journal contribution posted on 31.07.2019, 13:01 by R Bastiaenen, IM Nolte, PB Munroe, H Riese, C Nelson, H O'Connor, Y Gang, HR Warren, C Cabrera, W Reinhard, C Hengstenberg, FV Rijsdijk, T Spector, H Snieder, NJ Samani, Y Jamshidi, ER Behr
BACKGROUND: Early repolarization (ER) is a risk marker for sudden cardiac death. Higher risk is associated with horizontal/descending ST-segment ER in the inferior or inferolateral ECG leads. Studies in family cohorts have demonstrated substantial heritability for the ER pattern, but genome-wide association studies (GWAS) have failed to identify statistically significant and replicable genetic signals. METHODS AND RESULTS: We assessed the narrow-sense and common single nucleotide polymorphism (SNP) heritability of ER and ER subtypes using ECG data from 5829 individuals (TwinsUK, BRIGHT and GRAPHIC cohorts). ER prevalence was 8.3%. In 455 monozygous vs 808 dizygous twin pairs, concordances and twin correlations for ER subtypes (except horizontal/descending ST-segment ER) were higher and familial resemblance (except notched ER) was significant. Narrow-sense heritability estimates derived from 1263 female twin pairs using the structural equation program Mx ranged from 0.00-0.47 and common SNP heritability estimates derived from 4009 unrelated individuals of both sexes using Genome-wide Restricted Maximum Likelihood (GREML) ranged from 0.00-0.36, but none were statistically significant. CONCLUSION: From our data, ER shows limited genetic predisposition. There appears to be significant environmental influence and these modest narrow-sense and common SNP heritability estimates may explain why previous GWAS have been unsuccessful.
RB is a clinical lecturer supported by the National Institute for Health Research. ERB is supported by the Higher Education Funding Council for England and has a research grant from McColl's Ltd. Retail Group. YJ received support and funding from the British Heart Foundation - PG/12/38/29615 and PG/06/094. The TwinsUK study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and the British Heart Foundation. Tim Spector is holder of an ERC Advanced Principal Investigator award. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The BRIGHT study was supported by the Medical Research Council of Great Britain (grant number G9521010D); and by the Britisffh Heart Foundation (grant number PG/02/128). The GRAPHIC study was funded by the British Heart Foundation. This work forms part of the research themes contributing to the translational research portfolio for the NIHR Barts Cardiovascular Biomedical Research Centre (Munroe, Warren and Cabrera) and NIHR Leicester Cardiovascular Biomedical Research Centre (Samani). Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam.
CitationInternational Journal of Cardiology, 2019, 279, pp. 135-140
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences
VersionVoR (Version of Record)
Published inInternational Journal of Cardiology
PublisherElsevier, International Society for Adult Congenital Heart Disease
NotesSupplementary data to this article can be found online at https://doi.org/10.1016/j.ijcard.2018.09.119.