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

Resultado de la investigación: Article › revisión exhaustiva

3 Citas (Scopus)

Resumen

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.

Idioma original	English (US)
Páginas (desde-hasta)	E003300
Publicación	Circulation. Genomic and precision medicine
Volumen	14
N.º	4
DOI	https://doi.org/10.1161/CIRCGEN.120.003300
Estado	Published - ago. 1 2021
Publicado de forma externa	Sí

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. Genomic and precision medicine, 14(4), E003300. https://doi.org/10.1161/CIRCGEN.120.003300

Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes : A Multi-Ancestry Analysis. / Choi, Seung Hoan; Jurgens, Sean J.; Haggerty, Christopher M. et al.

En: Circulation. Genomic and precision medicine, Vol. 14, N.º 4, 01.08.2021, p. E003300.

Resultado de la investigación: Article › revisión exhaustiva

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. Genomic and precision medicine, vol. 14, n.º 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.}",

note = "Funding Information: The whole-genome sequencing for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Whole-genome sequencing for NHLBI TOPMed: the Atheroscle- rosis Risk in Communities (phs001211.v1.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1) and Baylor Human Genome Sequencing Center (3U54HG003273-12S2 and HHSN268201500015C). Whole-genome sequencing for NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish (phs000956.v1.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL121007-01S1). Whole-genome sequencing for NHL-BI TOPMed: Mount Sinai BioMe Biobank (phs001644.v1.p1) was performed at the Baylor Human Genome Sequencing Center (HHSN268201600033I) and McDonnell genome institute (HHSN268201600037I). Whole-genome sequencing for NHLBI TOPMed: Cleveland Family Study—Whole-genome sequencing collaboration (phs000954.v1.p1) was performed at the University of Washington northwest genomics center (3R01HL098433-05S1 and HH-SN268201600032I). Whole-genome sequencing for NHLBI TOPMed: Cardiovascular Health Study (phs001368.v1.p1) was performed at the Baylor Human Genome Sequencing Center (3U54HG003273-12S2, HHSN268201500015C, and HHSN268201600033I). Whole-genome sequencing for NHLBI TOPMed: Framingham Heart Study (phs000974.v1.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1 and 3U54HG003067-12S2). Whole-genome sequencing for NHLBI TOPMed: The Jackson Heart Study (phs000964.v1.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). Whole-genome sequencing for NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Whole-genome sequencing for NHLBI TOPMed: Womens Health Initiative (phs001237.v1.p1) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). The TOPMed component of the Amish Research Program was supported by the National Institutes of Health (NIH) grants R01 HL121007, U01 HL072515, and R01AG18728. The Mount Sinai BioMe Biobank has been supported by The Andrea and Charles Bronfman Philanthropies and, in part, by Federal funds from the NHLBI and NHGRI (U01HG00638001; U01HG007417; and X01HL134588). The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with Federal funds from the NHLBI, NIH, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). The CHS (Cardiovascular Health Study) was supported by contracts HH-SN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The CFS (Cleveland Family Study) has been supported, in part, by NIH grants (R01-HL046380, KL2-RR024990, R35-HL135818, and R01-HL113338). The FHS (Framingham Heart Study) acknowledges the support of contracts NO1-HC-25195 and HHSN268201500001 from the NHLBI and grant supplement R01 HL092577-06S1, and 18SFRN34110082 from American Heart Association for this research. We also acknowledge the dedication of the FHS study participants without whom this research would not be possible. Dr Vasan is supported, in part, by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. Dr Kornej has received funding from the Marie Sklodowska-Curie Actions under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement no. 838259). Dr Lunetta acknowledges support under contract R01 HL092577-10. Dr Benjamin is supported under contracts R01HL128914, 2R01 HL092577 from the NHLBI and 18SFRN34110082 from the American Heart Association. The JHS (Jackson Heart Study) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HH-SN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities (NIMHD). MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. MESA family is conducted and supported by the NHLBI in collaboration with MESA investigators. Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, and R01HL071259 and by the National Center for Research Resources, Grant UL1RR033176. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Women{\textquoteright}s Health Initiative program is funded by the NHLBI, NIH, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. We would further like to thank Jacques Rossouw, Shari Ludlam, Joan McGowan, Leslie Ford, and Nancy Geller from the NHLBI program office, Garnet Anderson, Ross Prentice, and Andrea LaCroix from the Clinical Coordinating Center (Fred Hutchinson Cancer Research Center, Seattle, WA), Investigators JoAnn E. Manson (Brigham and Women{\textquoteright}s Hospital, Harvard Medical School, Boston, MA), Barbara V. Howard (MedStar Health Research Institute/Howard University, Washington, DC), Marcia L. Stefanick (Stanford Prevention Research Center, Stanford, CA), Rebecca Jackson (The Ohio State University, Columbus, OH), Cynthia A. Thomson (University of Arizona, Tucson/Phoenix, AZ), Jean Wactawski-Wende (University at Buffalo, Buffalo, NY), Marian Limacher (University of Florida, Gainesville/Jacksonville, FL), Jennifer Robinson (University of Iowa, Iowa City/Davenport, IA), Lewis Kuller (University of Pittsburgh, Pittsburgh, PA), Sally Shumaker (Wake Forest University School of Medicine, Winston-Salem, NC), Robert Brunner (University of Nevada, Reno, NV), and Mark Espeland from the Women{\textquoteright}s Health Initiative Memory Study (Wake Forest University School of Medicine, Winston-Salem, NC). The DiscovEHR (MyCode) study was supported by the NHLBI through grant number R01HL141901. Dr Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Dr Sotoodehnia is supported by NIH grant R01HL141989, by AHA grant 19SFRN34830063, and by the Laughlin Family. Funding Information: Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.). Department of Translational Data Science and Informatics (C.M.H., B.K.F.), Heart Institute (C.M.H., B.K.F.), Phenomic Analytics and Clinical Data Core (B.L.), Department of Molecular and Functional Genomics (T.M.), and Department of Radiology (B.K.F.), Geisinger, Danville, PA. Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Center for Genomic Medicine (C.A.-T., H.L.R.), and Cardiac Arrhythmia Service (P.T.E., S.A.L.), Massachusetts General Hospital. Division of Sleep Medicine, Department of Medicine (B.E.C.) and Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (M.P., C.K.). The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Insti for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., H.J.L., J.I.R.). Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.). Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC (E.Z.S.). NHLBI and Boston University{\textquoteright}s Framingham Heart Study (J.K., E.J.B., R.S.V). Sections of Cardiovascular Medicine and Preventive Medicine, Boston Medical Center (J.K., R.S.V), Section of Computational Biomedicine, Department of Medicine (H.L.), and Department of Medicine (E.J.B., R.S.V), Boston University School of Medicine, MA. The Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Division of Nephrology, Department of Medicine (G.N.), and The Mindich Child Health and Development Institute (R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY. Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), Division of Cardiology, Department of Epidemiology (N.S.), Department of Epidemiology (B.M.P., S.R.H.), and Department of Health Services (B.M.P.), University of Washington, Seattle. Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology (B.E.C.) and Division of Sleep and Circadian Disorders (J.L.), Harvard Medical School, Brigham and Women{\textquoteright}s Hospital, Boston. Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA (C.A.-T.). Department of Biostatistics, University of Michigan, Ann Arbor (T.B.). Regeneron Genetics Center, Tarrytown, NY. Departments of Medicine, Brigham and Women{\textquoteright}s Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R.). University of Maryland School of Medicine (B.D.M.). Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.). Kaiser Permanente Washington Health Research Institute, Seattle (B.M.P.). Department of Epidemiology (E.J.B.) and Department of Biostatistics (K.L.L.), Boston University School of Public Health, MA. Departments of Medicine, Pediatrics, and Population Health Science, University of Mississippi Medical Center, Jackson (A.C.). Human Genetics Center, University of Texas Health Science Center, Houston (E.B.). McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (D.E.A.). Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville (S.S.R.). Department of Epidemiology, Gillings School of Global Public Health (E.A.W.) and Department of Medicine (E.A.W.), School of Medicine, University of North Carolina, Chapel Hill. Division of Cardiovascular Medicine, Stanford University, CA (M.P.). Dr Sotoodehnia is supported by NIH grant R01HL141989, by AHA grant 19SFRN34830063, and by the Laughlin Family. Publisher Copyright: {\textcopyright} 2021 Lippincott Williams and Wilkins. All rights reserved.",

year = "2021",

month = aug,

day = "1",

doi = "10.1161/CIRCGEN.120.003300",

language = "English (US)",

volume = "14",

pages = "E003300",

journal = "Circulation. Genomic and precision medicine",

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.

N1 - Funding Information: The whole-genome sequencing for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Whole-genome sequencing for NHLBI TOPMed: the Atheroscle- rosis Risk in Communities (phs001211.v1.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1) and Baylor Human Genome Sequencing Center (3U54HG003273-12S2 and HHSN268201500015C). Whole-genome sequencing for NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish (phs000956.v1.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL121007-01S1). Whole-genome sequencing for NHL-BI TOPMed: Mount Sinai BioMe Biobank (phs001644.v1.p1) was performed at the Baylor Human Genome Sequencing Center (HHSN268201600033I) and McDonnell genome institute (HHSN268201600037I). Whole-genome sequencing for NHLBI TOPMed: Cleveland Family Study—Whole-genome sequencing collaboration (phs000954.v1.p1) was performed at the University of Washington northwest genomics center (3R01HL098433-05S1 and HH-SN268201600032I). Whole-genome sequencing for NHLBI TOPMed: Cardiovascular Health Study (phs001368.v1.p1) was performed at the Baylor Human Genome Sequencing Center (3U54HG003273-12S2, HHSN268201500015C, and HHSN268201600033I). Whole-genome sequencing for NHLBI TOPMed: Framingham Heart Study (phs000974.v1.p1) was performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1 and 3U54HG003067-12S2). Whole-genome sequencing for NHLBI TOPMed: The Jackson Heart Study (phs000964.v1.p1) was performed at the University of Washington Northwest Genomics Center (HHSN268201100037C). Whole-genome sequencing for NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Whole-genome sequencing for NHLBI TOPMed: Womens Health Initiative (phs001237.v1.p1) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). The TOPMed component of the Amish Research Program was supported by the National Institutes of Health (NIH) grants R01 HL121007, U01 HL072515, and R01AG18728. The Mount Sinai BioMe Biobank has been supported by The Andrea and Charles Bronfman Philanthropies and, in part, by Federal funds from the NHLBI and NHGRI (U01HG00638001; U01HG007417; and X01HL134588). The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with Federal funds from the NHLBI, NIH, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). The CHS (Cardiovascular Health Study) was supported by contracts HH-SN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The CFS (Cleveland Family Study) has been supported, in part, by NIH grants (R01-HL046380, KL2-RR024990, R35-HL135818, and R01-HL113338). The FHS (Framingham Heart Study) acknowledges the support of contracts NO1-HC-25195 and HHSN268201500001 from the NHLBI and grant supplement R01 HL092577-06S1, and 18SFRN34110082 from American Heart Association for this research. We also acknowledge the dedication of the FHS study participants without whom this research would not be possible. Dr Vasan is supported, in part, by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. Dr Kornej has received funding from the Marie Sklodowska-Curie Actions under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 838259). Dr Lunetta acknowledges support under contract R01 HL092577-10. Dr Benjamin is supported under contracts R01HL128914, 2R01 HL092577 from the NHLBI and 18SFRN34110082 from the American Heart Association. The JHS (Jackson Heart Study) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HH-SN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities (NIMHD). MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. MESA family is conducted and supported by the NHLBI in collaboration with MESA investigators. Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, and R01HL071259 and by the National Center for Research Resources, Grant UL1RR033176. The provision of genotyping data was supported, in part, by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Women’s Health Initiative program is funded by the NHLBI, NIH, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. We would further like to thank Jacques Rossouw, Shari Ludlam, Joan McGowan, Leslie Ford, and Nancy Geller from the NHLBI program office, Garnet Anderson, Ross Prentice, and Andrea LaCroix from the Clinical Coordinating Center (Fred Hutchinson Cancer Research Center, Seattle, WA), Investigators JoAnn E. Manson (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA), Barbara V. Howard (MedStar Health Research Institute/Howard University, Washington, DC), Marcia L. Stefanick (Stanford Prevention Research Center, Stanford, CA), Rebecca Jackson (The Ohio State University, Columbus, OH), Cynthia A. Thomson (University of Arizona, Tucson/Phoenix, AZ), Jean Wactawski-Wende (University at Buffalo, Buffalo, NY), Marian Limacher (University of Florida, Gainesville/Jacksonville, FL), Jennifer Robinson (University of Iowa, Iowa City/Davenport, IA), Lewis Kuller (University of Pittsburgh, Pittsburgh, PA), Sally Shumaker (Wake Forest University School of Medicine, Winston-Salem, NC), Robert Brunner (University of Nevada, Reno, NV), and Mark Espeland from the Women’s Health Initiative Memory Study (Wake Forest University School of Medicine, Winston-Salem, NC). The DiscovEHR (MyCode) study was supported by the NHLBI through grant number R01HL141901. Dr Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Dr Sotoodehnia is supported by NIH grant R01HL141989, by AHA grant 19SFRN34830063, and by the Laughlin Family. Funding Information: Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.). Department of Translational Data Science and Informatics (C.M.H., B.K.F.), Heart Institute (C.M.H., B.K.F.), Phenomic Analytics and Clinical Data Core (B.L.), Department of Molecular and Functional Genomics (T.M.), and Department of Radiology (B.K.F.), Geisinger, Danville, PA. Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Center for Genomic Medicine (C.A.-T., H.L.R.), and Cardiac Arrhythmia Service (P.T.E., S.A.L.), Massachusetts General Hospital. Division of Sleep Medicine, Department of Medicine (B.E.C.) and Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (M.P., C.K.). The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Insti for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., H.J.L., J.I.R.). Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.). Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC (E.Z.S.). NHLBI and Boston University’s Framingham Heart Study (J.K., E.J.B., R.S.V). Sections of Cardiovascular Medicine and Preventive Medicine, Boston Medical Center (J.K., R.S.V), Section of Computational Biomedicine, Department of Medicine (H.L.), and Department of Medicine (E.J.B., R.S.V), Boston University School of Medicine, MA. The Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Division of Nephrology, Department of Medicine (G.N.), and The Mindich Child Health and Development Institute (R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY. Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), Division of Cardiology, Department of Epidemiology (N.S.), Department of Epidemiology (B.M.P., S.R.H.), and Department of Health Services (B.M.P.), University of Washington, Seattle. Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology (B.E.C.) and Division of Sleep and Circadian Disorders (J.L.), Harvard Medical School, Brigham and Women’s Hospital, Boston. Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA (C.A.-T.). Department of Biostatistics, University of Michigan, Ann Arbor (T.B.). Regeneron Genetics Center, Tarrytown, NY. Departments of Medicine, Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R.). University of Maryland School of Medicine (B.D.M.). Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.). Kaiser Permanente Washington Health Research Institute, Seattle (B.M.P.). Department of Epidemiology (E.J.B.) and Department of Biostatistics (K.L.L.), Boston University School of Public Health, MA. Departments of Medicine, Pediatrics, and Population Health Science, University of Mississippi Medical Center, Jackson (A.C.). Human Genetics Center, University of Texas Health Science Center, Houston (E.B.). McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (D.E.A.). Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville (S.S.R.). Department of Epidemiology, Gillings School of Global Public Health (E.A.W.) and Department of Medicine (E.A.W.), School of Medicine, University of North Carolina, Chapel Hill. Division of Cardiovascular Medicine, Stanford University, CA (M.P.). Dr Sotoodehnia is supported by NIH grant R01HL141989, by AHA grant 19SFRN34830063, and by the Laughlin Family. Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.

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

UR - http://www.scopus.com/inward/record.url?scp=85113741971&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85113741971&partnerID=8YFLogxK

U2 - 10.1161/CIRCGEN.120.003300

DO - 10.1161/CIRCGEN.120.003300

M3 - Article

C2 - 34319147

AN - SCOPUS:85113741971

VL - 14

SP - E003300

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 4

ER -

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

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