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

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 HolmenFolkert 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

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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.

Original language	English
Article number	68
Journal	Communications biology
Volume	1
Issue number	1
DOIs	https://doi.org/10.1038/s42003-018-0068-9
Publication status	Published - 2018

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Thorolfsdottir, R. B., Sveinbjornsson, G., Sulem, P., Nielsen, J. B., Jonsson, S., Halldorsson, G. H., Melsted, P., Ivarsdottir, E. V., Davidsson, O. B., Kristjansson, R. P., Thorleifsson, G., Helgadottir, A., Gretarsdottir, S., Norddahl, G., Rajamani, S., Torfason, B., Valgardsson, A. S., Sverrisson, J. T., Tragante, V., ... Stefansson, K. (2018). Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation. Communications biology, 1(1), Article 68. https://doi.org/10.1038/s42003-018-0068-9

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title = "Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation",

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.",

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

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year = "2018",

doi = "10.1038/s42003-018-0068-9",

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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, M-L, Halldorsson, BV, Jonsdottir, I, Hveem, K, Arnar, DO, Thorsteinsdottir, U, Gudbjartsson, DF, Holm, H & Stefansson, K 2018, 'Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation', Communications biology, vol. 1, no. 1, 68. https://doi.org/10.1038/s42003-018-0068-9

TY - JOUR

T1 - Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

AU - Thorolfsdottir, Rosa B

AU - Sveinbjornsson, Gardar

AU - Sulem, Patrick

AU - Nielsen, Jonas B

AU - Jonsson, Stefan

AU - Halldorsson, Gisli H

AU - Melsted, Pall

AU - Ivarsdottir, Erna V

AU - Davidsson, Olafur B

AU - Kristjansson, Ragnar P

AU - Thorleifsson, Gudmar

AU - Helgadottir, Anna

AU - Gretarsdottir, Solveig

AU - Norddahl, Gudmundur

AU - Rajamani, Sridharan

AU - Torfason, Bjarni

AU - Valgardsson, Atli S

AU - Sverrisson, Jon T

AU - Tragante, Vinicius

AU - Holmen, Oddgeir L

AU - Asselbergs, Folkert W

AU - Roden, Dan M

AU - Darbar, Dawood

AU - Pedersen, Terje R

AU - Sabatine, Marc S

AU - Willer, Cristen J

AU - Løchen, Maja-Lisa

AU - Halldorsson, Bjarni V

AU - Jonsdottir, Ingileif

AU - Hveem, Kristian

AU - Arnar, David O

AU - Thorsteinsdottir, Unnur

AU - Gudbjartsson, Daniel F

AU - Holm, Hilma

AU - Stefansson, Kari

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1038/s42003-018-0068-9

DO - 10.1038/s42003-018-0068-9

M3 - Article

C2 - 30271950

SN - 2399-3642

VL - 1

JO - Communications biology

JF - Communications biology

IS - 1

M1 - 68

ER -

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

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