Lu-Chen Weng, Shaan Khurshid, Amelia Weber Hall, Victor Nauffal, Valerie N Morrill, Yan V Sun, Joel T Rämö, Dominik Beer, Simon Lee, Girish Nadkarni, Renee Johnson, Laura Andreasen, Anne Clayton, Clive R Pullinger, Zachary T Yoneda, Daniel J Friedman, Matthew C Hyman, Renae L Judy, Allan C Skanes, Kate M Orland, Paloma Jordà, Timothy M Treu, Matthew T Oetjens, Rajesh Subbiah, Jacob P Hartmann, Heidi T May, John P Kane, Tariq Z Issa, Navid A Nafissi, Peter Leong-Sit, Marie-Pierre Dubé, Carolina Roselli, Seung Hoan Choi, Jean-Claude Tardif, Habib R Khan, Stacey Knight, Jesper H Svendsen, Bruce Walker, Richard Karlsson Linnér, J Michael Gaziano, Rafik Tadros, Diane Fatkin, Daniel J Rader, Svati H Shah, Dan M Roden, Gregory M Marcus, Ruth J F Loos, Scott M Damrauer, Christopher M Haggerty, Kelly Cho, Aarno Palotie, Morten S Olesen, Lee L Eckhardt, Jason D Roberts, Michael J Cutler, M Benjamin Shoemaker, Peter W F Wilson, Patrick T Ellinor, Steven A Lubitz
{"title":"Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias.","authors":"Lu-Chen Weng, Shaan Khurshid, Amelia Weber Hall, Victor Nauffal, Valerie N Morrill, Yan V Sun, Joel T Rämö, Dominik Beer, Simon Lee, Girish Nadkarni, Renee Johnson, Laura Andreasen, Anne Clayton, Clive R Pullinger, Zachary T Yoneda, Daniel J Friedman, Matthew C Hyman, Renae L Judy, Allan C Skanes, Kate M Orland, Paloma Jordà, Timothy M Treu, Matthew T Oetjens, Rajesh Subbiah, Jacob P Hartmann, Heidi T May, John P Kane, Tariq Z Issa, Navid A Nafissi, Peter Leong-Sit, Marie-Pierre Dubé, Carolina Roselli, Seung Hoan Choi, Jean-Claude Tardif, Habib R Khan, Stacey Knight, Jesper H Svendsen, Bruce Walker, Richard Karlsson Linnér, J Michael Gaziano, Rafik Tadros, Diane Fatkin, Daniel J Rader, Svati H Shah, Dan M Roden, Gregory M Marcus, Ruth J F Loos, Scott M Damrauer, Christopher M Haggerty, Kelly Cho, Aarno Palotie, Morten S Olesen, Lee L Eckhardt, Jason D Roberts, Michael J Cutler, M Benjamin Shoemaker, Peter W F Wilson, Patrick T Ellinor, Steven A Lubitz","doi":"10.1161/CIRCGEN.123.004320","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).</p><p><strong>Methods: </strong>We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.</p><p><strong>Results: </strong>Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate <i>NKX2-5</i> and <i>TTN</i> as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of <i>NKX2-5</i> and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate <i>SCN5A</i>, <i>SCN10A</i>, and <i>TTN/CCDC141</i>. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.</p><p><strong>Conclusions: </strong>Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004320"},"PeriodicalIF":6.0000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187659/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Genomic and Precision Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCGEN.123.004320","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/28 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).
Methods: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.
Results: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.
Conclusions: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.
期刊介绍:
Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations.
Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.