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Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy
The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide associati...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884864/ https://www.ncbi.nlm.nih.gov/pubmed/29618737 http://dx.doi.org/10.1038/s41598-018-23843-z |
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author | Napier, Melanie D. Franceschini, Nora Gondalia, Rahul Stewart, James D. Méndez-Giráldez, Raúl Sitlani, Colleen M. Seyerle, Amanda A. Highland, Heather M. Li, Yun Wilhelmsen, Kirk C. Yan, Song Duan, Qing Roach, Jeffrey Yao, Jie Guo, Xiuqing Taylor, Kent D. Heckbert, Susan R. Rotter, Jerome I. North, Kari E. Reiner, Alexander P. Zhang, Zhu-Ming Tinker, Lesley F. Liao, Duanping Laurie, Cathy C. Gogarten, Stephanie M. Lin, Henry J. Brody, Jennifer A. Bartz, Traci M. Psaty, Bruce M. Sotoodehnia, Nona Soliman, Elsayed Z. Avery, Christy L. Whitsel, Eric A. |
author_facet | Napier, Melanie D. Franceschini, Nora Gondalia, Rahul Stewart, James D. Méndez-Giráldez, Raúl Sitlani, Colleen M. Seyerle, Amanda A. Highland, Heather M. Li, Yun Wilhelmsen, Kirk C. Yan, Song Duan, Qing Roach, Jeffrey Yao, Jie Guo, Xiuqing Taylor, Kent D. Heckbert, Susan R. Rotter, Jerome I. North, Kari E. Reiner, Alexander P. Zhang, Zhu-Ming Tinker, Lesley F. Liao, Duanping Laurie, Cathy C. Gogarten, Stephanie M. Lin, Henry J. Brody, Jennifer A. Bartz, Traci M. Psaty, Bruce M. Sotoodehnia, Nona Soliman, Elsayed Z. Avery, Christy L. Whitsel, Eric A. |
author_sort | Napier, Melanie D. |
collection | PubMed |
description | The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10(−8)) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10(−8)) and multi-trait analysis (P = 2.9 × 10(−9)) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes. |
format | Online Article Text |
id | pubmed-5884864 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58848642018-04-09 Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy Napier, Melanie D. Franceschini, Nora Gondalia, Rahul Stewart, James D. Méndez-Giráldez, Raúl Sitlani, Colleen M. Seyerle, Amanda A. Highland, Heather M. Li, Yun Wilhelmsen, Kirk C. Yan, Song Duan, Qing Roach, Jeffrey Yao, Jie Guo, Xiuqing Taylor, Kent D. Heckbert, Susan R. Rotter, Jerome I. North, Kari E. Reiner, Alexander P. Zhang, Zhu-Ming Tinker, Lesley F. Liao, Duanping Laurie, Cathy C. Gogarten, Stephanie M. Lin, Henry J. Brody, Jennifer A. Bartz, Traci M. Psaty, Bruce M. Sotoodehnia, Nona Soliman, Elsayed Z. Avery, Christy L. Whitsel, Eric A. Sci Rep Article The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10(−8)) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10(−8)) and multi-trait analysis (P = 2.9 × 10(−9)) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes. Nature Publishing Group UK 2018-04-04 /pmc/articles/PMC5884864/ /pubmed/29618737 http://dx.doi.org/10.1038/s41598-018-23843-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Napier, Melanie D. Franceschini, Nora Gondalia, Rahul Stewart, James D. Méndez-Giráldez, Raúl Sitlani, Colleen M. Seyerle, Amanda A. Highland, Heather M. Li, Yun Wilhelmsen, Kirk C. Yan, Song Duan, Qing Roach, Jeffrey Yao, Jie Guo, Xiuqing Taylor, Kent D. Heckbert, Susan R. Rotter, Jerome I. North, Kari E. Reiner, Alexander P. Zhang, Zhu-Ming Tinker, Lesley F. Liao, Duanping Laurie, Cathy C. Gogarten, Stephanie M. Lin, Henry J. Brody, Jennifer A. Bartz, Traci M. Psaty, Bruce M. Sotoodehnia, Nona Soliman, Elsayed Z. Avery, Christy L. Whitsel, Eric A. Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy |
title | Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy |
title_full | Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy |
title_fullStr | Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy |
title_full_unstemmed | Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy |
title_short | Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy |
title_sort | genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884864/ https://www.ncbi.nlm.nih.gov/pubmed/29618737 http://dx.doi.org/10.1038/s41598-018-23843-z |
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