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 Cupples; Qing 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

doi:10.1136/jmedgenet-2016-104112

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 journal › Article › peer-review

9 Scopus citations

Abstract

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, p_interaction=3.9e^-9) and rs9830388 in UBE2E2 (β=25.2, p_interaction=1.7e^-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 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. 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 language	English (US)
Pages (from-to)	313-323
Number of pages	11
Journal	Journal of medical genetics
Volume	54
Issue number	5
DOIs	https://doi.org/10.1136/jmedgenet-2016-104112
State	Published - May 1 2017
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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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

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. / Noordam, Raymond; Sitlani, Colleen M.; Avery, Christy L. et al.
In: Journal of medical genetics, Vol. 54, No. 5, 01.05.2017, p. 313-323.

Research output: Contribution to journal › Article › peer-review

Noordam, R, Sitlani, CM, Avery, CL, Stewart, JD, Gogarten, SM, Wiggins, KL, Trompet, S, Warren, HR, Sun, F, Evans, DS, Li, X, Li, J, Smith, AV, Bis, JC, Brody, JA, Busch, EL, Caulfield, MJ, Chen, YDI, Cummings, SR, Cupples, LA, Duan, Q, Franco, OH, Méndez-Giráldez, R, Harris, TB, Heckbert, SR, van Heemst, D, Hofman, A, Floyd, JS, Kors, JA, Launer, LJ, Li, Y, Li-Gao, R, Lange, LA, Lin, HJ, de Mutsert, R, Napier, MD, Newton-Cheh, C, Poulter, N, Reiner, AP, Rice, KM, Roach, J, Rodriguez, CJ, Rosendaal, FR, Sattar, N, Sever, P, Seyerle, AA, Slagboom, PE, Soliman, EZ, Sotoodehnia, N, Stott, DJ, Stürmer, T, Taylor, KD, Thornton, TA, Uitterlinden, AG, Wilhelmsen, KC, Wilson, JG, Gudnason, V, Jukema, JW, Laurie, CC, Liu, Y, Mook-Kanamori, DO, Munroe, PB, Rotter, JI, Vasan, RS, Psaty, BM, Stricker, BH & Whitsel, EA 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, vol. 54, no. 5, pp. 313-323. https://doi.org/10.1136/jmedgenet-2016-104112

Noordam R, Sitlani CM, Avery CL, Stewart JD, Gogarten SM, Wiggins KL et al. 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. 2017 May 1;54(5):313-323. doi: 10.1136/jmedgenet-2016-104112

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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 = "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.",

keywords = "Genome-wide, QT interval electrocardiography, RR interval, drug-gene interaction, tri/tetracyclic antidepressants",

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

year = "2017",

month = may,

day = "1",

doi = "10.1136/jmedgenet-2016-104112",

language = "English (US)",

volume = "54",

pages = "313--323",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "5",

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TY - JOUR

T1 - A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals

T2 - A pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium

AU - Noordam, Raymond

AU - Sitlani, Colleen M.

AU - Avery, Christy L.

AU - Stewart, James D.

AU - Gogarten, Stephanie M.

AU - Wiggins, Kerri L.

AU - Trompet, Stella

AU - Warren, Helen R.

AU - Sun, Fangui

AU - Evans, Daniel S.

AU - Li, Xiaohui

AU - Li, Jin

AU - Smith, Albert V.

AU - Bis, Joshua C.

AU - Brody, Jennifer A.

AU - Busch, Evan L.

AU - Caulfield, Mark J.

AU - Chen, Yii Der I.

AU - Cummings, Steven R.

AU - Cupples, L. Adrienne

AU - Duan, Qing

AU - Franco, Oscar H.

AU - Méndez-Giráldez, Rául

AU - Harris, Tamara B.

AU - Heckbert, Susan R.

AU - van Heemst, Diana

AU - Hofman, Albert

AU - Floyd, James S.

AU - Kors, Jan A.

AU - Launer, Lenore J.

AU - Li, Yun

AU - Li-Gao, Ruifang

AU - Lange, Leslie A.

AU - Lin, Henry J.

AU - de Mutsert, Renée

AU - Napier, Melanie D.

AU - Newton-Cheh, Christopher

AU - Poulter, Neil

AU - Reiner, Alexander P.

AU - Rice, Kenneth M.

AU - Roach, Jeffrey

AU - Rodriguez, Carlos J.

AU - Rosendaal, Frits R.

AU - Sattar, Naveed

AU - Sever, Peter

AU - Seyerle, Amanda A.

AU - Slagboom, P. Eline

AU - Soliman, Elsayed Z.

AU - Sotoodehnia, Nona

AU - Stott, David J.

AU - Stürmer, Til

AU - Taylor, Kent D.

AU - Thornton, Timothy A.

AU - Uitterlinden, André G.

AU - Wilhelmsen, Kirk C.

AU - Wilson, James G.

AU - Gudnason, Vilmundur

AU - Jukema, J. W.

AU - Laurie, Cathy C.

AU - Liu, Yongmei

AU - Mook-Kanamori, Dennis O.

AU - Munroe, Patricia B.

AU - Rotter, Jerome I.

AU - Vasan, Ramachandran S.

AU - Psaty, Bruce M.

AU - Stricker, Bruno H.

AU - Whitsel, Eric A.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

KW - Genome-wide

KW - QT interval electrocardiography

KW - RR interval

KW - drug-gene interaction

KW - tri/tetracyclic antidepressants

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SN - 0022-2593

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JO - Journal of medical genetics

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ER -

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

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Keywords

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