Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis

Seung Hoan Choi; Sean J. Jurgens; Christopher M. Haggerty; Amelia W. Hall; Jennifer L. Halford; Valerie N. Morrill; Lu Chen Weng; Braxton Lagerman; Tooraj Mirshahi; Mary Pettinger; Xiuqing Guo; Henry J. Lin; Alvaro Alonso; Elsayed Z. Soliman; Jelena Kornej; Honghuang Lin; Arden Moscati; Girish N. Nadkarni; Jennifer A. Brody; Kerri L. Wiggins; Brian E. Cade; Jiwon Lee; Christina Austin-Tse; Tom Blackwell; Mark D. Chaffin; Christina J.Y. Lee; Heidi L. Rehm; Carolina Roselli; Susan Redline; Braxton D. Mitchell; Nona Sotoodehnia; Bruce M. Psaty; Susan R. Heckbert; Ruth J.F. Loos; Ramachandran S. Vasan; Emelia J. Benjamin; Adolfo Correa; Eric Boerwinkle; Dan E. Arking; Jerome I. Rotter; Stephen S. Rich; Eric A. Whitsel; Marco Perez; Charles Kooperberg; Brandon K. Fornwalt; Kathryn L. Lunetta; Patrick T. Ellinor; Steven A. Lubitz

doi:10.1161/CIRCGEN.120.003300

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis

Seung Hoan Choi, Sean J. Jurgens, Christopher M. Haggerty, Amelia W. Hall, Jennifer L. Halford, Valerie N. Morrill, Lu Chen Weng, Braxton Lagerman, Tooraj Mirshahi, Mary Pettinger, Xiuqing Guo, Henry J. Lin, Alvaro Alonso, Elsayed Z. Soliman, Jelena Kornej, Honghuang Lin, Arden Moscati, Girish N. Nadkarni, Jennifer A. Brody, Kerri L. WigginsBrian E. Cade, Jiwon Lee, Christina Austin-Tse, Tom Blackwell, Mark D. Chaffin, Christina J.Y. Lee, Heidi L. Rehm, Carolina Roselli, Susan Redline, Braxton D. Mitchell, Nona Sotoodehnia, Bruce M. Psaty, Susan R. Heckbert, Ruth J.F. Loos, Ramachandran S. Vasan, Emelia J. Benjamin, Adolfo Correa, Eric Boerwinkle, Dan E. Arking, Jerome I. Rotter, Stephen S. Rich, Eric A. Whitsel, Marco Perez, Charles Kooperberg, Brandon K. Fornwalt, Kathryn L. Lunetta, Patrick T. Ellinor, Steven A. Lubitz

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

6 Scopus citations

Abstract

Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10^-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10^-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

Original language	English (US)
Pages (from-to)	E003300
Journal	Circulation: Cardiovascular Genetics
Volume	14
Issue number	4
DOIs	https://doi.org/10.1161/CIRCGEN.120.003300
State	Published - Aug 1 2021
Externally published	Yes

Keywords

death, sudden, cardiac
epidemiology
genetics
genome
population

ASJC Scopus subject areas

Genetics
Cardiology and Cardiovascular Medicine
Genetics(clinical)

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10.1161/CIRCGEN.120.003300

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Choi, S. H., Jurgens, S. J., Haggerty, C. M., Hall, A. W., Halford, J. L., Morrill, V. N., Weng, L. C., Lagerman, B., Mirshahi, T., Pettinger, M., Guo, X., Lin, H. J., Alonso, A., Soliman, E. Z., Kornej, J., Lin, H., Moscati, A., Nadkarni, G. N., Brody, J. A., ... Lubitz, S. A. (2021). Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis. Circulation: Cardiovascular Genetics, 14(4), E003300. https://doi.org/10.1161/CIRCGEN.120.003300

Choi, SH, Jurgens, SJ, Haggerty, CM, Hall, AW, Halford, JL, Morrill, VN, Weng, LC, Lagerman, B, Mirshahi, T, Pettinger, M, Guo, X, Lin, HJ, Alonso, A, Soliman, EZ, Kornej, J, Lin, H, Moscati, A, Nadkarni, GN, Brody, JA, Wiggins, KL, Cade, BE, Lee, J, Austin-Tse, C, Blackwell, T, Chaffin, MD, Lee, CJY, Rehm, HL, Roselli, C, Redline, S, Mitchell, BD, Sotoodehnia, N, Psaty, BM, Heckbert, SR, Loos, RJF, Vasan, RS, Benjamin, EJ, Correa, A, Boerwinkle, E, Arking, DE, Rotter, JI, Rich, SS, Whitsel, EA, Perez, M, Kooperberg, C, Fornwalt, BK, Lunetta, KL, Ellinor, PT & Lubitz, SA 2021, 'Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis', Circulation: Cardiovascular Genetics, vol. 14, no. 4, pp. E003300. https://doi.org/10.1161/CIRCGEN.120.003300

@article{943b7a7bd0a842d3ba8caac51b8786f5,

title = "Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis",

abstract = "Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.",

keywords = "death, sudden, cardiac, epidemiology, genetics, genome, population",

author = "Choi, {Seung Hoan} and Jurgens, {Sean J.} and Haggerty, {Christopher M.} and Hall, {Amelia W.} and Halford, {Jennifer L.} and Morrill, {Valerie N.} and Weng, {Lu Chen} and Braxton Lagerman and Tooraj Mirshahi and Mary Pettinger and Xiuqing Guo and Lin, {Henry J.} and Alvaro Alonso and Soliman, {Elsayed Z.} and Jelena Kornej and Honghuang Lin and Arden Moscati and Nadkarni, {Girish N.} and Brody, {Jennifer A.} and Wiggins, {Kerri L.} and Cade, {Brian E.} and Jiwon Lee and Christina Austin-Tse and Tom Blackwell and Chaffin, {Mark D.} and Lee, {Christina J.Y.} and Rehm, {Heidi L.} and Carolina Roselli and Susan Redline and Mitchell, {Braxton D.} and Nona Sotoodehnia and Psaty, {Bruce M.} and Heckbert, {Susan R.} and Loos, {Ruth J.F.} and Vasan, {Ramachandran S.} and Benjamin, {Emelia J.} and Adolfo Correa and Eric Boerwinkle and Arking, {Dan E.} and Rotter, {Jerome I.} and Rich, {Stephen S.} and Whitsel, {Eric A.} and Marco Perez and Charles Kooperberg and Fornwalt, {Brandon K.} and Lunetta, {Kathryn L.} and Ellinor, {Patrick T.} and Lubitz, {Steven A.}",

year = "2021",

month = aug,

day = "1",

doi = "10.1161/CIRCGEN.120.003300",

language = "English (US)",

volume = "14",

pages = "E003300",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "4",

}

TY - JOUR

T1 - Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes

T2 - A Multi-Ancestry Analysis

AU - Choi, Seung Hoan

AU - Jurgens, Sean J.

AU - Haggerty, Christopher M.

AU - Hall, Amelia W.

AU - Halford, Jennifer L.

AU - Morrill, Valerie N.

AU - Weng, Lu Chen

AU - Lagerman, Braxton

AU - Mirshahi, Tooraj

AU - Pettinger, Mary

AU - Guo, Xiuqing

AU - Lin, Henry J.

AU - Alonso, Alvaro

AU - Soliman, Elsayed Z.

AU - Kornej, Jelena

AU - Lin, Honghuang

AU - Moscati, Arden

AU - Nadkarni, Girish N.

AU - Brody, Jennifer A.

AU - Wiggins, Kerri L.

AU - Cade, Brian E.

AU - Lee, Jiwon

AU - Austin-Tse, Christina

AU - Blackwell, Tom

AU - Chaffin, Mark D.

AU - Lee, Christina J.Y.

AU - Rehm, Heidi L.

AU - Roselli, Carolina

AU - Redline, Susan

AU - Mitchell, Braxton D.

AU - Sotoodehnia, Nona

AU - Psaty, Bruce M.

AU - Heckbert, Susan R.

AU - Loos, Ruth J.F.

AU - Vasan, Ramachandran S.

AU - Benjamin, Emelia J.

AU - Correa, Adolfo

AU - Boerwinkle, Eric

AU - Arking, Dan E.

AU - Rotter, Jerome I.

AU - Rich, Stephen S.

AU - Whitsel, Eric A.

AU - Perez, Marco

AU - Kooperberg, Charles

AU - Fornwalt, Brandon K.

AU - Lunetta, Kathryn L.

AU - Ellinor, Patrick T.

AU - Lubitz, Steven A.

PY - 2021/8/1

Y1 - 2021/8/1

N2 - Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

AB - Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

KW - death, sudden, cardiac

KW - epidemiology

KW - genetics

KW - genome

KW - population

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DO - 10.1161/CIRCGEN.120.003300

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AN - SCOPUS:85113741971

SN - 1942-325X

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JO - Circulation: Cardiovascular Genetics

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ER -

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis

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