@article {6600, title = {Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.}, journal = {Circulation}, volume = {130}, year = {2014}, month = {2014 Oct 7}, pages = {1225-35}, 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{\texttimes}10(-16)), GJA1 (rs13216675; RR=1.10; 95\% CI, 1.06-1.14; P=2.2{\texttimes}10(-8)), TBX5 (rs10507248; RR=1.12; 95\% CI, 1.08-1.16; P=5.7{\texttimes}10(-11)), and CAND2 (rs4642101; RR=1.10; 95\% CI, 1.06-1.14; P=9.8{\texttimes}10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95\% CI, 1.26-1.39; P=2.0{\texttimes}10(-25)) and CUX2 (rs6490029; RR=1.12; 95\% CI, 1.08-1.16; P=3.9{\texttimes}10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6{\texttimes}10(-19)), GJA1 (P=2.66{\texttimes}10(-6)), and TBX5 (P=1.36{\texttimes}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.

}, keywords = {Aged, Animals, Atrial Fibrillation, Chromosome Mapping, Connexin 43, Europe, Female, Gene Knockdown Techniques, Genetic Loci, Genetic Predisposition to Disease, Genotype, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Muscle Proteins, Nuclear Proteins, Quantitative Trait Loci, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, Ubiquitin-Protein Ligases, Zebrafish, Zebrafish Proteins}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.114.009892}, author = {Sinner, Moritz F and Tucker, Nathan R and Lunetta, Kathryn L and Ozaki, Kouichi and Smith, J Gustav and Trompet, Stella and Bis, Joshua C and Lin, Honghuang and Chung, Mina K and Nielsen, Jonas B and Lubitz, Steven A and Krijthe, Bouwe P and Magnani, Jared W and Ye, Jiangchuan and Gollob, Michael H and Tsunoda, Tatsuhiko and M{\"u}ller-Nurasyid, Martina and Lichtner, Peter and Peters, Annette and Dolmatova, Elena and Kubo, Michiaki and Smith, Jonathan D and Psaty, Bruce M and Smith, Nicholas L and Jukema, J Wouter and Chasman, Daniel I and Albert, Christine M and Ebana, Yusuke and Furukawa, Tetsushi and Macfarlane, Peter W and Harris, Tamara B and Darbar, Dawood and D{\"o}rr, Marcus and Holst, Anders G and Svendsen, Jesper H and Hofman, Albert and Uitterlinden, Andr{\'e} G and Gudnason, Vilmundur and Isobe, Mitsuaki and Malik, Rainer and Dichgans, Martin and Rosand, Jonathan and Van Wagoner, David R and Benjamin, Emelia J and Milan, David J and Melander, Olle and Heckbert, Susan R and Ford, Ian and Liu, Yongmei and Barnard, John and Olesen, Morten S and Stricker, Bruno H C and Tanaka, Toshihiro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T} }