04762nas a2201117 4500008004100000022001400041245011700055210006900172260001500241300001200256490000800268520162700276653000901903653001201912653002401924653002301948653001601971653001101987653001101998653003002009653001702039653003802056653001302094653002502107653001102132653001002143653000902153653001602162653002002178653002102198653002802219653002302247653002602270653002602296653003002322653001402352653002302366100002202389700002202411700002402433700001902457700001802476700002002494700001902514700001902533700001902552700002202571700002202593700002202615700002202637700001902659700002302678700002302701700003002724700002002754700002002774700002102794700001902815700002302834700002002857700002302877700001902900700002302919700002502942700001802967700002302985700002503008700002203033700001903055700001803074700002103092700002403113700001903137700002803156700002403184700002003208700001803228700002103246700002103267700002603288700002403314700002003338700001903358700002303377700001403400700001703414700001803431700002203449700002503471700002203496700001903518700002403537710002603561710002103587856003603608 2014 eng d a1524-453900aIntegrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.0 aIntegrating genetic transcriptional and functional analyses to i c2014 Oct 7 a1225-350 v1303 a
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.
10aAged10aAnimals10aAtrial Fibrillation10aChromosome Mapping10aConnexin 4310aEurope10aFemale10aGene Knockdown Techniques10aGenetic Loci10aGenetic Predisposition to Disease10aGenotype10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aMuscle Proteins10aNuclear Proteins10aQuantitative Trait Loci10aRepressor Proteins10aT-Box Domain Proteins10aTranscription Factors10aUbiquitin-Protein Ligases10aZebrafish10aZebrafish Proteins1 aSinner, Moritz, F1 aTucker, Nathan, R1 aLunetta, Kathryn, L1 aOzaki, Kouichi1 aSmith, Gustav1 aTrompet, Stella1 aBis, Joshua, C1 aLin, Honghuang1 aChung, Mina, K1 aNielsen, Jonas, B1 aLubitz, Steven, A1 aKrijthe, Bouwe, P1 aMagnani, Jared, W1 aYe, Jiangchuan1 aGollob, Michael, H1 aTsunoda, Tatsuhiko1 aMüller-Nurasyid, Martina1 aLichtner, Peter1 aPeters, Annette1 aDolmatova, Elena1 aKubo, Michiaki1 aSmith, Jonathan, D1 aPsaty, Bruce, M1 aSmith, Nicholas, L1 aJukema, Wouter1 aChasman, Daniel, I1 aAlbert, Christine, M1 aEbana, Yusuke1 aFurukawa, Tetsushi1 aMacfarlane, Peter, W1 aHarris, Tamara, B1 aDarbar, Dawood1 aDörr, Marcus1 aHolst, Anders, G1 aSvendsen, Jesper, H1 aHofman, Albert1 aUitterlinden, André, G1 aGudnason, Vilmundur1 aIsobe, Mitsuaki1 aMalik, Rainer1 aDichgans, Martin1 aRosand, Jonathan1 aVan Wagoner, David, R1 aBenjamin, Emelia, J1 aMilan, David, J1 aMelander, Olle1 aHeckbert, Susan, R1 aFord, Ian1 aLiu, Yongmei1 aBarnard, John1 aOlesen, Morten, S1 aStricker, Bruno, H C1 aTanaka, Toshihiro1 aKääb, Stefan1 aEllinor, Patrick, T1 aMETASTROKE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/6600