Abstract 14305: Functional Genomics Implicates Decreased Fam13B Expression as Causal for the Chromosome 5q31 Atrial Fibrillation Risk Locus
Introduction: Genome wide association studies (GWAS) identified an atrial fibrillation (AF) risk locus on chr. 5q31 near the WNT8A gene, but the mechanism for this association is unknown.
Objective: To use functional genomics to identify the SNP and gene responsible for the chr. 5q31 AF GWAS locus.
Methods and Results: RNAseq and SNP microarray analyses were performed on 265 left atrial appendages (LAA) from a biracial cohort. Global gene expression was ascertained by RNAseq and adjusted using surrogate variable analysis. For each gene we calculated the effect of every cis-SNP on gene expression to derive expression quantitative trait loci. At the 5q31 AF GWAS locus, we observed that WNT8A was not expressed in the LAA; however, the expression of an adjacent gene, FAM13B, was strongly associated with the AF susceptibility SNP rs2040862 (in European descent subjects p=4.83E-27, with each AF risk allele lowering expression by 15%). FAM13B encodes for a poorly characterized member of the Rho GTPase activation domain protein gene family. Many SNPs in linkage disequilibrium (LD) with rs2040862 were similarly associated with FAM13B expression, making it difficult to ascertain the causal SNP. In the African descent subjects with an altered LD structure, rs17171731 emerged as the SNP best associated with FAM13B expression, which was bolstered by fetal heart DNase1 hypersensitivity data from the Epigenome Roadmap Project. Reporter gene transfection studies in cardiomyocytes derived from H9 embryonic stem cells showed that the rs17171731 AF risk allele had stronger silencer activity vs. the reference allele (p<0.0001). Gel shift assays showed that the risk, but not the reference, allele was specifically shifted by heart nuclear extract protein. Expression of many genes that might alter susceptibility to AF was altered by siRNA knockdown of FAM13B in iPS-derived cardiomyocytes, including sodium channel subunits.
Conclusions: Functional genomic studies of human LAA demonstrated that the chr. 5q31 AF GWAS locus may be attributed to strong silencer activity of the AF risk allele of rs17171731, leading to decreased expression of FAM13B, which may alter cardiomyocyte ion channel activity to increase AF susceptibility.
Author Disclosures: J. Hsu: None. S. Gore-Panter: None. G. Tchou: None. L. Castel: None. B. Lovano: None. C.S. Moravec: None. J. Barnard: None. D.R. Van Wagoner: None. M.K. Chung: None. J.D. Smith: None.
- © 2016 by American Heart Association, Inc.