Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation

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Abstract
A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts. The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case–control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 ± 10 vs. 71 ± 13 years; Rotterdam 73 ± 8 vs. 69 ± 9 years; Vanderbilt 54 ± 14 vs. 57 ± 14 years; AFNet 62 ± 12 vs. 49 ± 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18–1.59; P = 3.1 × 10−5] to 2.52 in AFNet (95% CI 2.22–2.8; P = 1.8 × 10−49). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03–1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13–1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86–1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60–2.26; P = 3.3 × 10−13) for rs2200733 and of 1.36 (95% CI 1.26–1.47; P = 6.7 × 10−15) for rs10033464. The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.