Cardiac Structure
GWAS studies have also associated 4q25 with not only AF but an increased risk of stroke22. The mechanism of this association is thought to be AF itself, though associations of AF with stroke are notably present for both thrombotic and hemorrhagic forms. The LAA is a complex structure with important roles in both cardioembolism and AF arrhythmogenesis. Variations in LAA morphology are associated with discrete stroke risk13, 23. These studies have shown a non-chicken wing LAA morphology, a small LAA os and a larger LAA volume to be associated with an increased risk of stroke. Given that the 4q25 variants are strongly associated with both AF and stroke, and likewise LAA morphology is important in both AF and stroke pathogenesis, we sought to determine if the most common 4q25 risk variant is associated with LAA morphology. We observed that the RS2200733 4q25 variant is associated with LAA morphology with risk allele carriers 3.0 times more likely to have a non-CW morphology than non-carriers. Conversely, noncarriers were 4.0 times more likely to have a CW morphology compared to carriers. This finding does support cardiac development as a fundamental mediator of the PITX2 risk24. The complex relationship between appendage morphology, stroke risk, and atrial arrhythmogenesis will require experimental dissection, but this may be challenging outside large animal models.