In this study, we studied the gene-gene interaction for three AF loci replicated in the Chinese population, i.e. SNP rs2106261 in ZFHX3, rs2200733 near PITX2c, and rs3807989 in CAV1. We provide strong genetic evidence that SNP rs2200733 near PITX2c and rs2106261 in ZFHX3 interact with each other, resulting in a synergistic effect that increases the odds ratios (ORs) to risk of AF. This evidence concerns the gene ZFHX3 and atrial fibrillation.