Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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
_version_ 1783311891263651840
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
work_keys_str_mv AT napiermelanied genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT franceschininora genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT gondaliarahul genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT stewartjamesd genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT mendezgiraldezraul genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT sitlanicolleenm genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT seyerleamandaa genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT highlandheatherm genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT liyun genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT wilhelmsenkirkc genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT yansong genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT duanqing genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT roachjeffrey genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT yaojie genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT guoxiuqing genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT taylorkentd genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT heckbertsusanr genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT rotterjeromei genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT northkarie genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT reineralexanderp genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT zhangzhuming genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT tinkerlesleyf genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT liaoduanping genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT lauriecathyc genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT gogartenstephaniem genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT linhenryj genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT brodyjennifera genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT bartztracim genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT psatybrucem genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT sotoodehnianona genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT solimanelsayedz genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT averychristyl genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy
AT whitselerica genomewideassociationstudyandmetaanalysisidentifylociassociatedwithventricularandsupraventricularectopy