Abstract 4403: Significant Single Nucleotide Polymorphism Associated with Atrial Fibrillation Located on Chromosome 4q25 in a Whole Genome Association Study and Association with Left Atrial Gene Expression
Introduction: Heritability studies of atrial fibrillation (AF) suggest a complex genetic basis for common AF. Recently a locus on chromosome 4q25 was associated with AF in a genome-wide association study (GWAS), but the mechanism by which this locus is associated with AF is unknown.
Methods: To identify genetic variations associated with AF, we performed an analysis of AF as a secondary phenotype from a case-control GWAS of myocardial infarction. 210,178 autosomal SNPs of high quality were genotyped in 138 AF cases and 546 controls. Stratified score tests of the trend/additive model and general genotypic model were performed for each SNP. Genomic control and multidimensional scaling were used to control and assess population stratification. The SNP meeting genome-wide significance was genotyped in 46 left atrial appendage tissue samples for which we obtained expression levels for 22,184 transcripts. Cis expression traits within 1 megabase of the top SNP were tested for association with the SNP genotypes.
Results: One SNP (rs4611994) met our per-SNP genome-wide significance thresholds (both a conservative Bonferroni threshold or a more liberal FDR-based threshold) for association with AF, which was in perfect linkage disequilibrium with the locus on chromosome 4q25 found in the deCODE genetics AF study (r2 with SNP rs2200733=1.0). This SNP yielded an AF odds ratio of 2.28 under the additive model, with a p-value using genomic control/general genotype model of 5.0E-08, and a minor allele frequency 0.13 in controls and 0.25 in AF cases, and a genome-wide p-value of 0.046 by permutation analysis. In the 46 left atrial tissue samples, cis analysis demonstrated significant association between rs4611994 genotype and expression of LRIT3 (Leucine-rich repeat, immunoglobulin-like domain and transmembrane domain-containing protein 3) with q-value 2.22E-03 and the C isoform of PITX2 with q-value 7.50E-03.
Conclusions: Our GWAS for common AF has replicated the AF-associated locus on chromosome 4q25. The genotype at this locus was correlated with cis regulation of the LRIT3 and PITX2C transcripts, suggesting these genes as candidates for mechanistic studies.