Coding variants in RPL3L and MYZAP 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 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: Norway; Iceland
• Online Access: http://hdl.handle.net/10852/67557; http://urn.nb.no/URN:NBN:no-70733; 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.