Decreased FAM13B expression increases atrial fibrillation susceptibility by regulating sodium current and calcium handling

<p><strong>Objectives</strong>: To determine the causal genetic variant and gene and the mechanism for the atrial fibrillation (AF) genome wide association study (GWAS) locus on chromosome 5q31.</p> <p><strong>Background</strong>: <em>FAM13B</em> expression is strongly associated with the lead AF GWAS variant at 5q31.  However, the regulatory variant controlling <em>FAM13B</em> expression and the mechanism by which <em>FAM13B</em> impacts AF susceptibility are not known.</p> <p><strong>Methods</strong>: Bioinformatics, reporter gene transfections, gel shifts, and gene editing were used to identify the variant regulating <em>FAM13B</em> expression. RNAseq after <em>FAM13B</em> knockdown in stem cell-derived cardiomyocytes (iCMs) identified downstream processes. Patch clamp and calcium transient assays were used to assess downstream mechanisms. <em>Fam13b</em> knockout (KO) mice were studied for heart structural and functional changes, and pacing-induced arrhythmia.</p> <p><strong>Results</strong>: rs17171731 was identified as the regulatory variant controlling <em>FAM13B</em> expression, with decreased enhancer activity of the risk allele.  Knockdown of <em>FAM13B</em> in iCMs altered expression of &gt;1000 genes including <em>SCN2B</em> and led to pro-arrhythmogenic changes in the late sodium current and Ca²⁺ cycling.  FAM13B is a member of the Rho GTPase-activating protein (RhoGAP) gene family, but failed to demonstrate RhoGAP activity.  GFP-tagged <em>FAM13B</em> expressed in iCMs localized at the Z-disc and plasma membrane. Fam13b knockout mice had increased basal p-wave duration and QT interval, and were more susceptible to pacing-induced arrhythmias vs. controls.</p> <p><strong>Conclusions</strong>: This study went from an AF GWAS locus to identify the causal variant and gene, mechanisms for this association, and confirmed arrhythmia susceptibility in <em>Fam13b</em> KO mice. FAM13B and downstream effectors are potential targets for patient-specific therapeutics.</p>