AG-028321, N01-HC25195, HL-080025 and 6R01-NS-17950; NHLBI N01-HC-25195; Boston University School of Medicine and Boston Medical Center (LINGA-II); the Robert Dawson Evans Endowment; the Doris Duke Charitable Foundation; the SHARe project; Deutsche Forschungsgemeinschaft fellowship SCHN 1149/1-1; Affymetrix contract for genotyping services (N02-HL-6-4278); and Pfizer. KORA/AFNET: We thank B. P{\"u}tz, M. Putz and G. Fischer for their contributions to genotyping and imputation. Bundesministerium f{\"u}r Bildung und Forschung Nationales Genomforschungsnetz; 01-GS-0499, 01-GR-0103, 01-GR-0803, AFNET 01-GI-0204 01-GS-0838, the Leducq Foundation 07-CVD 03, Ludwig-Maximilians University (LMU) F{\"o}FoLe 557/569, the LMU Excellence Initiative, MC Health as part of LMUinnovativ, the Helmholtz Zentrum M{\"u}nchen f{\"u}r Gesundheit und Umwelt and the state of Bavaria. Rotterdam Study: We thank P. Arp, M. Jhamai, M. Moorhouse, M.Verkerk and S. Bervoets for their help in creating the database, K. Estrada for his help with the analyses and M. Struchalin for contributions to genotype imputation. Nederlandse Organisatie voor Wetenschappelijk Onderzoek (The Netherlands Organisation for Scientific Research) 175.010.2005.011, 911.03.012 and 050-060-810, the Research Institute of",

year = "2010",

month = feb,

doi = "10.1038/ng.517",

language = "English (US)",

volume = "42",

pages = "153--159",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Genome-wide association study of PR interval

AU - Pfeufer, Arne

AU - Van Noord, Charlotte

AU - Marciante, Kristin D.

AU - Arking, Dan E.

AU - Larson, Martin G.

AU - Smith, Albert Vernon

AU - Tarasov, Kirill V.

AU - Müller, Martina

AU - Sotoodehnia, Nona

AU - Sinner, Moritz F.

AU - Verwoert, Germaine C.

AU - Li, Man

AU - Kao, W. H.Linda

AU - Köttgen, Anna

AU - Coresh, Josef

AU - Bis, Joshua C.

AU - Psaty, Bruce M.

AU - Rice, Kenneth

AU - Rotter, Jerome I.

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - Kors, Jan A.

AU - Stricker, Bruno H.C.

AU - Uitterlinden, André G.

AU - Van Duijn, Cornelia M.

AU - Beckmann, Britt M.

AU - Sauter, Wiebke

AU - Gieger, Christian

AU - Lubitz, Steven A.

AU - Newton-Cheh, Christopher

AU - Wang, Thomas J.

AU - Magnani, Jared W.

AU - Schnabel, Renate B.

AU - Chung, Mina K.

AU - Barnard, John

AU - Smith, Jonathan D.

AU - Van Wagoner, David R.

AU - Vasan, Ramachandran S.

AU - Aspelund, Thor

AU - Eiriksdottir, Gudny

AU - Harris, Tamara B.

AU - Launer, Lenore J.

AU - Najjar, Samer S.

AU - Lakatta, Edward

AU - Schlessinger, David

AU - Uda, Manuela

AU - Abecasis, Gonçalo R.

AU - Müller-Myhsok, Bertram

AU - Ehret, Georg B.

AU - Boerwinkle, Eric

AU - Chakravarti, Aravinda

AU - Soliman, Elsayed Z.

AU - Lunetta, Kathryn L.

AU - Perz, Siegfried

AU - Wichmann, H. Erich

AU - Meitinger, Thomas

AU - Levy, Daniel

AU - Gudnason, Vilmundur

AU - Ellinor, Patrick T.

AU - Sanna, Serena

AU - Kääb, Stefan

AU - Witteman, Jacqueline C.M.

AU - Alonso, Alvaro

AU - Benjamin, Emelia J.

AU - Heckbert, Susan R.

N1 - Funding Information: Diseases in the Elderly, Netherlands Genome Initiative, Stichting Zorgonderzoek Nederland-Medische Wetenschappen (The Netherlands Organisation for Health Research and Development), Netherlands Hartstichting, Netherlands Ministry of Education Culture and Science, Netherlands Ministry of Health Welfare and Sports; the European Commission; Erasmus Medical Center, Erasmus University Rotterdam and the municipality of Rotterdam. SardiNIA: We thank A. Scuteri and M. Orrù for longstanding, continual support of the project and for phenotype characterization. NIA NO1-AG-1-2109, 263-MA-410953, NIH and NIA Intramural Research Programs, NHGRI and NHLBI. Role of the sponsors: None of the funding organizations had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review or approval of the manuscript. More detailed acknowledgments can be found in the Supplementary Note. Funding Information: We gratefully acknowledge all of the participants in the studies. AGES: US National Institutes of Health (NIH) N01-AG-12100, US National Institute on Aging (NIA) and NIH Intramural Research Programs, Hjartavernd (Icelandic Heart Association), Althingi (Icelandic parliament), US National Heart, Lung, and Blood Institute (NHLBI), US National Eye Institute and US National Institute on Deafness and Other Communication Disorders. ARIC: NHLBI N01-HC-55015, N01-HC-55016, N01-HC-55018 through N01-HC-55022, R01-HL-087641, R01-HL-59367, R01-HL-086694 and R01-HL-054512; US National Human Genome Research Institute (NHGRI) U01-HG004402; NIH HHSN268200625226C; and the Donald W. Reynolds Cardiovascular Clinical Research Center. Infrastructure was supported by NIH UL1-RR025005. CCAF: NHLBI R01-HL090620 and P50-HL077107, and intramural funding from the Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic. CHS: NHLBI N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01-HL-080295, R01-HL-087652 and R01-HL-088456; US National Center for Research Resources M01-RR-00425; National Institute of Diabetes and Digestive and Kidney Diseases DK063491; US National Institute of Neurological Disorders and Stroke; and the Cedars-Sinai Board of Governors. FHS: NIH N01-HC-25195, HL-076784, AG-028321, N01-HC25195, HL-080025 and 6R01-NS-17950; NHLBI N01-HC-25195; Boston University School of Medicine and Boston Medical Center (LINGA-II); the Robert Dawson Evans Endowment; the Doris Duke Charitable Foundation; the SHARe project; Deutsche Forschungsgemeinschaft fellowship SCHN 1149/1-1; Affymetrix contract for genotyping services (N02-HL-6-4278); and Pfizer. KORA/AFNET: We thank B. Pütz, M. Putz and G. Fischer for their contributions to genotyping and imputation. Bundesministerium für Bildung und Forschung Nationales Genomforschungsnetz; 01-GS-0499, 01-GR-0103, 01-GR-0803, AFNET 01-GI-0204 01-GS-0838, the Leducq Foundation 07-CVD 03, Ludwig-Maximilians University (LMU) FöFoLe 557/569, the LMU Excellence Initiative, MC Health as part of LMUinnovativ, the Helmholtz Zentrum München für Gesundheit und Umwelt and the state of Bavaria. Rotterdam Study: We thank P. Arp, M. Jhamai, M. Moorhouse, M.Verkerk and S. Bervoets for their help in creating the database, K. Estrada for his help with the analyses and M. Struchalin for contributions to genotype imputation. Nederlandse Organisatie voor Wetenschappelijk Onderzoek (The Netherlands Organisation for Scientific Research) 175.010.2005.011, 911.03.012 and 050-060-810, the Research Institute of

PY - 2010/2

Y1 - 2010/2

N2 - The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

AB - The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

UR - http://www.scopus.com/inward/record.url?scp=75749097235&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=75749097235&partnerID=8YFLogxK

U2 - 10.1038/ng.517

DO - 10.1038/ng.517

M3 - Article

C2 - 20062060

AN - SCOPUS:75749097235

SN - 1061-4036

VL - 42

SP - 153

EP - 159

JO - Nature genetics

JF - Nature genetics

IS - 2

ER -

Genome-wide association study of PR interval

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