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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.

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Figure 1: Manhattan plot of genome-wide association analyses.
Figure 2: Association results at each significantly associated locus.

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Acknowledgements

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 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.

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Study concept and design: A.P., D.E.A., A.V.S., N.S., J.I.R., A.H., B.H.C.S., C.M.v.D., G.E., A.C., K.L.L., V.G., P.T.E., S.S., S.K., J.C.M.W., E.J.B., S.R.H. Acquisition of data: A.P., C.v.N., D.E.A., K.V.T., M.F.S., J.I.R., F.R., J.A.K., B.H.C.S., A.G.U., B.M.B., W.S., C.G., C.N.-C., T.J.W., M.K.C., J.D.S., D.R.V.W., S.S.N., G.B.E., A.C., E.Z.S., S.P., J.C.M.W., A.A., S.R.H. Analysis and interpretation of data: A.P., C.v.N., K.D.M., D.E.A., A.V.S., M.M., N.S., G.C.V., M.L., J.I.R., C.N.-C., T.J.W., R.S.V., T.A., S.S.N., G.B.E., A.C., E.Z.S., K.L.L., S.P., V.G., E.J.B., S.R.H. Drafting the manuscript: A.P., D.E.A., N.S., P.T.E., S.K., E.J.B., S.R.H. Critical revision of the manuscript: C.v.N., K.D.M., M.G.L., A.V.S., K.V.T., M.M., M.F.S., G.C.V., W.H.L.K., A.K., J.C., J.C.B., B.M.P., K.R., J.I.R., F.R., A.H., J.A.K., B.H.C.S., A.G.U., C.M.v.D., B.M.B., C.G., S.A.L., C.N.-C., T.J.W., J.W.M., R.B.S., M.K.C., J.B., J.D.S., D.R.V.W., R.S.V., G.E., L.J.L., T.B.H., E.L., D.S., M.U., G.R.A., B.M.-M., E.B., E.Z.S., K.L.L., H.-E.W., T.M., D.L., V.G., S.S., J.C.M.W., A.A. Statistical analysis: A.P., C.v.N., D.E.A., M.G.L., A.V.S., M.M., G.C.V., M.L., W.H.L.K., J.C.B., K.R., T.A., K.L.L. Obtaining funding: A.P., M.F.S., B.M.P., J.I.R., F.R., A.H., A.G.U., M.K.C., J.D.S., R.S.V., G.E., D.S., M.U., G.R.A., E.B., A.C., H.-E.W., T.M., D.L., V.G., J.C.M.W., S.R.H. Study supervision: J.I.R., F.R., A.H., B.H.C.S., A.G.U., C.M.v.D., G.E., A.C., V.G., J.C.M.W., S.R.H. The following authors had full data access and take responsibility for analysis: A.P., C.v.N., M.M., J.I.R., A.C., K.L.L, S.R.H. Cohort study investigators: a list of investigators by cohort study may be found in the Supplementary Note.

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Correspondence to Arne Pfeufer or Susan R Heckbert.

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A.C. is a paid member of the scientific advisory board of Affymetrix, a role that is managed by the Committee on Conflict of Interest of the Johns Hopkins University School of Medicine.

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Pfeufer, A., van Noord, C., Marciante, K. et al. Genome-wide association study of PR interval. Nat Genet 42, 153–159 (2010). https://doi.org/10.1038/ng.517

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