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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

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Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain 8–10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval–associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

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Figure 1: Genome-wide association results for GWAS meta-analysis, annotated with gene names.

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Change history

  • 20 July 2014

    In the version of this article initially published online, the name of Fabiola del Greco M was misspelled in the author list. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

A full listing of acknowledgments is provided in the Supplementary Note.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

Author contributions are indicated by cohort and group. All coauthors revised and approved the manuscript.

Writing group. C.N.-C. takes overall responsibility for the QT-IGC study. The study design was developed by M.J.A., D.E.A., A. Chakravarti, L.C., P.I.W.d.B., T.T.K., P.B.M., C.N.-C., A. Pfeufer, S.L.P., P.J.S. and N.S. in consultation with the respective study groups. The manuscript was written by C.N.-C. The manuscript was critically revised in detail by members of the writing team before circulation to all coauthors.

GWAS cohorts. AGES: Phenotyping: V.G. Data analysis: A.V.S. Oversight: T.B.H., L.J.L., V.G. Amish studies: Clinical data collection, genotyping and oversight: A.R.S. EKG data collection: W.S.P. Analysis: A. Parsa, J.R.O. Interpretation: A. Parsa, W.S.P. ARIC: Study design: A.A., D.E.A., A. Chakravarti, W.H.L.K. Analyses: D.E.A., J.S.B., A. Chakravarti, G.E., H. Huang. Steering: D.E.A., A. Chakravarti. Writing: D.E.A., A. Chakravarti. BLSA: Analysis: T.T. Phenotype collection: J.B.S. Overall project supervision: L. Ferrucci. BRIGHT: Phenotyping: M. Brown, M.J.C., P.W.M., P.B.M., N.J.S. Genotyping: P.B.M., S.J.N. Analysis: S.J.N. Overall study supervision: M. Brown, M.J.C., P.B.M., N.J.S. Carlantino: Sample and/or data collection: M.C., L.Z. Overall study supervision: P.G. Data collection and/or statistical analysis: S.U. CHS: Study design: J.C.B., S.R.H., B.M.P., N.S. Data collection: S.R.H., B.M.P., D.S.S. Genotyping: J.I.R. Analysis, interpretation: J.C.B., N.S. Supervision of analyses: B.M.P. Funding for GWAS: B.M.P. Croatia-Korcula and Croatia-Split: GWAS analysis: C.H. Data collection, phenotype measurement, data entry and field work supervision: I.K., O.P. Study design and funding: I.R., A.F.W. DCCT/EDIC: Analyses: D.W. Supervision of analyses: A.D.P. deCODE: Data collection: D.O.A., H. Hólm. Study design: K. Stefansson, U.T., H. Hólm, D.F.G., D.O.A. Data alignment, imputation and statistical analysis: D.F.G. Additional analysis and interpretation of results: K. Stefansson, U.T., H. Hólm, D.F.G., D.O.A. eMERGE: Data curation and GWAS analysis: R.L.Z., Y.B. Supervision of quality control and analysis of data set: M.D.R. Study conception and analysis framework: D.M.R. Algorithm for case ascertainment: J.C.D. ERF: Analysis: A. Isaacs. Data acquisition: C.M.v.D., A. Isaacs, B.A.O., J.A.K., A.G.U. Overall study principal investigators: C.M.v.D., B.A.O. FHS: Analysis plan development: C.N.-C., C.J.O., P.A.N., M.G.L. GWAS analysis: X.Y., M.G.L. Secured funding: C.N.-C., C.J.O. FVG: Data collection: M. Bobbo. Primary analysis: A. Iorio. Statistical analysis: A.P.D.A. Overall study supervision: G.S. Health2000: Data analysis, replication genotyping and quality control: A.M.L. Primary data analysis: A. Marjamaa. Phenotyping, including ECGs: A.J. Electrocardiographic measurements: K.P. GWAS and replication genotyping: M.P. Design of ECG study, analysis and interpretation: L.O. Genetic data collection and analysis: K.K.K. Principal investigator and supervision: V.S. HealthABC: Data collection and supervision: S.R.C., Y.L. Data analysis: D.S.E., M.A.N. HNR: Data collection: H.K. Data generation: H.K., T.W.M. Genetic data generation: M.M.N., P.H., T.W.M. Data analysis: L.E., P.H., T.W.M., M.M.N. Overall study design and principal investigators: R.E., K.-H.J. KORA-F3/S4: Overall QT project supervision: A. Pfeufer. Genotyping oversight: T.M. ECG collection, measurement and interpretation: M.F.S., S. Perz, B.M.B., E.M. Primary genetic analysis: C.G., M.M.-N. Interpretation of results: C.G., A. Pfeufer, H.P., S. Kääb, T.M., M.W. Overall study principal investigator: A. Peters. LifeLines: Phenotyping: R.A.d.B., P.A.v.d.V. Genotyping: L. Franke. Analyses: I.M.N. and L. Franke. MICROS: Sample recruitment and overall study principal investigator: P.P.P. Study supervision, genotyping and data coordination: A.A.H. Data analysis: F.D.G.M., C.F. ORCADES: Phenotype collection: S.H.W. Genotype generation: H.C., J.F.W. GWAS analysis: P.N. Raised funding: J.F.W. Overall study supervision: J.F.W. PopGen: Recruitment and phenotyping: N.E.E.M., N.F. Genotyping and data preparation: A.F. Data preparation and analysis: D.E. PREVEND: Phenotyping: M.P.v.d.B., D.J.v.V., G.N. Genotyping and data analysis: F.W.A., I.M.L., P.v.d.H. Obtained funding: G.N., D.J.v.V., F.W.A., P.v.d.H. Rotterdam Study I and II: Study concept and design: M.E., B.H.S. Data acquisition: M.E., O.H.F., B.P.K., J.A.K., A.H., J.C.M.W., B.H.S., A.G.U. Statistical analysis: M.E. Interpretation: M.E., B.H.S. Obtained funding: A.H., J.C.M.W., A.G.U., B.H.S. Study supervision: B.H.S. SardiNIA: Phenotyping: M.O. Genotyping and data analysis: G.R.A., E.G.L., A. Mulas, M.O., S.S., D.S., K.V.T., M.U. Overall study supervision and principal investigators: D.S., M.U. SHIP: Data acquisition: M.D., M.R.P.M., U.V., S.B.F. Statistical analysis: U.V., M.D., M.R.P.M. Interpretation: U.V., M.D., S.B.F. Obtained funding: S.B.F., U.V. TwinsUK: Study concept and design: H.S., Y.J. Data acquisition: T.D.S. Statistical analysis and interpretation: I.M.N., H.S., Y.J. Obtained funding: Y.J., T.D.S. Young Finns Study: Data collection: T.J.L., O.T.R., M. Kähönen, J.S.V. Genotyping: T.J.L., N.M. Genotyping: T.J.L. Phenotype preparation: O.T.R., M. Kähönen, J.S.V. Analysis: T.J.L., O.T.R., M. Kähönen, J.S.V., L.-P.L. Obtained funding: T.J.L., O.T.R., M. Kähönen, J.S.V.

Directly genotyped SNP replication cohorts. (Author contributions for cohorts that contributed to both GWAS and replication genotyping are shown under the GWAS entry above.) BRHS: Analysis: R.W.M. Custodian of genetic resource: R.W.M., P.H.W. Data collection for genetic resource: P.H.W. Development of genetic resource: A.D.H. Overall study supervision and principal investigators: P.H.W., R.W.M. ECG analyses: P.W.M. Bruneck: Data analysis, interpretation and writing: S. Kiechl. DNA preparation: F. Kronenberg, C.L. ECG measurement and database: M. Knoflach. Supervision, funding, administration and principal investigator: J.W. Carla: Study concept and design: K.H.G., K.W. Genotyping: H.M.z.S. Supervision: K.W. Study design and analysis: A.K. Study concept, supervision and principal investigator: J.H. Cyprus: Study concept, funding, supervision and analysis: A.N.N. Data acquisition, analysis and interpretation: M.G. Genetic, biochemical data acquisition and statistical analysis: A.G.P. Czech Post-MONICA: Data collection and submission: J.A.H., V.A. Galicia: Cohort collection: M. Brion. Study design: M. Brion. Genotyping platform management: A. Carracedo. Genotyping: M.T. Analysis: M.T. Interpretation: M. Brion, A. Carracedo. Financial support: A. Carracedo. Intergene: Genotyping, data analysis and epidemiology expertise: F.N. Genotyping and genetic expertise: Å.T.N. Study design, data collection and disease area knowledge: D.S.T. MIDSPAN Family Study: Data acquisition, statistical analysis and interpretation: S. Padmanabhan. Genotyping: W.K.L. Overall study supervision, data collection and funding: A.F.D., G.C.M.W. PIVUS: Genotyping: A.-C.S. Phenotyping: L.L., J.Ä., J.S. Data analysis: S.G. Overall supervision and principal investigator: E.I. SAPHIR: DNA preparation: F. Kronenberg, C.L. Data collection: L.K., B.P., B.S. Data analysis: L.K., F. Kronenberg, C.L., B.P., B.S. Study design and principal investigator: B.P. ULSAM: Genotyping: A.-C.S. Phenotyping: L.L., J.Ä., J.S. Data analysis: S.G. Overall supervision and principal investigator: E.I. Whitehall II: Data collection and submission: M. Kumari. Overall supervision: M. Kivimaki. Funding: A.D.H.

Meta-analysis of GWAS and replication. D.E.A. and S.L.P. independently performed quality control and meta-analysis of GWAS and replication association results. Polygenic analysis: R.D.K. P.I.W.d.B., A. Pfeufer. and C.N.-C. supervised the analyses.

Non-QT trait lookups. CARe-COGENT: Meta-analysis and lookup: J.G.S. HRGEN: Meta-analysis and lookup: M.d.H. Overall study supervision: R.J.F.L. QRS GWAS: Study supervision: N.S. Meta-analysis: D.E.A., P.I.W.d.B. Results lookup: S.L.P.

Non-cardiac eQTL analyses. Data set acquisition: A.S.P., V.E. Analysis and interpretation: A.D.J. Cell type–specific enrichment tests: S.R., K. Slowikowski.

Left ventricle eQTL analyses. Overall supervision: T.P.C. Recruitment, sample collection: K.M., C.E.M. Sample processing and expression analysis: J. Brandimarto. Statistical analysis: M.M.

Left ventricle enhancer analyses. Analysis: X.W. Overall supervision: L.A.B., M. Kellis.

Mouse knockout. Enrichment tests: S.R., K. Slowikowski. Candidate gene list: P.v.d.H.

LQTS mutation screening. Amsterdam: SLC8A1 sequencing: T.T.K. Clinical data collection: A.B., N.H., A.A.M.W. Study supervision: C.R.B., A.A.M.W. London: Recruitment, phenotyping and strategy: E.R.B. Screening for mutations in LQT1, LQT2 and LQT3 and sample management: C.D. Mayo Clinic: LQTS cohort characteristic organization: D.J.T. TRPM7 mutation analysis and interpretation: D.J.T., A.M.-D., J.R.G. Patient collection, study design, data review and overall supervision: M.J.A. Munich: Study oversight: S. Kääb, A. Pfeufer. Patient collection: B.M.B., E.M. Genotyping: H.P. Nantes: Scientific management: J.-J.S. Clinical, genetic information collection: S.C. ATP2A2 sequencing: S.C. Screening for mutations in LQT1, LQT2 and LQT3 and clinical data collection: J. Barc. LQTS gene diagnosis management: F. Kyndt. Patient enrollment: V.P. Pavia: Patient collection, patient selection and molecular screening supervision: L.C., P.J.S. SRL mutation screening: A.G., R.I. Toronto: Identification of patients with LQTS free of LQT1, LQT2 and LQT3 mutations: R.M.H. Program codevelopment: S.W.S.

DAPPLE analysis. Concept, design and analysis: E.J.R. Supervision: K.L., M.J.D.

Immunoprecipitation experiments. Proteomic experiments and analysis: A.L. Overall study supervision: J.V.O.

Corresponding author

Correspondence to Christopher Newton-Cheh.

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Competing interests

H. Hólm is a former and D.O.A., D.F.G., K. Stefansson and U.T. are current full or part-time employees of deCODE Genetics/Amgen, Inc. A.S.P. was previously an employee of Merck Research Laboratory and is a current employee of Sanofi. F.N. is an employee of AstraZeneca. B.P. serves on the data and safety monitoring board for a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.S. serves on the advisory board of Itrim. M.J.A. is a consultant for Boston Scientific, Gilead Sciences, Medtronic and St. Jude Medical. M.J.A. and the Mayo Clinic receive royalties from Transgenomic with respect to their FAMILION-LQTS and FAMILION-CPVT genetic tests.

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Full list of members and affiliations appear in the Supplementary Note.

Full list of members and affiliations appear in the Supplementary Note.

Full list of members and affiliations appear in the Supplementary Note.

Full list of members and affiliations appear in the Supplementary Note.

Full list of members and affiliations appear in the Supplementary Note.

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Supplementary Figures 1–5, Supplementary Tables 1–3 and 5–18, and Supplementary Note (PDF 12908 kb)

Supplementary Table 4

Metabochip QT replication + fine-mapping of SNP content. (XLSX 835 kb)

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Arking, D., Pulit, S., Crotti, L. et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet 46, 826–836 (2014). https://doi.org/10.1038/ng.3014

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