Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

doi:10.1038/s42003-018-0068-9

. 2018 Jun 12:1:68.

doi: 10.1038/s42003-018-0068-9. eCollection 2018.

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

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. Hilma.Holm@decode.is.
²⁶ deCODE genetics/Amgen, Inc., Reykjavik, Iceland. kstefans@decode.is.
²⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland. kstefans@decode.is.

PMID: 30271950
PMCID: PMC6123807
DOI: 10.1038/s42003-018-0068-9

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Rosa B Thorolfsdottir et al. Commun Biol. 2018.

. 2018 Jun 12:1:68.

doi: 10.1038/s42003-018-0068-9. eCollection 2018.

Authors

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. Hilma.Holm@decode.is.
²⁶ deCODE genetics/Amgen, Inc., Reykjavik, Iceland. kstefans@decode.is.
²⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland. kstefans@decode.is.

PMID: 30271950
PMCID: PMC6123807
DOI: 10.1038/s42003-018-0068-9

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.

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Conflict of interest statement

The following authors affiliated with deCODE genetics/Amgen, Inc. are employed by the company: R.B.T., G.S., P.S., S.J., G.H.H., P.M., E.V.I., O.B.D., R.P.K., G.T., A.H., S.G., G.N., S.R., V.T., B.V.H., I.J., D.O.A., U.T., D.F.G., H.H., and K.S. T.R.P. has received consulting and/or speakers honoraria from Amgen, Sanofi, and Merck (all minor). M.S.S. has received research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Poxel, and Takeda and consulting honoraria from Amgen, CVS Caremark, Esperion, Intarcia, Ionis, Janssen Research and Development, MedImmune, and Merck. B.T., A.S.V., J.B.N., J.T.S., O.L.H., F.W.A., D.M.R., D.D., C.J.W., M.-L.L., and K.H. have no relationship with industry to disclose.

Figures

**Fig. 1**
Heatmap showing the effects of atrial fibrillation variants on ECG traits in sinus rhythm ECGs, excluding atrial fibrillation cases. See Thorolfsdottir et al. ECG measurements were available for 62,974 individuals without atrial fibrillation. Each column shows the estimated effect of the risk allele of an atrial fibrillation variant on various ECG traits. The effect of each variant, annotated with the corresponding gene name, is scaled with the log₁₀-atrial fibrillation odds ratio. Red color represents a positive effect on the ECG variable and blue color a negative effect. The effect is shown only for significant associations after adjusting for multiple testing with a false discovery rate procedure for each variant. Non-significant associations are white in the heatmap

**Fig. 2**
The effect of the splice-donor variant c.1167+1G>A in *RPL3L* on splicing. a Quantification of two forms of RPL3L transcripts; the primary isoform, ENST00000268661, and a novel isoform with skipping of exon 9 resulting from c.1167+1G>A. It also shows the proportion of novel isoform among all transcripts. A total of 167 samples, all from the right atrium, where included in the analysis. Two of those came from carriers of c.1167+1G>A. The figure demonstrates that only the two carriers have the novel isoform with skipping of exon 9. Their exon skipping proportion is ~0.5 while it is zero in non-carriers. b A schematic illustration of the splicing of RPL3L among carriers and non-carriers of c.1167+G>A. The variant is in a splice-donor site by the second last exon and results in exon skipping. The skipped exon is 120 base pairs and therefore its deletion is in-frame

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References

1. Chugh SS, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837–847. doi: 10.1161/CIRCULATIONAHA.113.005119. - DOI - PMC - PubMed
1. Calenda BW, Fuster V, Halperin JL, Granger CB. Stroke risk assessment in atrial fibrillation: risk factors and markers of atrial myopathy. Nat. Rev. Cardiol. 2016;13:549–559. doi: 10.1038/nrcardio.2016.106. - DOI - PubMed
1. Goldberger JJ, et al. Evaluating the atrial myopathy underlying atrial fibrillation: identifying the arrhythmogenic and thrombogenic substrate. Circulation. 2015;132:278–291. doi: 10.1161/CIRCULATIONAHA.115.016795. - DOI - PMC - PubMed
1. Bapat, A., Anderson, C. D., Ellinor, P. T. & Lubitz, S. A. Genomic basis of atrial fibrillation. Heart104, 201–206 (2017). - PubMed
1. Holm H, et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat. Genet. 2011;43:316–320. doi: 10.1038/ng.781. - DOI - PMC - PubMed

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[1] Chugh SS, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837–847. doi: 10.1161/CIRCULATIONAHA.113.005119. - DOI - PMC - PubMed

[2] Chugh SS, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837–847. doi: 10.1161/CIRCULATIONAHA.113.005119. - DOI - PMC - PubMed

[3] Calenda BW, Fuster V, Halperin JL, Granger CB. Stroke risk assessment in atrial fibrillation: risk factors and markers of atrial myopathy. Nat. Rev. Cardiol. 2016;13:549–559. doi: 10.1038/nrcardio.2016.106. - DOI - PubMed

[4] Calenda BW, Fuster V, Halperin JL, Granger CB. Stroke risk assessment in atrial fibrillation: risk factors and markers of atrial myopathy. Nat. Rev. Cardiol. 2016;13:549–559. doi: 10.1038/nrcardio.2016.106. - DOI - PubMed

[5] Goldberger JJ, et al. Evaluating the atrial myopathy underlying atrial fibrillation: identifying the arrhythmogenic and thrombogenic substrate. Circulation. 2015;132:278–291. doi: 10.1161/CIRCULATIONAHA.115.016795. - DOI - PMC - PubMed

[6] Goldberger JJ, et al. Evaluating the atrial myopathy underlying atrial fibrillation: identifying the arrhythmogenic and thrombogenic substrate. Circulation. 2015;132:278–291. doi: 10.1161/CIRCULATIONAHA.115.016795. - DOI - PMC - PubMed

[7] Bapat, A., Anderson, C. D., Ellinor, P. T. & Lubitz, S. A. Genomic basis of atrial fibrillation. Heart104, 201–206 (2017). - PubMed

[8] Bapat, A., Anderson, C. D., Ellinor, P. T. & Lubitz, S. A. Genomic basis of atrial fibrillation. Heart104, 201–206 (2017). - PubMed

[9] Holm H, et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat. Genet. 2011;43:316–320. doi: 10.1038/ng.781. - DOI - PMC - PubMed

[10] Holm H, et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat. Genet. 2011;43:316–320. doi: 10.1038/ng.781. - DOI - PMC - PubMed

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Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Affiliations

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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References

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