Sinner, Moritz F3; Tucker, Nathan R3; Lunetta, Kathryn L3; Ozaki, Kouichi3; Smith, J Gustav3; Trompet, Stella3; Bis, Joshua C3; Lin, Honghuang3; Chung, Mina K3; Nielsen, Jonas B3; Lubitz, Steven A3; Krijthe, Bouwe P3; Magnani, Jared W3; Ye, Jiangchuan3; Gollob, Michael H3; Tsunoda, Tatsuhiko3; Müller-Nurasyid, Martina3; Lichtner, Peter3; Peters, Annette3; Dolmatova, Elena3; Kubo, Michiaki3; Smith, Jonathan D3; Psaty, Bruce M3; Smith, Nicholas L3; Jukema, J Wouter3; Chasman, Daniel I3; Albert, Christine M3; Ebana, Yusuke3; Furukawa, Tetsushi3; Macfarlane, Peter W3; Harris, Tamara B3; Darbar, Dawood3; Dörr, Marcus3; Holst, Anders G3; Svendsen, Jesper H4; Hofman, Albert3; Uitterlinden, Andre G3; Gudnason, Vilmundur3; Isobe, Mitsuaki3; Malik, Rainer3; Dichgans, Martin3; Rosand, Jonathan3; Van Wagoner, David R3; Benjamin, Emelia J3; Milan, David J3; Melander, Olle3; Heckbert, Susan R3; Ford, Ian3; Liu, Yongmei3; Barnard, John3; Olesen, Morten S5; Stricker, Bruno H C3; Tanaka, Toshihiro3; Kääb, Stefan3; Ellinor, Patrick T3
1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Section of Heart and Circulatory Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet5 Section of Heart and Circulatory Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet
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 single-nucleotide 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.
Circulation, 2014, Vol 130, Issue 15, p. 1225-1235