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Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.

Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.

Author information

1
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
2
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
3
deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
4
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
5
HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
6
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
7
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
8
Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
9
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, USA.
10
Regeneron Genetics Center, Tarrytown, NY, USA.
11
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
12
Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
13
Medical Device Development and Regulation Research Center, The University of Tokyo, Tokyo, Japan.
14
Department of Cardiology, St. Olav's University Hospital, Trondheim, Norway.
15
Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
16
Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
17
Department of Cardiology, St. Olav's University Hospital, Trondheim University Hospital, Trondheim, Norway.
18
Department of Medicine, Landspitali - National University Hospital, Reykjavik, Iceland.
19
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
20
Fundación Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
21
Geisinger Health System, Danville, PA, USA.
22
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
23
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway. goncalo@umich.edu.
24
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA. goncalo@umich.edu.
25
HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. kristian.hveem@ntnu.no.
26
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway. kristian.hveem@ntnu.no.
27
Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway. kristian.hveem@ntnu.no.
28
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA. cristen@umich.edu.
29
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA. cristen@umich.edu.
30
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. cristen@umich.edu.

Abstract

To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5)1, or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an 'atrial cardiomyopathy'2, either during fetal heart development or as a response to stress in the adult heart.

PMID:
30061737
PMCID:
PMC6530775
DOI:
10.1038/s41588-018-0171-3
[Indexed for MEDLINE]
Free PMC Article

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