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

Sinner MF, Tucker NR, Lunetta KL, Ozaki K, Smith JG, Trompet S, Bis JC, Lin H, Chung MK, Nielsen JB, Lubitz SA, Krijthe BP, Magnani JW, Ye J, Gollob MH, Tsunoda T, Müller-Nurasyid M, Lichtner P, Peters A, Dolmatova E, Kubo M, Smith JD, Psaty BM, Smith NL, Jukema JW, Chasman DI, Albert CM, Ebana Y, Furukawa T, Macfarlane PW, Harris TB, Darbar D, Dörr M, Holst AG, Svendsen JH, Hofman A, Uitterlinden AG, Gudnason V, Isobe M, Malik R, Dichgans M, Rosand J, Van Wagoner DR, METASTROKE Consortium, AFGen Consortium, Benjamin EJ, Milan DJ, Melander O, Heckbert SR, Ford I, Liu Y, Barnard J, Olesen MS, Stricker BH, Tanaka T, Kääb S, Ellinor PT
Circulation. 2014 130 (15): 1225-35

PMID: 25124494 · PMCID: PMC4190011 · DOI:10.1161/CIRCULATIONAHA.114.009892

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.

© 2014 American Heart Association, Inc.

MeSH Terms (25)

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

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