Coding variants in and increase risk of atrial fibrillation.

• Published in: Communications Biology
• Main Authors: Thorolfsdottir, Rosa B, Sveinbjornsson, Gardar, Sulem, Patrick, Nielsen, Jonas B, Jonsson, Stefan, Halldorsson, Gisli H, Melsted, Pall, Ivarsdottir, Erna V, Davidsson, Olafur B, Kristjansson, Ragnar P, Thorleifsson, Gudmar, Helgadottir, Anna, Gretarsdottir, Solveig, Norddahl, Gudmundur, Rajamani, Sridharan, Torfason, Bjarni, Valgardsson, Atli S, Sverrisson, Jon T, Tragante, Vinicius, Holmen, Oddgeir L, Asselbergs, Folkert W, Roden, Dan M, Darbar, Dawood, Pedersen, Terje R, Sabatine, Marc S, Willer, Cristen J, Løchen, Maja-Lisa, Halldorsson, Bjarni V, Jonsdottir, Ingileif, Hveem, Kristian, Arnar, David O, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F, Holm, Hilma, Stefansson, Kari
• Other Authors: 1 deCODE genetics/Amgen, Inc., Reykjavik, Iceland. 2 2Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 3 3Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI USA. 4 4Department of Human Genetics, University of Michigan, Ann Arbor, MI USA. 5 5School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. 6 6Department of Cardiothoracic Surgery, Landspitali University Hospital, Reykjavik, Iceland. 7 Department of Medicine, Akureyri Regional Hospital, Akureyri, Iceland. 8 Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. 9 9HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. 10 10K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway. 11 11Department of Cardiology, St. Olav's University Hospital, Trondheim, Norway. 12 12Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands. 13 13Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK. 14 14Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK. 15 15Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN USA. 16 16Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL USA. 17 17Center For Preventive Medicine, Oslo University Hospital and Medical Faculty, University of Oslo, Oslo, Norway. 18 18TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA USA. 19 19Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI USA. 20 20Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway. 21 21Reykjavik University, Reykjavik, Iceland. 22 22Department of immunology, Landspitali University Hospital, Reykjavik, Iceland. 23 Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway. 24 24Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Nature Publishing Group 2019
• Subjects: Gáttatif; Gen; Atrial Fibrillation; Genes; Norway; Iceland
• Online Access: http://hdl.handle.net/2336/621003; https://doi.org/10.1038/s42003-018-0068-9

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download 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. NIH