Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation

Moritz F. Sinner, Nathan R. Tucker, Kathryn L. Lunetta, Kouichi Ozaki, J. Gustav Smith, Stella Trompet, Joshua C. Bis, Honghuang Lin, Mina K. Chung, Jonas B. Nielsen, Steven A. Lubitz, Bouwe P. Krijthe, Jared W. Magnani, Jiangchuan Ye, Michael H. Gollob, Tatsuhiko Tsunoda, Martina Müller-Nurasyid, Peter Lichtner, Annette Peters, Elena DolmatovaMichiaki Kubo, Jonathan D. Smith, Bruce M. Psaty, Nicholas L. Smith, J. Wouter Jukema, Daniel I. Chasman, Christine M. Albert, Yusuke Ebana, Tetsushi Furukawa, Peter W. Macfarlane, Tamara B. Harris, Dawood Darbar, Marcus Dörr, Anders G. Holst, Jesper H. Svendsen, Albert Hofman, Andre G. Uitterlinden, Vilmundur Gudnason, Mitsuaki Isobe, Rainer Malik, Martin Dichgans, Jonathan Rosand, David R. Van Wagoner, Emelia J. Benjamin, David J. Milan, Olle Melander, Susan R. Heckbert, Ian Ford, Yongmei Liu, John Barnard, Morten S. Olesen, Bruno H.C. Stricker, Toshihiro Tanaka, Stefan Kääb, Patrick T. Ellinor

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Background-Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. Methods and Results-To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10-16), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10-8), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10-11), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10-9). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10-25) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10-9). The top singlenucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10-19), GJA1 (P=2.66×10-6), and TBX5 (P=1.36×10-5). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). Conclusions-We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

Original languageEnglish
Pages (from-to)1225-1235
Number of pages11
JournalCirculation
Volume130
Issue number15
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Sinner, M. F., Tucker, N. R., Lunetta, K. L., Ozaki, K., Smith, J. G., Trompet, S., Bis, J. C., Lin, H., Chung, M. K., Nielsen, J. B., Lubitz, S. A., Krijthe, B. P., Magnani, J. W., Ye, J., Gollob, M. H., Tsunoda, T., Müller-Nurasyid, M., Lichtner, P., Peters, A., ... Ellinor, P. T. (2014). Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. Circulation, 130(15), 1225-1235. https://doi.org/10.1161/CIRCULATIONAHA.114.009892