Daniel F Gudbjartsson1,2, Hilma Holm3,4, Patrick Sulem3, Gisli Masson3, Asmundur Oddsson3, Olafur Th Magnusson3, Jona Saemundsdottir3, Hafdis Th Helgadottir3, Hannes Helgason3, Hrefna Johannsdottir3, Solveig Gretarsdottir3, Sigurjon A Gudjonsson3, Inger Njølstad5, Maja-Lisa Løchen5,6, Larry Baum7, Ronald C W Ma8, Gunnlaugur Sigfusson9, Augustine Kong3,2, Guðmundur Thorgeirsson4,10, Jon Th Sverrisson11, Unnur Thorsteinsdottir3,10, Kari Stefansson3,10, David O Arnar1,4,10. 1. deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland daniel.gudbjartsson@decode.is davidar@landspitali.is. 2. School of Engineering and Natural Sciences, University of Iceland, Hjardarhaga 4, 107 Reykjavik, Iceland. 3. deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland. 4. Department of Medicine, Landspitali- The National University Hospital, Hringbraut, 101 Reykjavik, Iceland. 5. Institute of Community Medicine, University of Tromsø, Postboks 6050, Langnes, 9037 Tromsø, Norway. 6. Department of Cardiology, University Hospital of North Norway, Sykehusvegen 38, 9019 Tromsø, Norway. 7. School of Pharmacy, Chinese University of Hong Kong, Hong Kong. 8. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, 30 Ngan Shing Street, Sha Tin 999077 Hong Kong. 9. Children's Hospital, Landspitali- The National University Hospital, Hringbraut 101 Reykjavik, Iceland. 10. Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland. 11. Department of Internal Medicine, Akureyri Hospital, Eyrarlandsvegur, 600 Akureyri, Iceland.
Abstract
AIMS: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. METHODS AND RESULTS: We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. CONCLUSIONS: Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. METHODS AND RESULTS: We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosinMYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. CONCLUSIONS: Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia. Published on behalf of the European Society of Cardiology. All rights reserved.
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