DOI: 10.5061/dryad.nk98sf7xj
title: Decreased FAM13B expression increases atrial fibrillation susceptibility by regulating sodium current and calcium handling

description: Objectives: 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.
 Background: FAM13B expression is strongly associated
 with the lead AF GWAS variant at 5q31.  However, the
 regulatory variant controlling FAM13B expression and the
 mechanism by which FAM13B impacts AF susceptibility are
 not known. Methods: Bioinformatics, reporter gene transfections, gel
 shifts, and gene editing were used to identify the variant
 regulating FAM13B expression. RNAseq
 after FAM13B knockdown in stem cell-derived
 cardiomyocytes (iCMs) identified downstream processes. Patch clamp and
 calcium transient assays were used to assess downstream
 mechanisms. Fam13b knockout (KO) mice were studied for heart
 structural and functional changes, and pacing-induced arrhythmia. Results:
 rs17171731 was identified as the regulatory variant
 controlling FAM13B expression, with decreased enhancer
 activity of the risk allele.  Knockdown
 of FAM13B in iCMs altered expression of &gt;1000
 genes including SCN2B 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 FAM13B
 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. Conclusions: This study went from an AF GWAS locus to identify
 the causal variant and gene, mechanisms for this association, and
 confirmed arrhythmia susceptibility in Fam13b KO
 mice. FAM13B and downstream effectors are potential targets for
 patient-specific therapeutics.
description: Excel and proprietary software: Labscribe ECG Analysis software
 (iWorx RA834).
description: # Decreased FAM13B expression increases atrial fibrillation susceptibility
 by regulating sodium current and calcium handling Data repositories: Left
 atrial appendage variance normalized RNAseq gene expression levels for
 each subject are available in the GEO database, accession number GSE69890.
 Human LAA eQTL data can be obtained on our web browser:
 .\ Custom scripts for eQTL analyses
 are available here: .\ RNAseq
 data from iCell cardiomyocyte FAM13B siRNA vs. scrambled siRNA treatment
 are available in the GEO database, accession number GSE221262. Data for
 graphs: Excel file with worksheets for different figures ## Description of
 the data and file structure The Excel file has different worksheets for
 different figures. The zip file has mouse electophysiology folders for 4
 types of mice, WT, FAM13B KO of both males and females. These files
 consist of Excel files, ascii and txt files that can be opened in
 Microsoft Notepad or other text editors. ## Sharing/Access information
 Links to other publicly accessible locations of the data: *
 *
 Data was derived from the following
 sources: * Experiments done at the Cleveland Clinic and Ohio State
 University ## Code/Software Custom scripts for eQTL analyses are available
 here: