Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Source at https://doi.org/10.1038/s42003-018-0068-9. 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 fibrillatio...

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Bibliographic Details
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 Lingaas, Asselbergs, Folkert W, Roden, Dan M, Darbar, Dawood, Pedersen, Terje Rolf, 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
Format: Article in Journal/Newspaper
Language:English
Published: Nature Research 2018
Subjects:
VDP::Medical disciplines: 700::Health sciences: 800::Community medicine
Social medicine: 801
VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin
sosialmedisin: 801
Norway
Iceland
Online Access:https://hdl.handle.net/10037/15271
https://doi.org/10.1038/s42003-018-0068-9
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Summary:Source at https://doi.org/10.1038/s42003-018-0068-9. 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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