Sequencing of scn5a identifies rare and common variants associated with cardiac conduction: Cohorts for heart and aging research in genomic epidemiology (charge) consortium

Jared W. Magnani; Jennifer A. Brody; Bram P. Prins; Dan E. Arking; Honghuang Lin; Xiaoyan Yin; Ching Ti Liu; Alanna C. Morrison; Feng Zhang; Tim D. Spector; Alvaro Alonso; Joshua C. Bis; Susan R. Heckbert; Thomas Lumley; Colleen M. Sitlani; L. Adrienne Cupples; Steven A. Lubitz; Elsayed Z. Soliman; Sara L. Pulit; Christopher Newton-Cheh; Christopher J. O'Donnell; Patrick T. Ellinor; Emelia J. Benjamin; Donna M. Muzny; Richard A. Gibbs; Jireh Santibanez; Herman A. Taylor; Jerome I. Rotter; Leslie A. Lange; Bruce M. Psaty; Rebecca Jackson; Stephen S. Rich; Eric Boerwinkle; Yalda Jamshidi; Nona Sotoodehnia

doi:10.1161/CIRCGENETICS.113.000098

Sequencing of scn5a identifies rare and common variants associated with cardiac conduction: Cohorts for heart and aging research in genomic epidemiology (charge) consortium

Jared W. Magnani, Jennifer A. Brody, Bram P. Prins, Dan E. Arking, Honghuang Lin, Xiaoyan Yin, Ching Ti Liu, Alanna C. Morrison, Feng Zhang, Tim D. Spector, Alvaro Alonso, Joshua C. Bis, Susan R. Heckbert, Thomas Lumley, Colleen M. Sitlani, L. Adrienne Cupples, Steven A. Lubitz, Elsayed Z. Soliman, Sara L. Pulit, Christopher Newton-ChehChristopher J. O'Donnell, Patrick T. Ellinor, Emelia J. Benjamin, Donna M. Muzny, Richard A. Gibbs, Jireh Santibanez, Herman A. Taylor, Jerome I. Rotter, Leslie A. Lange, Bruce M. Psaty, Rebecca Jackson, Stephen S. Rich, Eric Boerwinkle, Yalda Jamshidi, Nona Sotoodehnia

Epidemiology

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11 Scopus citations

Abstract

Background-The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction. Methods and Results-In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-Analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10^-3). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10 ^-4 and P=5.2×10-3, respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10 ^-3). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10^-7 and P=2.69×10^-4, respectively) and rs6599230 was associated with PR shortening (P=2.67×1010 ^-5). Conclusions-By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

Original language	English (US)
Pages (from-to)	365-373
Number of pages	9
Journal	Circulation: Cardiovascular Genetics
Volume	7
Issue number	3
DOIs	https://doi.org/10.1161/CIRCGENETICS.113.000098
State	Published - Jun 2014

Keywords

Electrocardiography
Genomics

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Magnani, J. W., Brody, J. A., Prins, B. P., Arking, D. E., Lin, H., Yin, X., Liu, C. T., Morrison, A. C., Zhang, F., Spector, T. D., Alonso, A., Bis, J. C., Heckbert, S. R., Lumley, T., Sitlani, C. M., Cupples, L. A., Lubitz, S. A., Soliman, E. Z., Pulit, S. L., ... Sotoodehnia, N. (2014). Sequencing of scn5a identifies rare and common variants associated with cardiac conduction: Cohorts for heart and aging research in genomic epidemiology (charge) consortium. Circulation: Cardiovascular Genetics, 7(3), 365-373. https://doi.org/10.1161/CIRCGENETICS.113.000098

Sequencing of scn5a identifies rare and common variants associated with cardiac conduction: Cohorts for heart and aging research in genomic epidemiology (charge) consortium. / Magnani, Jared W.; Brody, Jennifer A.; Prins, Bram P. et al.
In: Circulation: Cardiovascular Genetics, Vol. 7, No. 3, 06.2014, p. 365-373.

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

Magnani, JW, Brody, JA, Prins, BP, Arking, DE, Lin, H, Yin, X, Liu, CT, Morrison, AC, Zhang, F, Spector, TD, Alonso, A, Bis, JC, Heckbert, SR, Lumley, T, Sitlani, CM, Cupples, LA, Lubitz, SA, Soliman, EZ, Pulit, SL, Newton-Cheh, C, O'Donnell, CJ, Ellinor, PT, Benjamin, EJ, Muzny, DM, Gibbs, RA, Santibanez, J, Taylor, HA, Rotter, JI, Lange, LA, Psaty, BM, Jackson, R, Rich, SS, Boerwinkle, E, Jamshidi, Y & Sotoodehnia, N 2014, 'Sequencing of scn5a identifies rare and common variants associated with cardiac conduction: Cohorts for heart and aging research in genomic epidemiology (charge) consortium', Circulation: Cardiovascular Genetics, vol. 7, no. 3, pp. 365-373. https://doi.org/10.1161/CIRCGENETICS.113.000098

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title = "Sequencing of scn5a identifies rare and common variants associated with cardiac conduction: Cohorts for heart and aging research in genomic epidemiology (charge) consortium",

abstract = "Background-The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction. Methods and Results-In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-Analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10-3). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10 -4 and P=5.2×10-3, respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10 -3). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10-7 and P=2.69×10-4, respectively) and rs6599230 was associated with PR shortening (P=2.67×1010 -5). Conclusions-By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.",

keywords = "Electrocardiography, Genomics",

author = "Magnani, {Jared W.} and Brody, {Jennifer A.} and Prins, {Bram P.} and Arking, {Dan E.} and Honghuang Lin and Xiaoyan Yin and Liu, {Ching Ti} and Morrison, {Alanna C.} and Feng Zhang and Spector, {Tim D.} and Alvaro Alonso and Bis, {Joshua C.} and Heckbert, {Susan R.} and Thomas Lumley and Sitlani, {Colleen M.} and Cupples, {L. Adrienne} and Lubitz, {Steven A.} and Soliman, {Elsayed Z.} and Pulit, {Sara L.} and Christopher Newton-Cheh and O'Donnell, {Christopher J.} and Ellinor, {Patrick T.} and Benjamin, {Emelia J.} and Muzny, {Donna M.} and Gibbs, {Richard A.} and Jireh Santibanez and Taylor, {Herman A.} and Rotter, {Jerome I.} and Lange, {Leslie A.} and Psaty, {Bruce M.} and Rebecca Jackson and Rich, {Stephen S.} and Eric Boerwinkle and Yalda Jamshidi and Nona Sotoodehnia",

year = "2014",

month = jun,

doi = "10.1161/CIRCGENETICS.113.000098",

language = "English (US)",

volume = "7",

pages = "365--373",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "3",

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TY - JOUR

T1 - Sequencing of scn5a identifies rare and common variants associated with cardiac conduction

T2 - Cohorts for heart and aging research in genomic epidemiology (charge) consortium

AU - Magnani, Jared W.

AU - Brody, Jennifer A.

AU - Prins, Bram P.

AU - Arking, Dan E.

AU - Lin, Honghuang

AU - Yin, Xiaoyan

AU - Liu, Ching Ti

AU - Morrison, Alanna C.

AU - Zhang, Feng

AU - Spector, Tim D.

AU - Alonso, Alvaro

AU - Bis, Joshua C.

AU - Heckbert, Susan R.

AU - Lumley, Thomas

AU - Sitlani, Colleen M.

AU - Cupples, L. Adrienne

AU - Lubitz, Steven A.

AU - Soliman, Elsayed Z.

AU - Pulit, Sara L.

AU - Newton-Cheh, Christopher

AU - O'Donnell, Christopher J.

AU - Ellinor, Patrick T.

AU - Benjamin, Emelia J.

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

AU - Santibanez, Jireh

AU - Taylor, Herman A.

AU - Rotter, Jerome I.

AU - Lange, Leslie A.

AU - Psaty, Bruce M.

AU - Jackson, Rebecca

AU - Rich, Stephen S.

AU - Boerwinkle, Eric

AU - Jamshidi, Yalda

AU - Sotoodehnia, Nona

PY - 2014/6

Y1 - 2014/6

N2 - Background-The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction. Methods and Results-In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-Analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10-3). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10 -4 and P=5.2×10-3, respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10 -3). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10-7 and P=2.69×10-4, respectively) and rs6599230 was associated with PR shortening (P=2.67×1010 -5). Conclusions-By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

AB - Background-The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction. Methods and Results-In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-Analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10-3). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10 -4 and P=5.2×10-3, respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10 -3). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10-7 and P=2.69×10-4, respectively) and rs6599230 was associated with PR shortening (P=2.67×1010 -5). Conclusions-By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

KW - Electrocardiography

KW - Genomics

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ER -

Sequencing of scn5a identifies rare and common variants associated with cardiac conduction: Cohorts for heart and aging research in genomic epidemiology (charge) consortium

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