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

Raymond Noordam, Colleen M. Sitlani, Christy L. Avery, James D. Stewart, Stephanie M. Gogarten, Kerri L. Wiggins, Stella Trompet, Helen R. Warren, Fangui Sun, Daniel S. Evans, Xiaohui Li, Jin Li, Albert V. Smith, Joshua C. Bis, Jennifer A. Brody, Evan L. Busch, Mark J. Caulfield, Yii Der I. Chen, Steven R. Cummings, L. Adrienne CupplesQing Duan, Oscar H. Franco, Rául Méndez-Giráldez, Tamara B. Harris, Susan R. Heckbert, Diana van Heemst, Albert Hofman, James S. Floyd, Jan A. Kors, Lenore J. Launer, Yun Li, Ruifang Li-Gao, Leslie A. Lange, Henry J. Lin, Renée de Mutsert, Melanie D. Napier, Christopher Newton-Cheh, Neil Poulter, Alexander P. Reiner, Kenneth M. Rice, Jeffrey Roach, Carlos J. Rodriguez, Frits R. Rosendaal, Naveed Sattar, Peter Sever, Amanda A. Seyerle, P. Eline Slagboom, Elsayed Z. Soliman, Nona Sotoodehnia, David J. Stott, Til Stürmer, Kent D. Taylor, Timothy A. Thornton, André G. Uitterlinden, Kirk C. Wilhelmsen, James G. Wilson, Vilmundur Gudnason, J. W. Jukema, Cathy C. Laurie, Yongmei Liu, Dennis O. Mook-Kanamori, Patricia B. Munroe, Jerome I. Rotter, Ramachandran S. Vasan, Bruce M. Psaty, Bruno H. Stricker, Eric A. Whitsel

Research output: Contribution to journalArticle

4 Scopus citations


Background: 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. Methods and results: 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 BRE (β=56.3, pinteraction=3.9e-9) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly 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. Conclusions: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

Original languageEnglish (US)
Pages (from-to)313-323
Number of pages11
JournalJournal of medical genetics
Issue number5
StatePublished - May 1 2017



  • Genome-wide
  • QT interval electrocardiography
  • RR interval
  • drug-gene interaction
  • tri/tetracyclic antidepressants

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Noordam, R., Sitlani, C. M., Avery, C. L., Stewart, J. D., Gogarten, S. M., Wiggins, K. L., Trompet, S., Warren, H. R., Sun, F., Evans, D. S., Li, X., Li, J., Smith, A. V., Bis, J. C., Brody, J. A., Busch, E. L., Caulfield, M. J., Chen, Y. D. I., Cummings, S. R., ... Whitsel, E. A. (2017). 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. Journal of medical genetics, 54(5), 313-323. https://doi.org/10.1136/jmedgenet-2016-104112