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Drug-Gene Interactions and the Search for Missing Heritability: A Cross-Sectional Pharmacogenomics Study of the QT Interval


Avery, Christy L.; Sitlani, Colleen M.; Arking, Dan E.; Arnett, Donna K.; Bis, Joshua C.; Boerwinkle, Eric A.; Buckley, Brendan M.; Chen, Yii-Der Ida; de Craen, Antonius J. M.; & Eijgelsheim, Mark, et al. (2014). Drug-Gene Interactions and the Search for Missing Heritability: A Cross-Sectional Pharmacogenomics Study of the QT Interval. Pharmacogenomics Journal, 14(1), 6-13. PMCID: PMC3766418


Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 x 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.


Reference Type

Journal Article

Year Published


Journal Title

Pharmacogenomics Journal


Avery, Christy L.
Sitlani, Colleen M.
Arking, Dan E.
Arnett, Donna K.
Bis, Joshua C.
Boerwinkle, Eric A.
Buckley, Brendan M.
Chen, Yii-Der Ida
de Craen, Antonius J. M.
Eijgelsheim, Mark
Enquobahrie, Daniel A.
Evans, Daniel S.
Ford, Ian
Garcia, Melissa E.
Gudnason, Vilmundur G.
Harris, Tamara B.
Heckbert, Susan R.
Hochner, Hagit H.
Hofman, Albert
Hsueh, Wen-Chi
Isaacs, Aaron J.
Jukema, J. Wouter
Knekt, Paul
Kors, Jan A.
Krijthe, Bouwe P.
Kristiansson, Kati
Laaksonen, Maarit A.
Liu, Yongmei
Li, Xin
Macfarlane, Peter W.
Newton-Cheh, Christopher H.
Nieminen, Markku S.
Oostra, Ben A.
Peloso, Gina M.
Porthan, Kimmo
Rice, Kenneth M.
Rivadeneira, Fernando
Rotter, Jerome I.
Salomaa, Veikko
Sattar, Naveed
Siscovick, David S.
Slagboom, P. Eline
Smith, Albert V.
Sotoodehnia, Nona
Stott, David J.
Stricker, Bruno H.
Stürmer, Til
Trompet, Stella
Uitterlinden, Andre G.
van Duijn, Cornelia M.
Westendorp, Rudi G. J.
Witteman, Jacqueline C. M.
Whitsel, Eric A.
Psaty, Bruce M.