A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

Abstract

Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in <i>BRE</i> (β=56.3, p_interaction=3.9e^-9) and rs9830388 in <i>UBE2E2</i> (β=25.2, p_interaction=1.7e^-8). In Hispanic/Latino cohorts, rs2291477 in <i>TGFBR3</i> significantly modified the association between TCAs and QT intervals (β=9.3, p_interaction=2.55e^-8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (p_interaction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries. Among Europeans, TCA interactions with variants in <i>BRE</i> and <i>UBE2E2</i> were identified in relation to RR intervals. Among Hispanic/Latinos, variants in <i>TGFBR3</i> modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.