Loss of the Atrial Fibrillation-Related Gene, , Results in Atrial Dilation and Arrhythmias.

Background: (zinc finger homeobox 3), a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the locus and examine the impact of loss on cardiac function in mice.

Methods: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the locus. Cardiac function was assessed by echocardiography, magnetic resonance imaging, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted loss ( Het and knockout, respectively). Human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by .

Results: We found single-nucleotide polymorphism (SNP) rs12931021 modulates an enhancer regulating expression, and the AF risk allele is associated with decreased transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than Het and wild-type mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF.

Conclusions: Our findings implicate as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for in the control of cardiac genes and signaling pathways essential for normal atrial function.