Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Honghuang Lin; Jessica van Setten; Albert V. Smith; Nathan A. Bihlmeyer; Helen R. Warren; Jennifer A. Brody; Farid Radmanesh; Leanne Hall; Niels Grarup; Martina Muller-Nurasyid; Thibaud Boutin; Niek Verweij; Henry J. Lin; Ruifang Li-Gao; Marten E. van den Berg; Jonathan Marten; Stefan Weiss; Bram P. Prins; Jeffrey Haessler; Leo-Pekka Lyytikainen; Hao Mei; Tamara B. Harris; Lenore J. Launer; Man Li; Alvaro Alonso; Elsayed Z. Soliman; John M. Connell; Paul L. Huang; Lu-Chen Weng; Heather S. Jameson; William Hucker; Alan Hanley; Nathan R. Tucker; Yii-Der Ida Chen; Joshua C. Bis; Kenneth M. Rice; Colleen M. Sitlani; Jan A. Kors; Zhijun Xie; Chengping Wen; Jared W. Magnani; Christopher P. Nelson; Jorgen K. Kanters; Moritz F. Sinner; Konstantin Strauch; Annette Peters; Melanie Waldenberger; Thomas Meitinger; Jette Bork-Jensen; Oluf Pedersen; Allan Linneberg; Igor Rudan; Rudolf A. de Boer; Peter van der Meer; Jie Yao; Xiuqing Guo; Kent D. Taylor; Nona Sotoodehnia; Jerome I. Rotter; Dennis O. Mook-Kanamori; Stella Trompet; Fernando Rivadeneira; Andre Uitterlinden; Mark Eijgelsheim; Sandosh Padmanabhan; Blair H. Smith; Henry Volzke; Massimo Mangino; Timothy D. Spector; Michiel L. Bots; Marco Perez; Mika Kahonen; Olli T. Raitakari; Vilmundur Gudnason; Dan E. Arking; Patricia B. Munroe; Bruce M. Psaty; Cornelia M. van Duijn; Emelia J. Benjamin; Jonathan Rosand; Nilesh J. Samani; Torben Hansen; Stefan Kaab; Ozren Polasek; Pim van der Harst; Susan R. Heckbert; J. Wouter Jukema; Bruno H. Stricker; Caroline Hayward; Marcus Dorr; Yalda Jamshidi; Folkert W. Asselbergs; Charles Kooperberg; Terho Lehtimaki; James G. Wilson; Patrick T. Ellinor; Steven A. Lubitz; Aaron Isaacs

doi:10.1161/CIRCGEN.117.002037

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Honghuang Lin^*, Jessica van Setten, Albert V. Smith, Nathan A. Bihlmeyer, Helen R. Warren, Jennifer A. Brody, Farid Radmanesh, Leanne Hall, Niels Grarup, Martina Muller-Nurasyid, Thibaud Boutin, Niek Verweij, Henry J. Lin, Ruifang Li-Gao, Marten E. van den Berg, Jonathan Marten, Stefan Weiss, Bram P. Prins, Jeffrey Haessler, Leo-Pekka LyytikainenHao Mei, Tamara B. Harris, Lenore J. Launer, Man Li, Alvaro Alonso, Elsayed Z. Soliman, John M. Connell, Paul L. Huang, Lu-Chen Weng, Heather S. Jameson, William Hucker, Alan Hanley, Nathan R. Tucker, Yii-Der Ida Chen, Joshua C. Bis, Kenneth M. Rice, Colleen M. Sitlani, Jan A. Kors, Zhijun Xie, Chengping Wen, Jared W. Magnani, Christopher P. Nelson, Jorgen K. Kanters, Moritz F. Sinner, Konstantin Strauch, Annette Peters, Melanie Waldenberger, Thomas Meitinger, Jette Bork-Jensen, Oluf Pedersen, Allan Linneberg, Igor Rudan, Rudolf A. de Boer, Peter van der Meer, Jie Yao, Xiuqing Guo, Kent D. Taylor, Nona Sotoodehnia, Jerome I. Rotter, Dennis O. Mook-Kanamori, Stella Trompet, Fernando Rivadeneira, Andre Uitterlinden, Mark Eijgelsheim, Sandosh Padmanabhan, Blair H. Smith, Henry Volzke, Massimo Mangino, Timothy D. Spector, Michiel L. Bots, Marco Perez, Mika Kahonen, Olli T. Raitakari, Vilmundur Gudnason, Dan E. Arking, Patricia B. Munroe, Bruce M. Psaty, Cornelia M. van Duijn, Emelia J. Benjamin, Jonathan Rosand, Nilesh J. Samani, Torben Hansen, Stefan Kaab, Ozren Polasek, Pim van der Harst, Susan R. Heckbert, J. Wouter Jukema, Bruno H. Stricker, Caroline Hayward, Marcus Dorr, Yalda Jamshidi, Folkert W. Asselbergs, Charles Kooperberg, Terho Lehtimaki, James G. Wilson, Patrick T. Ellinor, Steven A. Lubitz^*, Aaron Isaacs

^*Corresponding author for this work

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

Abstract

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2x10(-6)), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9x10(-11)) and SCN5A (P=1.1x10(-7)) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

Original language	English
Article number	e002037
Number of pages	11
Journal	Circulation: Genomic and Precision Medicine
Volume	11
Issue number	5
DOIs	https://doi.org/10.1161/CIRCGEN.117.002037
Publication status	Published - 1 May 2018

Keywords

atrioventricular node
genetic loci
genome-wide association study
LONG QT SYNDROME
GENOME-WIDE ASSOCIATION
SUDDEN CARDIAC DEATH
ATRIAL-FIBRILLATION
DILATED CARDIOMYOPATHY
QRS DURATION
SCN5A GENE
CONDUCTION
VARIANTS
SCN10A
SUSCEPTIBILITY
LOCI
HERITABILITY
MUTATIONS

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10.1161/CIRCGEN.117.002037

http://discovery.dundee.ac.uk/ws/files/20412059/Manuscript_exome_chip_PR.pdf

Cite this

Lin, H., van Setten, J., Smith, A. V., Bihlmeyer, N. A., Warren, H. R., Brody, J. A., Radmanesh, F., Hall, L., Grarup, N., Muller-Nurasyid, M., Boutin, T., Verweij, N., Lin, H. J., Li-Gao, R., van den Berg, M. E., Marten, J., Weiss, S., Prins, B. P., Haessler, J., ... Isaacs, A. (2018). Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. Circulation: Genomic and Precision Medicine, 11(5), Article e002037 . https://doi.org/10.1161/CIRCGEN.117.002037

@article{29bd5037fb924ad1a290ba89736d6754,

title = "Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval",

abstract = "BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2x10(-6)), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9x10(-11)) and SCN5A (P=1.1x10(-7)) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.",

keywords = "atrioventricular node, genetic loci, genome-wide association study, LONG QT SYNDROME, GENOME-WIDE ASSOCIATION, SUDDEN CARDIAC DEATH, ATRIAL-FIBRILLATION, DILATED CARDIOMYOPATHY, QRS DURATION, SCN5A GENE, CONDUCTION, VARIANTS, SCN10A, SUSCEPTIBILITY, LOCI, HERITABILITY, MUTATIONS",

author = "Honghuang Lin and {van Setten}, Jessica and Smith, {Albert V.} and Bihlmeyer, {Nathan A.} and Warren, {Helen R.} and Brody, {Jennifer A.} and Farid Radmanesh and Leanne Hall and Niels Grarup and Martina Muller-Nurasyid and Thibaud Boutin and Niek Verweij and Lin, {Henry J.} and Ruifang Li-Gao and {van den Berg}, {Marten E.} and Jonathan Marten and Stefan Weiss and Prins, {Bram P.} and Jeffrey Haessler and Leo-Pekka Lyytikainen and Hao Mei and Harris, {Tamara B.} and Launer, {Lenore J.} and Man Li and Alvaro Alonso and Soliman, {Elsayed Z.} and Connell, {John M.} and Huang, {Paul L.} and Lu-Chen Weng and Jameson, {Heather S.} and William Hucker and Alan Hanley and Tucker, {Nathan R.} and Chen, {Yii-Der Ida} and Bis, {Joshua C.} and Rice, {Kenneth M.} and Sitlani, {Colleen M.} and Kors, {Jan A.} and Zhijun Xie and Chengping Wen and Magnani, {Jared W.} and Nelson, {Christopher P.} and Kanters, {Jorgen K.} and Sinner, {Moritz F.} and Konstantin Strauch and Annette Peters and Melanie Waldenberger and Thomas Meitinger and Jette Bork-Jensen and Oluf Pedersen and Allan Linneberg and Igor Rudan and {de Boer}, {Rudolf A.} and {van der Meer}, Peter and Jie Yao and Xiuqing Guo and Taylor, {Kent D.} and Nona Sotoodehnia and Rotter, {Jerome I.} and Mook-Kanamori, {Dennis O.} and Stella Trompet and Fernando Rivadeneira and Andre Uitterlinden and Mark Eijgelsheim and Sandosh Padmanabhan and Smith, {Blair H.} and Henry Volzke and Massimo Mangino and Spector, {Timothy D.} and Bots, {Michiel L.} and Marco Perez and Mika Kahonen and Raitakari, {Olli T.} and Vilmundur Gudnason and Arking, {Dan E.} and Munroe, {Patricia B.} and Psaty, {Bruce M.} and {van Duijn}, {Cornelia M.} and Benjamin, {Emelia J.} and Jonathan Rosand and Samani, {Nilesh J.} and Torben Hansen and Stefan Kaab and Ozren Polasek and {van der Harst}, Pim and Heckbert, {Susan R.} and Jukema, {J. Wouter} and Stricker, {Bruno H.} and Caroline Hayward and Marcus Dorr and Yalda Jamshidi and Asselbergs, {Folkert W.} and Charles Kooperberg and Terho Lehtimaki and Wilson, {James G.} and Ellinor, {Patrick T.} and Lubitz, {Steven A.} and Aaron Isaacs",

year = "2018",

month = may,

day = "1",

doi = "10.1161/CIRCGEN.117.002037",

language = "English",

volume = "11",

journal = "Circulation: Genomic and Precision Medicine",

issn = "2574-8300",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "5",

}

Lin, H, van Setten, J, Smith, AV, Bihlmeyer, NA, Warren, HR, Brody, JA, Radmanesh, F, Hall, L, Grarup, N, Muller-Nurasyid, M, Boutin, T, Verweij, N, Lin, HJ, Li-Gao, R, van den Berg, ME, Marten, J, Weiss, S, Prins, BP, Haessler, J, Lyytikainen, L-P, Mei, H, Harris, TB, Launer, LJ, Li, M, Alonso, A, Soliman, EZ, Connell, JM, Huang, PL, Weng, L-C, Jameson, HS, Hucker, W, Hanley, A, Tucker, NR, Chen, Y-DI, Bis, JC, Rice, KM, Sitlani, CM, Kors, JA, Xie, Z, Wen, C, Magnani, JW, Nelson, CP, Kanters, JK, Sinner, MF, Strauch, K, Peters, A, Waldenberger, M, Meitinger, T, Bork-Jensen, J, Pedersen, O, Linneberg, A, Rudan, I, de Boer, RA, van der Meer, P, Yao, J, Guo, X, Taylor, KD, Sotoodehnia, N, Rotter, JI, Mook-Kanamori, DO, Trompet, S, Rivadeneira, F, Uitterlinden, A, Eijgelsheim, M, Padmanabhan, S, Smith, BH, Volzke, H, Mangino, M, Spector, TD, Bots, ML, Perez, M, Kahonen, M, Raitakari, OT, Gudnason, V, Arking, DE, Munroe, PB, Psaty, BM, van Duijn, CM, Benjamin, EJ, Rosand, J, Samani, NJ, Hansen, T, Kaab, S, Polasek, O, van der Harst, P, Heckbert, SR, Jukema, JW, Stricker, BH, Hayward, C, Dorr, M, Jamshidi, Y, Asselbergs, FW, Kooperberg, C, Lehtimaki, T, Wilson, JG, Ellinor, PT, Lubitz, SA & Isaacs, A 2018, 'Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval', Circulation: Genomic and Precision Medicine, vol. 11, no. 5, e002037 . https://doi.org/10.1161/CIRCGEN.117.002037

TY - JOUR

T1 - Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

AU - Lin, Honghuang

AU - van Setten, Jessica

AU - Smith, Albert V.

AU - Bihlmeyer, Nathan A.

AU - Warren, Helen R.

AU - Brody, Jennifer A.

AU - Radmanesh, Farid

AU - Hall, Leanne

AU - Grarup, Niels

AU - Muller-Nurasyid, Martina

AU - Boutin, Thibaud

AU - Verweij, Niek

AU - Lin, Henry J.

AU - Li-Gao, Ruifang

AU - van den Berg, Marten E.

AU - Marten, Jonathan

AU - Weiss, Stefan

AU - Prins, Bram P.

AU - Haessler, Jeffrey

AU - Lyytikainen, Leo-Pekka

AU - Mei, Hao

AU - Harris, Tamara B.

AU - Launer, Lenore J.

AU - Li, Man

AU - Alonso, Alvaro

AU - Soliman, Elsayed Z.

AU - Connell, John M.

AU - Huang, Paul L.

AU - Weng, Lu-Chen

AU - Jameson, Heather S.

AU - Hucker, William

AU - Hanley, Alan

AU - Tucker, Nathan R.

AU - Chen, Yii-Der Ida

AU - Bis, Joshua C.

AU - Rice, Kenneth M.

AU - Sitlani, Colleen M.

AU - Kors, Jan A.

AU - Xie, Zhijun

AU - Wen, Chengping

AU - Magnani, Jared W.

AU - Nelson, Christopher P.

AU - Kanters, Jorgen K.

AU - Sinner, Moritz F.

AU - Strauch, Konstantin

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Meitinger, Thomas

AU - Bork-Jensen, Jette

AU - Pedersen, Oluf

AU - Linneberg, Allan

AU - Rudan, Igor

AU - de Boer, Rudolf A.

AU - van der Meer, Peter

AU - Yao, Jie

AU - Guo, Xiuqing

AU - Taylor, Kent D.

AU - Sotoodehnia, Nona

AU - Rotter, Jerome I.

AU - Mook-Kanamori, Dennis O.

AU - Trompet, Stella

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre

AU - Eijgelsheim, Mark

AU - Padmanabhan, Sandosh

AU - Smith, Blair H.

AU - Volzke, Henry

AU - Mangino, Massimo

AU - Spector, Timothy D.

AU - Bots, Michiel L.

AU - Perez, Marco

AU - Kahonen, Mika

AU - Raitakari, Olli T.

AU - Gudnason, Vilmundur

AU - Arking, Dan E.

AU - Munroe, Patricia B.

AU - Psaty, Bruce M.

AU - van Duijn, Cornelia M.

AU - Benjamin, Emelia J.

AU - Rosand, Jonathan

AU - Samani, Nilesh J.

AU - Hansen, Torben

AU - Kaab, Stefan

AU - Polasek, Ozren

AU - van der Harst, Pim

AU - Heckbert, Susan R.

AU - Jukema, J. Wouter

AU - Stricker, Bruno H.

AU - Hayward, Caroline

AU - Dorr, Marcus

AU - Jamshidi, Yalda

AU - Asselbergs, Folkert W.

AU - Kooperberg, Charles

AU - Lehtimaki, Terho

AU - Wilson, James G.

AU - Ellinor, Patrick T.

AU - Lubitz, Steven A.

AU - Isaacs, Aaron

PY - 2018/5/1

Y1 - 2018/5/1

N2 - BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2x10(-6)), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9x10(-11)) and SCN5A (P=1.1x10(-7)) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

AB - BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2x10(-6)), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9x10(-11)) and SCN5A (P=1.1x10(-7)) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

KW - atrioventricular node

KW - genetic loci

KW - genome-wide association study

KW - LONG QT SYNDROME

KW - GENOME-WIDE ASSOCIATION

KW - SUDDEN CARDIAC DEATH

KW - ATRIAL-FIBRILLATION

KW - DILATED CARDIOMYOPATHY

KW - QRS DURATION

KW - SCN5A GENE

KW - CONDUCTION

KW - VARIANTS

KW - SCN10A

KW - SUSCEPTIBILITY

KW - LOCI

KW - HERITABILITY

KW - MUTATIONS

U2 - 10.1161/CIRCGEN.117.002037

DO - 10.1161/CIRCGEN.117.002037

M3 - Article

C2 - 29748316

SN - 2574-8300

VL - 11

JO - Circulation: Genomic and Precision Medicine

JF - Circulation: Genomic and Precision Medicine

IS - 5

M1 - e002037

ER -