Abstract
The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 × 10−8. Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.
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Acknowledgements
We gratefully acknowledge all participants in the community-based studies of ARIC, KORA, SardiNIA, GenNOVA and Heinz Nixdorf Recall Study, and all the members of our laboratories for helpful discussion of this study. We thank G. Fischer for help with genotype imputation and data management for the KORA samples, Y. Li for her help on statistical analysis, K. Tarasov for in silico promotor analysis, A. Cao for his valuable advice and support in the SardiNIA project and all ARIC, KORA, SardiNIA, GenNOVA and Heinz Nixdorf Recall Study investigators for study design and continued operation.
We also thank C. Egger and Y. D'Elia for the valuable support in data management and data administration; S. Melville and M. Facheris for the important work of drug classification in the GenNOVA project; and the primary care practitioners R. Stocker, S. Waldner, T. Pizzecco, J. Plangger, U. Marcadent and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the GenNOVA project.
ARIC is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. In addition, we acknowledge support from NHLBI grants HL86694 and HL054512, and the Donald W. Reynolds Cardiovascular Clinical Research Center at Johns Hopkins University for genotyping and data analysis relevant to this study. A.K. is supported by a German Research Foundation Fellowship.
The KORA study was funded by grants by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN), the German National Competence network on atrial fibrillation (AFNET) and the Bioinformatics for the Functional Analysis of Mammalian Genomes program (BFAM) by grants to S.K. (NGFN 01GS0499, 01GS0838 and AF-Net 01GI0204/N), A.P. (NGFN 01GR0803, 01EZ0874), H.–E.W. (NGFN 01GI0204) and to T.M. (NGFN 01GR0103). S.K. is also supported by a grant from the Fondation Leducq. The KORA platform is funded by the BMBF and by the State of Bavaria.
The SardiNIA team was supported by Contract NO1-AG-1-2109 from the National Institute on Aging and in part by the Intramural Research Program of the US National Institute on Aging, NIH. The efforts of G.R.A. were supported in part by contract 263-MA-410953 from the National Institute on Aging to the University of Michigan and by research grants from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute (to G.R.A.).
The GenNOVA study was supported by the Ministry of Health of the Autonomous Province of Bolzano and the South Tyrolean Sparkasse Foundation.
The Heinz Nixdorf Recall Study was funded by a grant of the Heinz Nixdorf Foundation (Chairman: G. Schmidt).
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Designed the scientific rationale of the work: A.P., S.S., D.E.A., R.J.P., S.S.N., A.A.H., D.S., T.M., M.U., J.C., S.K., G.R.A., A.C. Obtained funding: A.P., R.E., K.-H.J., S.N., G.S., A.A.H., E.L., H.-E.W., D.S., E.B., T.M., M.U., J.C., S.K., G.R.A., A.C. Analyzed EKG readings: A.P., S.S., D.E.A., C.F., M.O., S.P., M.F.S., B.M.-M., C.H., S.S.N., S.M., F.M., E.L. Performed genotyping: A.P., S.S., D.E.A., T.W.M., A.A.H., P.P.P., T.M., A.C. Performed genotype imputation: A.P., S.S., D.E.A., M.M., C.P., B.P., T.W.M., B.M.-M., A.A.H. Performed statistical analysis: A.P., S.S., D.E.A., M.M., C.F., C.P., G.B.E., C.G., F.M. Performed metaanalysis: A.P., S.S., D.E.A., V.G., M.M., C.P. Drafted manuscript: A.P., S.S., D.E.A., G.R.A., A.C. Critically revised manuscript: M.M., M.O., A.K., G.U., M.B., M.L., A.S., M.F.S., C.H., T.W.M., M.D., S.M., L.C., R.E., K.-H.J., S.N., G.S., F.M., A.A.H., B.M.-M., P.P.P., H.-E.W., D.S., E.B., T.M., M.U., J.C.
List of investigators by cohort:
ARIC (Atherosclerosis Risk in Communities Study): D.E.A., G.B.E., A.K., M.B., M.L., R.J.P., W.H.L.K., E.B., J.C., A.C.
GenNOVA: F.M., C.P., C.F., A.A.H., P.P.P.
KORA (Kooperative Gesundheitsforschung in der Region Ausgsburg): A.P., M.M., S.P., M.F.S., C.H., C.G., B.P., B.M.-M., G.S., S.K., H.-E.W., T.M.
HNR (Heinz Nixdorf Recall Study): T.W.M., S.M., R.E., K.-H.J.
SardiNIA: S.S., V.G., M.O., G.U., A.S., S.N., M.D., L.C., S.N., E.L., D.S., M.U., G.R.A.
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Aravinda Chakravarti is on the Scientific Advisory Board of Affymetrix. This potential conflict of interest is managed by the policies of Johns Hopkins University.
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Pfeufer, A., Sanna, S., Arking, D. et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet 41, 407–414 (2009). https://doi.org/10.1038/ng.362
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DOI: https://doi.org/10.1038/ng.362
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