A molecular pathway analysis informs the genetic risk for arrhythmias during antipsychotic treatment

Arrhythmias are a frequent and potentially fatal side effect of antipsychotic treatment. Strict ECG monitoring and clinical interviews are the standards used to prevent arrhythmias. A biologic predictive tool is missing. The identification of a genetic makeup at risk of antipsychotic-induced arrhythmias is the aim of the present investigation. The aim of this study was to identify a molecular pathway enriched in single nucleotide polymorphisms associated with antipsychotic-induced QTc modifications. In total, 661 schizophrenic individuals from the CATIE study, M=486 (73.52%), mean age=40.92±11.02, were included. QTc variation was measured as a phase-specific change-created variable. A nested mixed regression for a repeated-measures model served in R for the analysis of the clinical and treatment-related covariates and molecular pathway analysis. Plink was used for the genetic genome-wide analysis. Quality checking was the standard (genotype call rate>0.95; minor allele frequency>0.01; Hardy-Weinberg equilibrium<0.0001) and the inflation factor was controlled by λ values. Quetiapine and perphenazine were associated with QTc variation during phase 1. No other significant association was detected. No significant inflation was detected. A number of molecular pathways were associated with QT variation at a conservative (adjusted) P value less than 0.05, including pathways related to neuronal wiring and collagen biosynthesis, along with pathways related to K+ currents and cardiac contraction. Pathways related to neuronal wiring, collagen biosynthesis, and ion currents were identified as possibly involved in QTc modifications during antispsychotic treatment in SKZ patients.