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 |
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Article number | e002037 |
Journal | Circulation. Genomic and precision medicine |
Volume | 11 |
Issue number | 5 |
Pages (from-to) | 1-11 |
ISSN | 2574-8300 |
DOIs | |
Publication status | Published - 2018 |
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Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. / Lin, Honghuang; van Setten, Jessica; Smith, Albert V; Bihlmeyer, Nathan A; Warren, Helen R; Brody, Jennifer A; Radmanesh, Farid; Hall, Leanne; Grarup, Niels; Müller-Nurasyid, Martina; Boutin, Thibaud; Verweij, Niek; Lin, Henry J; Li-Gao, Ruifang; van den Berg, Marten E; Marten, Jonathan; Weiss, Stefan; Prins, Bram P; Haessler, Jeffrey; Lyytikäinen, Leo-Pekka; Mei, Hao; Harris, Tamara B; Launer, Lenore J; Li, Man; Alonso, Alvaro; Soliman, Elsayed Z; Connell, John M; Huang, Paul L; Weng, Lu-Chen; Jameson, Heather S; Hucker, William; Hanley, Alan; Tucker, Nathan R; Chen, Yii-Der Ida; Bis, Joshua C; Rice, Kenneth M; Sitlani, Colleen M; Kors, Jan A; Xie, Zhijun; Wen, Chengping; Magnani, Jared W; Nelson, Christopher P; Kanters, Jørgen K.; Sinner, Moritz F; Strauch, Konstantin; Peters, Annette; Waldenberger, Melanie; Meitinger, Thomas; Bork-Jensen, Jette; Pedersen, Oluf; Linneberg, Allan; Rudan, Igor; de Boer, Rudolf A; van der Meer, Peter; Yao, Jie; Guo, Xiuqing; Taylor, Kent D; Sotoodehnia, Nona; Rotter, Jerome I; Mook-Kanamori, Dennis O; Trompet, Stella; Rivadeneira, Fernando; Uitterlinden, André; Eijgelsheim, Mark; Padmanabhan, Sandosh; Smith, Blair H; Völzke, Henry; Felix, Stephan B; Homuth, Georg; Völker, Uwe; Mangino, Massimo; Spector, Timothy D; Bots, Michiel L; Perez, Marco; Kähönen, Mika; Raitakari, Olli T; Gudnason, Vilmundur; Arking, Dan E; Munroe, Patricia B; Psaty, Bruce M; van Duijn, Cornelia M; Benjamin, Emelia J; Rosand, Jonathan; Samani, Nilesh J; Hansen, Torben; Kääb, Stefan; Polasek, Ozren; van der Harst, Pim; Heckbert, Susan R; Jukema, J Wouter; Stricker, Bruno H; Hayward, Caroline; Dörr, Marcus; Jamshidi, Yalda; Asselbergs, Folkert W; Kooperberg, Charles; Lehtimäki, Terho; Wilson, James G; Ellinor, Patrick T; Lubitz, Steven A; Isaacs, Aaron.
In: Circulation. Genomic and precision medicine, Vol. 11, No. 5, e002037, 2018, p. 1-11.Research output: Contribution to journal › Journal article › Research › peer-review
}
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 - 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, André
AU - Eijgelsheim, Mark
AU - Padmanabhan, Sandosh
AU - Smith, Blair H
AU - Völzke, Henry
AU - Felix, Stephan B
AU - Homuth, Georg
AU - Völker, Uwe
AU - Mangino, Massimo
AU - Spector, Timothy D
AU - Bots, Michiel L
AU - Perez, Marco
AU - Kähönen, 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 - Kääb, 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 - Dörr, Marcus
AU - Jamshidi, Yalda
AU - Asselbergs, Folkert W
AU - Kooperberg, Charles
AU - Lehtimäki, Terho
AU - Wilson, James G
AU - Ellinor, Patrick T
AU - Lubitz, Steven A
AU - Isaacs, Aaron
N1 - © 2018 American Heart Association, Inc.
PY - 2018
Y1 - 2018
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
VL - 11
SP - 1
EP - 11
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
SN - 2574-8300
IS - 5
M1 - e002037
ER -