BACKGROUND: Three distinct genetic loci on chromosomes 1q21, 4q25, and 16q22 have been associated with atrial fibrillation (AF) in genome-wide association studies (GWAS). Five additional loci have been associated primarily with the PR interval and subsequently with AF. We aimed to investigate if 8 single nucleotide polymorphisms (SNPs), representing the 8 genomic loci previously linked with AF in genome-wide association studies, were associated with early-onset lone AF. METHODS: We included 209 patients with early-onset lone AF, and a control group consisting of 534 individuals free of AF. The 8 SNPs were genotyped using TaqMan assays (Applied Biosystems, Foster City, CA). RESULTS: Three SNPs were found to be significantly associated with early-onset lone AF: rs2200733 closest to PITX2 (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.16-2.27; P = 0.004), rs3807989 near to CAV1 (OR 1.35; 95% CI, 1.06-1.72; P = 0.015), and rs11047543 near to SOX5 (OR 1.70; 95% CI, 1.18-2.44; P = 0.004). When correcting for multiple testing, rs2200733 and rs11047543 were still significantly associated with AF. CONCLUSIONS: Three SNPs, rs2200733 (4q25), rs3807989 (7p31), and rs11047543 (12p12), were associated with early-onset lone AF. All 3 SNPs are positioned close to genes that in previous studies have been demonstrated to be important for cardiac morphology/development, thereby suggesting a link between these SNPs and structural heart disease. Our results however, indicate that variants in these 3 loci are associated with AF through mechanisms that do not involve major structural abnormalities in the heart.