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

Circulation. 2014 Oct 7;130(15):1225-35. doi: 10.1161/CIRCULATIONAHA.114.009892. Epub 2014 Aug 14.

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=6.5×10(-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.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Atrial Fibrillation / ethnology
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / physiopathology
  • Chromosome Mapping
  • Connexin 43 / genetics*
  • Connexin 43 / physiology
  • Europe
  • Female
  • Gene Knockdown Techniques
  • Genetic Loci / physiology
  • Genetic Predisposition to Disease / ethnology
  • Genotype
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / physiology
  • Humans
  • Japan
  • Male
  • Middle Aged
  • Muscle Proteins
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology
  • Quantitative Trait Loci
  • Repressor Proteins / genetics*
  • Repressor Proteins / physiology
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / physiology
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / physiology
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / physiology

Substances

  • CAND2 protein, human
  • CUX1 protein, human
  • Cand2 protein, zebrafish
  • Connexin 43
  • GJA1 protein, human
  • Homeodomain Proteins
  • Muscle Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Transcription Factors
  • Zebrafish Proteins
  • homeobox protein PITX2
  • NEURL1 protein, human
  • Ubiquitin-Protein Ligases
  • neurl1aa protein, zebrafish

Grant support