Polygenic Risk Score predicts QTc-prolongation and Short-Term Mortality in Patients using QT-prolonging Psychoactive Medications

Background: There is a genetic component to the QT-interval. This study investigated whether a polygenic risk score for QTc (PRSQTc) could predict ∆QTc and short-term mortality in first-time users of QT-prolonging medications (QTPM) with a known risk of Torsade de Pointes. Methods: First-time users of psychoactive QTPM in the Copenhagen Hospital Biobank and the Danish Blood Donor Study from 2009-2021 were included. ∆QTc was calculated and all-cause 30-day mortality following initiation of treatment was explored. All models were adjusted for conventional QT-prolonging risk factors, and models investigating death were additionally adjusted for potential comorbidity confounders. Results: The PRSQTc could predict ∆QTc (2.88 milliseconds (ms) for every increase of standard deviation in PRSQTc (P <0.001)) following treatment initiation. Individuals in the top ≥80 % of PRSQTc had a higher risk of ∆QTc of ≥60 ms compared to individuals in <80 % PRSQTc (OR = 4.88 P = 0.019). Furthermore, the study has also shown that the shorter QTc before initiation of QTPM, the higher the risk of greater ∆QTc. A high PRSQTc could also predict short-term mortality following treatment initiation: Individuals in the top PRSQTc ≥90 % had an odds ratio of 1.84 (P-value = 0.002) for short-term mortality compared to individuals with PRSQTc <90 %. Individuals in the top PRSQTc ≥99 % had an odds ratio of 4.95 (P-value = 0.009) for short-term mortality compared to individuals in the <99 % PRSQTc It could be replicated that PRSQTc ≥90 % was a predictor of short-term mortality with OR 1.52 (P-value = 0.002) compared to PRSQTc <90 % in a bigger cohort (N=15.249). Conclusion: PRSQTc seems to be predictive of ∆QTc following initiation of treatment. PRSQTc proves to be a sufficient predictor of 30-day mortality after initiation of QT-prolonging psychoactive drugs with a known risk of Torsade de Pointes. If used in a clinical setting, PRSQT may help prevent sudden cardiac deaths associated with QTPM.