Alterations in the calcium homoeostasis that may confer a higher risk of atrial fibrillation to carriers of the 4q25 risk variant rs13143308T. Schematic outline of the mechanisms identified in the present study (blue rectangle) that may contribute to increase the risk of atrial fibrillation in carriers of the rs13143308T risk variant. Briefly, carriers of this variant present higher SERCA2a expression and RyR2 phosphorylation at ser2808 than carriers of the normal rs13143308G variant, which may account for the higher spark frequency in myocytes from patients with the risk variant. The higher incidence of spontaneous calcium release, in turn, will stimulate electrogenic Na⁺-Ca²⁺ exchange, giving rise to the higher incidence of I_TI currents in carriers of the risk variant, and hence increase the frequency of DADs large enough to trigger spontaneous atrial electrical activity and induce atrial fibrillation.