PT - JOURNAL ARTICLE AU - Alexander Teumer AU - Teresa Trenkwalder AU - Thorsten Kessler AU - Yalda Jamshidi AU - Marten E. van den Berg AU - Bernhard Kaess AU - Christopher P. Nelson AU - Rachel Bastiaenen AU - Marzia De Bortoli AU - Alessandra Rossini AU - Isabel Deisenhofer AU - Klaus Stark AU - Solmaz Assa AU - Peter S. Braund AU - Claudia Cabrera AU - Anna F. Dominiczak AU - Martin Gögele AU - Leanne M. Hall AU - M. Arfan Ikram AU - Maryam Kavousi AU - Karl J. Lackner AU - Lifelines Cohort Study AU - Christian Müller AU - Thomas Münzel AU - Matthias Nauck AU - Sandosh Padmanabhan AU - Norbert Pfeiffer AU - Tim D. Spector AU - Andre G. Uitterlinden AU - Niek Verweij AU - Uwe Völker AU - Helen R. Warren AU - Mobeen Zafar AU - Stephan B. Felix AU - Jan A. Kors AU - Harold Snieder AU - Patricia B. Munroe AU - Cristian Pattaro AU - Christian Fuchsberger AU - Georg Schmidt AU - Ilja M. Nolte AU - Heribert Schunkert AU - Peter Pramstaller AU - Philipp S. Wild AU - Pim van der Harst AU - Bruno H. Stricker AU - Renate B. Schnabel AU - Nilesh J. Samani AU - Christian Hengstenberg AU - Marcus Dörr AU - Elijah R. Behr AU - Wibke Reinhard TI - <em>KCND3</em> is a novel susceptibility locus for early repolarization AID - 10.1101/673640 DP - 2019 Jan 01 TA - bioRxiv PG - 673640 4099 - http://biorxiv.org/content/early/2019/06/18/673640.short 4100 - http://biorxiv.org/content/early/2019/06/18/673640.full AB - The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (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. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p&lt;5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. Replication of two loci in four additional studies including 1,124 cases and 12,510 controls confirmed the association at the KCND3 gene locus with a pooled odds ratio of 0.82, p=7.7E-12 (rs1545300 minor allele T). A subsequent GWAS meta-analysis combining all samples did not reveal additional loci. The lead SNP of the discovery stage (rs12090194) was in strong linkage disequilibrium with rs1545300 (r2=0.96, D’=1). Summary statistics based conditional analysis did not reveal any secondary signals. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both the left ventricle of the heart and in tibial artery.In this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, revealing a promising candidate for functional studies.