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Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.
- Source :
-
Circulation [Circulation] 2014 Oct 07; Vol. 130 (15), pp. 1225-35. Date of Electronic Publication: 2014 Aug 14. - Publication Year :
- 2014
-
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.<br />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).<br />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.<br /> (© 2014 American Heart Association, Inc.)
- Subjects :
- Aged
Animals
Atrial Fibrillation ethnology
Atrial Fibrillation physiopathology
Chromosome Mapping
Connexin 43 physiology
Europe
Female
Gene Knockdown Techniques
Genetic Loci physiology
Genetic Predisposition to Disease ethnology
Genotype
Homeodomain Proteins physiology
Humans
Japan
Male
Middle Aged
Muscle Proteins
Nuclear Proteins physiology
Quantitative Trait Loci
Repressor Proteins physiology
T-Box Domain Proteins physiology
Transcription Factors genetics
Transcription Factors physiology
Ubiquitin-Protein Ligases physiology
Zebrafish
Zebrafish Proteins genetics
Zebrafish Proteins physiology
Homeobox Protein PITX2
Atrial Fibrillation genetics
Connexin 43 genetics
Homeodomain Proteins genetics
Nuclear Proteins genetics
Repressor Proteins genetics
T-Box Domain Proteins genetics
Ubiquitin-Protein Ligases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 130
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 25124494
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.114.009892