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Open AccessArticle

Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

1
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
2
Laboratory for Molecular Cardiology, Department of Cardiology, Centre for Cardiac, Vascular, Pulmonary and Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen O, Denmark
3
Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, 3004 Drammen, Norway
4
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
5
Department of Cardiology, Institute of Clinical Medicine, University of Oslo, 0450 Oslo, Norway
6
Department of Cardiology, Copenhagen University Hospital, Bispebjerg, 2400 Copenhagen NV, Denmark
7
Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(2), 372; https://doi.org/10.3390/jcm9020372
Received: 10 December 2019 / Revised: 24 January 2020 / Accepted: 25 January 2020 / Published: 29 January 2020
(This article belongs to the Special Issue Genetics of Hereditary Heart Diseases)
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 (n = 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 (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), 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 (p = 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 (p = 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. View Full-Text
Keywords: atrial fibrillation; genetics; arrhythmia; cardiology; next-generation sequencing; cardiomyopathy atrial fibrillation; genetics; arrhythmia; cardiology; next-generation sequencing; cardiomyopathy
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MDPI and ACS Style

Vad, O.B.; Paludan-Müller, C.; Ahlberg, G.; Kalstø, S.M.; Ghouse, J.; Andreasen, L.; Haunsø, S.; Tveit, A.; Sajadieh, A.; Christophersen, I.E.; Svendsen, J.H.; Olesen, M.S. Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation. J. Clin. Med. 2020, 9, 372.

AMA Style

Vad OB, Paludan-Müller C, Ahlberg G, Kalstø SM, Ghouse J, Andreasen L, Haunsø S, Tveit A, Sajadieh A, Christophersen IE, Svendsen JH, Olesen MS. Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation. Journal of Clinical Medicine. 2020; 9(2):372.

Chicago/Turabian Style

Vad, Oliver B.; Paludan-Müller, Christian; Ahlberg, Gustav; Kalstø, Silje M.; Ghouse, Jonas; Andreasen, Laura; Haunsø, Stig; Tveit, Arnljot; Sajadieh, Ahmad; Christophersen, Ingrid E.; Svendsen, Jesper H.; Olesen, Morten S. 2020. "Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation" J. Clin. Med. 9, no. 2: 372.

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