Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Rosa B Thorolfsdottir; Gardar Sveinbjornsson; Patrick Sulem; Jonas B Nielsen; Stefan Jonsson; Gisli H Halldorsson; Pall Melsted; Erna V Ivarsdottir; Olafur B Davidsson; Ragnar P Kristjansson; Gudmar Thorleifsson; Anna Helgadottir; Solveig Gretarsdottir; Gudmundur Norddahl; Sridharan Rajamani; Bjarni Torfason; Atli S Valgardsson; Jon T Sverrisson; Vinicius Tragante; Oddgeir L Holmen; Folkert W Asselbergs; Dan M Roden; Dawood Darbar; Terje R Pedersen; Marc S Sabatine; Cristen J Willer; Maja-Lisa Løchen; Bjarni V Halldorsson; Ingileif Jonsdottir; Kristian Hveem; David O Arnar; Unnur Thorsteinsdottir; Daniel F Gudbjartsson; Hilma Holm; Kari Stefansson

doi:10.1038/s42003-018-0068-9

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Commun Biol. 2018 Jun 12:1:68. doi: 10.1038/s42003-018-0068-9. eCollection 2018.

Authors

Rosa B Thorolfsdottir^{1

2}, Gardar Sveinbjornsson¹, Patrick Sulem¹, Jonas B Nielsen^{3

4}, Stefan Jonsson¹, Gisli H Halldorsson¹, Pall Melsted^{1

5}, Erna V Ivarsdottir¹, Olafur B Davidsson¹, Ragnar P Kristjansson¹, Gudmar Thorleifsson¹, Anna Helgadottir¹, Solveig Gretarsdottir¹, Gudmundur Norddahl¹, Sridharan Rajamani¹, Bjarni Torfason^{2

6}, Atli S Valgardsson⁶, Jon T Sverrisson⁷, Vinicius Tragante^{1

8}, Oddgeir L Holmen^{9

10

11}, Folkert W Asselbergs^{8

12

13

14}, Dan M Roden¹⁵, Dawood Darbar¹⁶, Terje R Pedersen¹⁷, Marc S Sabatine¹⁸, Cristen J Willer^{3

4

19}, Maja-Lisa Løchen²⁰, Bjarni V Halldorsson^{1

21}, Ingileif Jonsdottir^{1

2

22}, Kristian Hveem^{9

10

23}, David O Arnar^{1

2

24}, Unnur Thorsteinsdottir^{1

2}, Daniel F Gudbjartsson^{1

5}, Hilma Holm²⁵, Kari Stefansson^{26

27}

Affiliations

¹ deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
² Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
³ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁶ Department 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 HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
¹⁰ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ Department of Cardiology, St. Olav's University Hospital, Trondheim, Norway.
¹² Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
¹³ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
¹⁴ Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK.
¹⁵ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
¹⁷ Center For Preventive Medicine, Oslo University Hospital and Medical Faculty, University of Oslo, Oslo, Norway.
¹⁸ TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
²⁰ Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway.
²¹ Reykjavik University, Reykjavik, Iceland.
²² Department of immunology, Landspitali University Hospital, Reykjavik, Iceland.
²³ Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
²⁴ Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland.
²⁵ deCODE genetics/Amgen, Inc., Reykjavik, Iceland. [email protected].
²⁶ deCODE genetics/Amgen, Inc., Reykjavik, Iceland. [email protected].
²⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland. [email protected].

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.

Abstract

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