title: 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 inBRE(β=56.3, pinteraction=3.9e-9) and rs9830388 inUBE2E2(β=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 inTGFBR3significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=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 (pinteraction>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 inBREandUBE2E2were identified in relation to RR intervals. Among Hispanic/Latinos, variants inTGFBR3modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.
authors.affiliation: Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.|Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
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authors.identifier: 0000-0003-2749-1279
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authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.|Department of BESC, Epidemiology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
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authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Department of Health Services, University of Washington, Seattle, Washington, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
authors.forename: Bruce M
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mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D004562:Electrocardiography; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics
chemical_list: D000929:Antidepressive Agents, Tricyclic
keywords: Genome-wide; QT interval electrocardiography; RR interval; drug-gene interaction; tri/tetracyclic antidepressants