Genome-Wide Association Study for Idiopathic Ventricular Tachyarrhythmias Identifies Key Role of and in Calcium Homeostasis and Cardiac Rhythm Maintenance.

Background: Idiopathic ventricular tachycardia (VT) occurs in structurally normal hearts and accounts for a significant number of all types of VT. The genome-wide association study is the most effective strategy for identifying novel genetic variants for common diseases. However, no genome-wide association study has been reported for idiopathic VT.

Methods: We conducted the first genome-wide association study for idiopathic VT in the Chinese Han population using a discovery population with 246 cases and 648 controls and a replication population with 222 cases and >4072 controls. Candidate VT genes were functionally characterized in zebrafish. Real-time RT-PCR analysis was used to determine the effects of candidate genes on expression of ion channels and regulators. Patch-clamping was used to record L-type calcium current from neonatal rat cardiomyocytes with overexpression of candidate genes.

Results: We identified 4 significant loci represented by rs78960694 (minor allele frequency [MAF]=5.02% in cases and 1.84% in controls; =4.30×1012, odds ratio [OR]=3.91) and rs2229095 (MAF=3.25% in cases and 1.63% in controls; =1.02×107, OR=3.44) near and in , respectively, rs68126098 in (MAF=40.98% in cases and 32.07% in controls; 2.40×108, OR=1.53), rs2390325 between and (MAF=21.19% in cases and 15.12% in controls; =1.92×107, OR=1.62), and rs270065 in (MAF=33.63% in cases and 40.25% in controls; =9.51×107, OR=0.69). Note that the associations of idiopathic VT for variant rs78960694 and variant rs68126098 reach genome-wide significance (<5.00×108). Overexpression of either or increased the heart rate in zebrafish, and enhanced expression of , or in zebrafish embryos, HEK293, and AC16 cardiomyocytes. Overexpression of either or significantly increased L-type Ca2+ current density.

Conclusions: The first genome-wide association study identifies 4 novel loci and 2 risk genes ( and ) for idiopathic VT. These findings identify new molecular determinants for cardiac calcium homeostasis and rhythm maintenance and provide novel targets for diagnosis and treatment for idiopathic VT.