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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.

Keywords: atrial fibrillation; epidemiology; gene expression; genetics; polymorphism; single nucleotide; zebrafish.

Conflict of interest statement

Conflict of Interest Disclosures: None.


Figure 1
Figure 1
Flow-chart illustrating the study design and major results. Novel chromosomal loci associated with AF were identified independently in cohorts of European and Japanese descent by means of GWAS and subsequent replication. Signals in or around NEURL, TBX5, CAND2, GJA1, and CUX2 were detected. Additional studies revealed increased atrial action potential durations after knockdown of NEURL and CAND2, an interaction between NEURL and PITX2, an association of GJA1, TBX5, and CUX2 with stroke, and eQTL associations with CAND2, GJA1, TBX5, CEP68, LINC00467, NKX2.5, TMEM116, and WIPF1 in left atrial and other tissues. APD – action potential duration.
Figure 2
Figure 2
Regional plots for novel atrial fibrillation susceptibility loci in Europeans and Japanese. Panels A-D (A: NEURL B: TBX5 C: GJA1 D: CAND2) show 4 novel loci detected in Europeans, panels E (NEURL) and F (CUX2) show 2 novel loci detected in Japanese. At each novel locus (p≤5×10−8), SNPs are plotted using the genomic position (NCBI Build 36) and discovery stage P values. In each panel, the sentinel SNP is labeled in purple. Each dot represents a SNP. The strength of the linkage disequilibrium of SNPs with the sentinel-SNP is indicated by a color gradient according to the legend in each panel, where red indicates strong, and blue indicates weak linkage disequilibrium. Estimated recombination rates are shown by the blue line, and spikes indicate locations of frequent recombination. Below each panel, the chromosomal positions of the SNPs and regional candidate genes are annotated. Linkage disequilibrium and recombination rates in panels A-F are based on the CEU HapMap release 22 (European) and JPT + CHB HapMap release 22 (Japanese), respectively. All regional association plots prepared using LocusZoom.
Figure 3
Figure 3
Analysis of neurla, cand1, cand2, and cux2b knockdown in zebrafish. A: Brightfield micrographs of anesthetized 72hpf embryos injected with morpholinos. Scale bar = 500µm. B: Measurement of ventricular fractional shortening. C: Analysis of resting heart rate. D: Atrial action potential durations as assayed by optical mapping in zebrafish hearts. *Represents p<0.05 when compared to control. E: Representative traces of atrial action potentials from optical mapping. All numbers within bars indicate which morpholino was used for the presented data. Where no labels are shown, data represent pooled data obtained from all effective morpholinos. CN – control. n=number of biological replicates for a given experiment.

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