Abstract 1964: A Genome-Wide Association Study in Icelanders Identifies a Novel Sequence Variant on Chromosome 16q22 That is Additive to 4q25 Variants for Atrial Fibrillation Risk
Introduction. Atrial fibrillation (AF) is a common arrhythmia in humans and a major cause of morbidity and mortality. We have previously reported a genome-wide study identifying sequence variants on chromosome 4q25 that confer risk of AF. We have now expanded our cohort for genome-wide association stud, in the attempt to discover additional variants that associate with the common forms of AF.
Methods. A sample set of 2,385 Icelandic patients with AF and/or atrial flutter (AFl) and 33,752 Icelandic population controls were genotyped with the Illumina HumanHap300 and HumanHapCNV370 bead chips, yielding 304,226 SNPs that were tested individually for association. Of the top ten SNPs, seven represented the previously discovered signal on chromosome 4q25. The remaining three SNPs were genotyped in three replication cohorts of European descent, from Iceland (989 cases and 2,027 controls), Norway (725 cases and 725 controls) and the United States (735 cases and 729 controls).
Results. One SNP, rs7193343, on chromosome 16q22, showed genome-wide significant association with AF in the combined Icelandic sample set and this association was replicated in the non-Icelandic samples, with an odds ratio (OR) for AF of 1.21 (95% CI: 1.14 –1.29) for all four sample sets combined. This variant does not associate with hypertension, coronary artery disease, or obesity, all known risk factors for AF. The at-risk allele of this variant has a population frequency of 20% in controls of European descent and was independent of the two independent variants near the PITX2 gene on 4q25. The data support the use of a multiplicative model- all 3 variants combined define AF risk relative to the general population ranging from 0.6 fold to 4 fold.
Conclusions. A sequence variant on chromosome 16q22 associates with common AF in populations of European descent and adds to the risk from the two variants previously discovered on 4q25. This is the third independent common sequence variant with association to AF that has been replicated in several populations and is further evidence of an important genetic contribution to the pathogenesis of this complex arrhythmia.