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 Müller-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 Lyytikäinen; 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; Jørgen K Kanters; Moritz F Sinner; Konstantin Strauch; Annette Peters; Melanie Waldenberger; Jette Bork-Jensen; Allan Linneberg; Torben Hansen

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 Müller-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 LyytikäinenHao 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, Jørgen K Kanters, Moritz F Sinner, Konstantin Strauch, Annette Peters, Melanie Waldenberger, Jette Bork-Jensen, Allan Linneberg, Torben Hansen

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<1.2×10-6), 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=5.9×10-11) and SCN5A (P=1.1×10-7) 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
Journal	Circulation. Genomic and precision medicine
Volume	11
Issue number	5
Pages (from-to)	e002037
ISSN	2574-8300
DOIs	https://doi.org/10.1161/CIRCGEN.117.002037
Publication status	Published - May 2018

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Lin, H., van Setten, J., Smith, A. V., Bihlmeyer, N. A., Warren, H. R., Brody, J. A., Radmanesh, F., Hall, L., Grarup, N., Müller-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., ... Hansen, T. (2018). Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. Circulation. Genomic and precision medicine, 11(5), e002037. https://doi.org/10.1161/CIRCGEN.117.002037

Lin, H, van Setten, J, Smith, AV, Bihlmeyer, NA, Warren, HR, Brody, JA, Radmanesh, F, Hall, L, Grarup, N, Müller-Nurasyid, M, Boutin, T, Verweij, N, Lin, HJ, Li-Gao, R, van den Berg, ME, Marten, J, Weiss, S, Prins, BP, Haessler, J, Lyytikäinen, 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, Bork-Jensen, J, Linneberg, A & Hansen, T 2018, 'Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval', Circulation. Genomic and precision medicine, vol. 11, no. 5, pp. e002037. https://doi.org/10.1161/CIRCGEN.117.002037

@article{22958a7874e741efae070f1de8fe851a,

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<1.2×10-6), 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=5.9×10-11) and SCN5A (P=1.1×10-7) 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.",

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 M{\"u}ller-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 Lyytik{\"a}inen 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, {J{\o}rgen K} and Sinner, {Moritz F} and Konstantin Strauch and Annette Peters and Melanie Waldenberger and Jette Bork-Jensen and Allan Linneberg and Torben Hansen",

note = "{\textcopyright} 2018 American Heart Association, Inc.",

year = "2018",

month = may,

doi = "10.1161/CIRCGEN.117.002037",

language = "English",

volume = "11",

pages = "e002037",

journal = "Circulation. Genomic and precision medicine",

issn = "2574-8300",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "5",

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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 - Müller-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 - Lyytikäinen, 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, Jørgen K

AU - Sinner, Moritz F

AU - Strauch, Konstantin

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Bork-Jensen, Jette

AU - Linneberg, Allan

AU - Hansen, Torben

PY - 2018/5

Y1 - 2018/5

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<1.2×10-6), 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=5.9×10-11) and SCN5A (P=1.1×10-7) 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<1.2×10-6), 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=5.9×10-11) and SCN5A (P=1.1×10-7) 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.

U2 - 10.1161/CIRCGEN.117.002037

DO - 10.1161/CIRCGEN.117.002037

M3 - Journal article

C2 - 29748316

SN - 2574-8300

VL - 11

SP - e002037

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

IS - 5

ER -

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

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