Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-ons...
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doaj-79e01b3cbfe74e9fbec3debc81e0abd62020-11-25T02:17:31ZengMDPI AGJournal of Clinical Medicine2077-03832020-01-019237210.3390/jcm9020372jcm9020372Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial FibrillationOliver Bundgaard Vad0Christian Paludan-Müller1Gustav Ahlberg2Silje Madeleine Kalstø3Jonas Ghouse4Laura Andreasen5Stig Haunsø6Arnljot Tveit7Ahmad Sajadieh8Ingrid Elisabeth Christophersen9Jesper Hastrup Svendsen10Morten Salling Olesen11Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, DenmarkDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, DenmarkDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, DenmarkDepartment of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, 3004 Drammen, NorwayDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, DenmarkDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, DenmarkLaboratory for Molecular Cardiology, Department of Cardiology, Centre for Cardiac, Vascular, Pulmonary and Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen O, DenmarkDepartment of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, 3004 Drammen, NorwayDepartment of Cardiology, Copenhagen University Hospital, Bispebjerg, 2400 Copenhagen NV, DenmarkDepartment of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, 3004 Drammen, NorwayLaboratory for Molecular Cardiology, Department of Cardiology, Centre for Cardiac, Vascular, Pulmonary and Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen O, DenmarkDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, DenmarkAtrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (<i>n</i> = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (<i>DMD</i>), actin-associated <i>LIM</i> protein (<i>PDLIM3</i>), and fukutin (<i>FKTN</i>)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (<i>p</i> = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (<i>p</i> = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.https://www.mdpi.com/2077-0383/9/2/372atrial fibrillationgeneticsarrhythmiacardiologynext-generation sequencingcardiomyopathy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Oliver Bundgaard Vad Christian Paludan-Müller Gustav Ahlberg Silje Madeleine Kalstø Jonas Ghouse Laura Andreasen Stig Haunsø Arnljot Tveit Ahmad Sajadieh Ingrid Elisabeth Christophersen Jesper Hastrup Svendsen Morten Salling Olesen |
spellingShingle |
Oliver Bundgaard Vad Christian Paludan-Müller Gustav Ahlberg Silje Madeleine Kalstø Jonas Ghouse Laura Andreasen Stig Haunsø Arnljot Tveit Ahmad Sajadieh Ingrid Elisabeth Christophersen Jesper Hastrup Svendsen Morten Salling Olesen Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation Journal of Clinical Medicine atrial fibrillation genetics arrhythmia cardiology next-generation sequencing cardiomyopathy |
author_facet |
Oliver Bundgaard Vad Christian Paludan-Müller Gustav Ahlberg Silje Madeleine Kalstø Jonas Ghouse Laura Andreasen Stig Haunsø Arnljot Tveit Ahmad Sajadieh Ingrid Elisabeth Christophersen Jesper Hastrup Svendsen Morten Salling Olesen |
author_sort |
Oliver Bundgaard Vad |
title |
Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation |
title_short |
Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation |
title_full |
Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation |
title_fullStr |
Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation |
title_full_unstemmed |
Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation |
title_sort |
loss-of-function variants in cytoskeletal genes are associated with early-onset atrial fibrillation |
publisher |
MDPI AG |
series |
Journal of Clinical Medicine |
issn |
2077-0383 |
publishDate |
2020-01-01 |
description |
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (<i>n</i> = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (<i>DMD</i>), actin-associated <i>LIM</i> protein (<i>PDLIM3</i>), and fukutin (<i>FKTN</i>)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (<i>p</i> = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (<i>p</i> = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy. |
topic |
atrial fibrillation genetics arrhythmia cardiology next-generation sequencing cardiomyopathy |
url |
https://www.mdpi.com/2077-0383/9/2/372 |
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