KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern
Alexander Teumer, et al.
Alexander Teumer, et al.
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Clinical Research and Public Health Cardiology Genetics

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

Abstract

BACKGROUND The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODS To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTS We identified a genome-wide significant (P < 5 × 10–8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10–12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONS In this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDING This project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 – STATS). For detailed funding information per study, see the Supplemental Acknowledgments.

Authors

Alexander Teumer, Teresa Trenkwalder, Thorsten Kessler, Yalda Jamshidi, Marten E. van den Berg, Bernhard Kaess, Christopher P. Nelson, Rachel Bastiaenen, Marzia De Bortoli, Alessandra Rossini, Isabel Deisenhofer, Klaus Stark, Solmaz Assa, Peter S. Braund, Claudia Cabrera, Anna F. Dominiczak, Martin Gögele, Leanne M. Hall, M. Arfan Ikram, Maryam Kavousi, Karl J. Lackner, Lifelines Cohort Study, Christian Müller, Thomas Münzel, Matthias Nauck, Sandosh Padmanabhan, Norbert Pfeiffer, Tim D. Spector, Andre G. Uitterlinden, Niek Verweij, Uwe Völker, Helen R. Warren, Mobeen Zafar, Stephan B. Felix, Jan A. Kors, Harold Snieder, Patricia B. Munroe, Cristian Pattaro, Christian Fuchsberger, Georg Schmidt, Ilja M. Nolte, Heribert Schunkert, Peter P. Pramstaller, Philipp S. Wild, Pim van der Harst, Bruno H. Stricker, Renate B. Schnabel, Nilesh J. Samani, Christian Hengstenberg, Marcus Dörr, Elijah R. Behr, Wibke Reinhard

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Figure 3

Colocalization results.

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Colocalization results. Illustrations of the SMR test for the early repo...
Illustrations of the SMR test for the early repolarization pattern (ERP) risk and the expression quantitative trait loci (eQTLs) at the rs1545300 locus at chromosome 1p13.2 for the (A) left ventricle of the heart, (B) tibial artery, and (C) minor salivary gland tissue. The sample sizes for the eQTLs are n = 272, n = 388, and n = 85 in A, B, and C, respectively. In A–C, the GWAS regional association plot with ERP risk of the combined GWAS (n = 39,456), with level of significance of the SMR test (y axis) for each transcript in the locus indicated by a diamond positioned at the center of the transcript is shown (top). A significant SMR test represented by a purple diamond indicates an association of the transcript level of the respective genes (purple label) with the trait. For all 3 tissues, an increased gene expression level shown by a significant SMR test was associated with a higher risk of ERP. A filled purple diamond indicates a HEIDI test P > 0.05 and, thus, a likely colocalization. The regional association distribution with changes in expression of the highlighted (purple) gene transcript in the respective tissue is shown below. The x axis shows GRCh37/hg19 genomic coordinates throughout.