Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

• Main Authors: Thorolfsdottir, RB, Sveinbjornsson, G, Sulem, P, Nielsen, JB, Jonsson, S, Halldorsson, GH, Melsted, P, Ivarsdottir, EV, Davidsson, OB, Kristjansson, RP, Thorleifsson, G, Helgadottir, A, Gretarsdottir, S, Norddahl, G, Rajamani, S, Torfason, B, Valgardsson, AS, Sverrisson, JT, Tragante, V, Holmen, OL, Asselbergs, FW, Roden, DM, Darbar, D, Pedersen, TR, Sabatine, MS, Willer, CJ, Løchen, ML, Halldorsson, BV, Jonsdottir, I, Hveem, K, Arnar, DO, Thorsteinsdottir, U, Gudbjartsson, DF, Holm, H, Stefansson, K
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2018
• Subjects: Norway; Iceland
• Online Access: https://discovery.ucl.ac.uk/id/eprint/10080849/1/s42003-018-0068-9.pdf; https://discovery.ucl.ac.uk/id/eprint/10080849/

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.