A Missense Variant in PLEC Increases Risk of Atrial Fibrillation

Research output: Contribution to journalArticle

Authors

  • Rosa B. Thorolfsdottir
  • Gardar Sveinbjornsson
  • Patrick Sulem
  • Anna Helgadottir
  • Solveig Gretarsdottir
  • Stefania Benonisdottir
  • Audur Magnusdottir
  • Olafur B. Davidsson
  • Sridharan Rajamani
  • Dan M. Roden
  • Dawood Darbar
  • Terje R. Pedersen
  • Marc S. Sabatine
  • Ingileif Jonsdottir
  • David O. Arnar
  • Unnur Thorsteinsdottir
  • Daniel F. Gudbjartsson
  • Hilma Holm
  • Kari Stefansson

External Institution(s)

  • deCODE Genetics
  • University of Oslo
  • University of Iceland
  • Landspitali University Hospital

Details

Original languageEnglish (US)
Pages (from-to)2157-2168
Number of pages12
JournalJournal of the American College of Cardiology
Volume70
Issue number17
StatusPublished - Oct 24 2017
Peer-reviewedYes

Abstract

Background Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4. Objectives The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements. Methods The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals. Results The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10−18), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10−10), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive. Conclusions The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF.

    Research areas

  • arrhythmia, atrial fibrillation, electrocardiogram, plectin

Citation formats

APA

Thorolfsdottir, R. B., Sveinbjornsson, G., Sulem, P., Helgadottir, A., Gretarsdottir, S., Benonisdottir, S., ... Stefansson, K. (2017). A Missense Variant in PLEC Increases Risk of Atrial Fibrillation. Journal of the American College of Cardiology, 70(17), 2157-2168. https://doi.org/10.1016/j.jacc.2017.09.005

Harvard

Thorolfsdottir, RB, Sveinbjornsson, G, Sulem, P, Helgadottir, A, Gretarsdottir, S, Benonisdottir, S, Magnusdottir, A, Davidsson, OB, Rajamani, S, Roden, DM, Darbar, D, Pedersen, TR, Sabatine, MS, Jonsdottir, I, Arnar, DO, Thorsteinsdottir, U, Gudbjartsson, DF, Holm, H & Stefansson, K 2017, 'A Missense Variant in PLEC Increases Risk of Atrial Fibrillation', Journal of the American College of Cardiology, vol. 70, no. 17, pp. 2157-2168. https://doi.org/10.1016/j.jacc.2017.09.005