Integrating Genetic, Transcriptional, and Functional Analyses to Identify Five Novel Genes for Atrial Fibrillation

BACKGROUND: Atrial fibrillation (AF) affects over 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 utilized a multifaceted approach, combining large-scale genotyping in two ethnically distinct populations, cis-eQTL mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501, RR=1.18, 95%CI 1.13 - 1.23, p=6.5x10^-16), GJA1 (rs13216675, RR=1.10, 95%CI 1.06 - 1.14, p=2.2x10^-8), TBX5 (rs10507248, RR=1.12, 95%CI 1.08 - 1.16, p=5.7x10^-11), and CAND2 (rs4642101, RR=1.10, 95%CI 1.06 - 1.14, p=9.8x10^-9). In Japanese, novel loci were identified near NEURL (rs6584555, RR=1.32, 95%CI 1.26-1.39, p=2.0x10^-25) and CUX2 (rs6490029, RR=1.12, 95%CI 1.08-1.16, p=3.9x10^-9). The top SNPs or their proxies were identified as cis-eQTLs for the genes CAND2 (p=2.6x10^-19), GJA1 (p=2.66x10^-6), and TBX5 (p=1.36x10^-05). 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 five novel loci for AF. Our results further expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.