Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation
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Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation. / Vad, Oliver Bundgaard; Paludan-Mueller, Christian; Ahlberg, Gustav; Kalsto, Silje Madeleine; Ghouse, Jonas; Andreasen, Laura; Haunso, Stig; Tveit, Arnljot; Sajadieh, Ahmad; Christophersen, Ingrid Elisabeth; Svendsen, Jesper Hastrup; Olesen, Morten Salling.
I: Journal of Clinical Medicine, Bind 9, Nr. 2, 372, 2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation
AU - Vad, Oliver Bundgaard
AU - Paludan-Mueller, Christian
AU - Ahlberg, Gustav
AU - Kalsto, Silje Madeleine
AU - Ghouse, Jonas
AU - Andreasen, Laura
AU - Haunso, Stig
AU - Tveit, Arnljot
AU - Sajadieh, Ahmad
AU - Christophersen, Ingrid Elisabeth
AU - Svendsen, Jesper Hastrup
AU - Olesen, Morten Salling
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - atrial fibrillation
KW - genetics
KW - arrhythmia
KW - cardiology
KW - next-generation sequencing
KW - cardiomyopathy
KW - DILATED CARDIOMYOPATHY
KW - DUCHENNE
KW - PREVALENCE
KW - MANAGEMENT
KW - MUTATIONS
KW - TISSUE
U2 - 10.3390/jcm9020372
DO - 10.3390/jcm9020372
M3 - Journal article
C2 - 32013268
VL - 9
JO - Journal of Clinical Medicine
JF - Journal of Clinical Medicine
SN - 2077-0383
IS - 2
M1 - 372
ER -
ID: 248151867