Abstract

Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.

Rosa Thorolfsdottir et al. report a genome-wide association study of atrial fibrillation in 29,502 cases and 767,760 controls from Iceland and the UK Biobank. They identify a significant association with coding variants in RPL3L, the first ribosomal gene implicated in atrial fibrillation, and MYZAP, an intercalated disc gene.

Details

Title
Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation
Author
Thorolfsdottir, Rosa B 1 ; Sveinbjornsson Gardar 2 ; Sulem, Patrick 2   VIAFID ORCID Logo  ; Nielsen, Jonas B 3   VIAFID ORCID Logo  ; Jonsson, Stefan 4   VIAFID ORCID Logo  ; Halldorsson Gisli H 4   VIAFID ORCID Logo  ; Melsted Pall 5 ; Ivarsdottir, Erna V 2   VIAFID ORCID Logo  ; Davidsson, Olafur B 2 ; Kristjansson, Ragnar P 2 ; Thorleifsson Gudmar 2 ; Helgadottir Anna 2   VIAFID ORCID Logo  ; Gretarsdottir Solveig 2 ; Norddahl Gudmundur 2 ; Sridharan, Rajamani 2 ; Torfason Bjarni 6 ; Valgardsson, Atli S 7   VIAFID ORCID Logo  ; Sverrisson Jon T 8 ; Tragante Vinicius 9 ; Holmen, Oddgeir L 10 ; Asselbergs, Folkert W 11 ; Roden, Dan M 12 ; Darbar Dawood 13 ; Pedersen, Terje R 14 ; Sabatine, Marc S 15 ; Willer, Cristen J 16   VIAFID ORCID Logo  ; Maja-Lisa, Løchen 17 ; Halldorsson Bjarni V 18   VIAFID ORCID Logo  ; Jonsdottir Ingileif 19 ; Hveem Kristian 20 ; Arnar, David O 21 ; Thorsteinsdottir Unnur 22 ; Gudbjartsson, Daniel F 23 ; Holm Hilma 2 ; Stefansson Kari 24 

1  deCODE genetics/Amgen, Inc., Reykjavik, Iceland; University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
2  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.14013.37) 
3  University of Michigan, Department of Internal Medicine, Division of Cardiovascular Medicine, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Department of Human Genetics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
4  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.214458.e) 
5  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.214458.e); University of Iceland, School of Engineering and Natural Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
6  University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021); Landspitali University Hospital, Department of Cardiothoracic Surgery, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
7  Landspitali University Hospital, Department of Cardiothoracic Surgery, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
8  Akureyri Regional Hospital, Department of Medicine, Akureyri, Iceland (GRID:grid.410540.4) 
9  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.410540.4); University Medical Center Utrecht, University of Utrecht, Department of Cardiology, Division Heart & Lungs, Utrecht, The Netherlands (GRID:grid.410540.4) 
10  Norwegian University of Science and Technology, HUNT Research Centre, Department of Public Health and General Practice, Levanger, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Norwegian University of Science and Technology, K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); St. Olav’s University Hospital, Department of Cardiology, Trondheim, Norway (GRID:grid.52522.32) (ISNI:0000 0004 0627 3560) 
11  University Medical Center Utrecht, University of Utrecht, Department of Cardiology, Division Heart & Lungs, Utrecht, The Netherlands (GRID:grid.52522.32); Netherlands Heart Institute, Durrer Center for Cardiovascular Research, Utrecht, The Netherlands (GRID:grid.411737.7); University College London, Institute of Cardiovascular Science, Faculty of Population Health Sciences, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University College London, Farr Institute of Health Informatics Research and Institute of Health Informatics, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
12  Vanderbilt University Medical Center, Departments of Medicine, Pharmacology, and Biomedical Informatics, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
13  University of Illinois at Chicago, Division of Cardiology, Department of Medicine, Chicago, USA (GRID:grid.185648.6) (ISNI:0000 0001 2175 0319) 
14  University of Oslo, Center For Preventive Medicine, Oslo University Hospital and Medical Faculty, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
15  Brigham and Women’s Hospital and Harvard Medical School, TIMI Study Group, Division of Cardiovascular Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
16  University of Michigan, Department of Internal Medicine, Division of Cardiovascular Medicine, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Department of Human Genetics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Department of Computational Medicine and Bioinformatics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
17  UiT The Arctic University of Norway, Department of Community Medicine, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000000122595234) 
18  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.10919.30); Reykjavik University, Reykjavik, Iceland (GRID:grid.9580.4) (ISNI:0000 0004 0643 5232) 
19  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.9580.4); University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021); Landspitali University Hospital, Department of immunology, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
20  Norwegian University of Science and Technology, HUNT Research Centre, Department of Public Health and General Practice, Levanger, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Norwegian University of Science and Technology, K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); Nord-Trøndelag Hospital Trust, Department of Medicine, Levanger Hospital, Levanger, Norway (GRID:grid.414625.0) (ISNI:0000 0004 0627 3093) 
21  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.414625.0); University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021); Landspitali University Hospital, Department of Medicine, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
22  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.410540.4); University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
23  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.14013.37); University of Iceland, School of Engineering and Natural Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
24  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.14013.37); University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
Publication year
2018
Publication date
2018
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-018-0068-9
ProQuest document ID
2389699581
Copyright
© The Author(s) 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.