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.

434 European ancestry individuals, 202 African ancestry individuals, 25 individuals