Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation.,Circulation: Genomic and Precision Medicine

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Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation.
Circulation: Genomic and Precision Medicine ( IF 6.0 ) Pub Date : 2020-08-21 , DOI: 10.1161/circgen.119.002874
Lu-Chen Weng _{1,

2} , Amelia Weber Hall _{1,

2} , Seung Hoan Choi ₂ , Sean J Jurgens ₂ , Jeffrey Haessler ₃ , Nathan A Bihlmeyer ₄ , Niels Grarup ₅ , Honghuang Lin _{6,

7} , Alexander Teumer _{8,

9} , Ruifang Li-Gao ₁₀ , Jie Yao ₁₁ , Xiuqing Guo _{11,

12} , Jennifer A Brody ₁₃ , Martina Müller-Nurasyid _{14,

15,

16} , Katharina Schramm _{14,

15,

16} , Niek Verweij _{17,

18} , Marten E van den Berg ₁₉ , Jessica van Setten ₂₀ , Aaron Isaacs _{21,

22} , Julia Ramírez _{23,

24} , Helen R Warren _{23,

24} , Sandosh Padmanabhan ₂₅ , Jan A Kors ₂₆ , Rudolf A de Boer ₁₈ , Peter van der Meer ₁₈ , Moritz F Sinner _{15,

27} , Melanie Waldenberger _{27,

28,

29} , Bruce M Psaty _{30,

31} , Kent D Taylor _{11,

12} , Uwe Völker _{8,

32} , Jørgen K Kanters ₃₃ , Man Li ₃₄ , Alvaro Alonso ₃₅ , Marco V Perez ₃₆ , Ilonca Vaartjes ₃₇ , Michiel L Bots ₃₇ , Paul L Huang ₁ , Susan R Heckbert ₃₈ , Henry J Lin _{11,

12} , Jelena Kornej ₆ , Patricia B Munroe _{23,

24} , Cornelia M van Duijn _{39,

40} , Folkert W Asselbergs _{20,

41,

42} , Bruno H Stricker _{43,

44,

45} , Pim van der Harst _{18,

46,

47} , Stefan Kääb _{15,

27} , Annette Peters _{27,

28,

48} , Nona Sotoodehnia ₁₃ , Jerome I Rotter _{11,

49} , Dennis O Mook-Kanamori _{10,

50} , Marcus Dörr _{8,

51} , Stephan B Felix _{8,

51} , Allan Linneberg _{52,

53} , Torben Hansen ₅ , Dan E Arking ₄ , Charles Kooperberg ₃ , Emelia J Benjamin _{6,

54,

55} , Kathryn L Lunetta _{6,

56} , Patrick T Ellinor _{1,

2,

57} , Steven A Lubitz _{2,

57}

Affiliation

Cardiovascular Research Center (L.-C.W., A.W.H., P.L.H., P.T.E.), MGH, Boston.
Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA (L.-C.W., A.W.H., S.H.C., S.J.J., P.T.E., S.A.L.).
Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA (J.H., C.K.).
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (N.A.B., D.E.A.).
Novo Nordisk Foundation Center for Basic Metabolic Research (N.G., T.H.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
Boston University & NHLBI's Framingham Heart Study, Framingham, MA (H.L., J.K., E.J.B., K.L.L.).
Section of Computational Biomedicine, Department of Medicine (H.L.), Boston University School of Medicine, Boston, MA.
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Germany (A.T., U.V., M.D., S.B.F.).
Institute for Community Medicine (A.T.), University Medicine Greifswald, Germany.
Department of Clinical Epidemiology (R.L.-G., D.O.M.-K.), Leiden University Medical Center, the Netherlands.
The Institute for Translational Genomics & Population Sciences at Harbor-UCLA Medical Center, Torrance, CA (J.Y., X.G., K.D.T., H.J.L., J.I.R.).
Department of Pediatrics (X.G., K.D.T., H.J.L.), David Geffen School of Medicine at UCLA, Los Angeles, CA.
Cardiovascular Health Research Unit, Department of Medicine (J.A.B., N.S.), University of Washington.
Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany (M.M.-N., K.S.).
Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Germany (M.M.-N., K.S., M.F.S., S.K.).
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany (M.M.-N., K.S.).
Genomics plc, Oxford, United Kingdom (N.V.).
Department of Cardiology (N.V., R.A.d.B., P.v.d.M., P.v.d.H.), University of Groningen & University Medical Center.
Department of Epidemiology (M.E.v.d.B.).
Erasmus MC, Medical Center Rotterdam, Division of Heart & Lungs, Department of Cardiology, University of Utrecht, University Medical Center Utrecht (J.v.S., F.W.A.).
CARIM School for Cardiovascular Diseases (A.I.), Maastricht University, the Netherlands.
Department of Physiology (A.I.), Maastricht University, the Netherlands.
National Institute for Health Research, Barts Cardiovascular Biomedical Research Center (J.R., H.R.W., P.B.M.), Queen Mary University of London, London.
William Harvey Research Institute, Barts & The London School of Medicine & Dentistry (J.R., H.R.W., P.B.M.), Queen Mary University of London, London.
Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, United Kingdom (S.P.).
Department of Medicine Informatics (J.A.K.), Erasmus University Medical Center, Rotterdam, the Netherlands.
DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance (M.F.S., M.W., S.K., A.P.).
Institute of Epidemiology (M.W., A.P.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Research Unit of Molecular Epidemiology (M.W.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology & Health Services (B.M.P.), University of Washington.
Kaiser Permanente Washington Health Research Institute, Seattle, WA (B.M.P.).
Interfaculty Institute for Genetics & Functional Genomics (U.V.), University Medicine Greifswald, Germany.
Lab of Experimental Cardiology (J.K.K.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT (M.L.).
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).
Department of Medicine, Stanford University, Palo Alto, CA (M.V.P.).
Julius Center for Health Sciences & Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands (I.V., M.L.B.).
Cardiovascular Health Research Unit, Department of Epidemiology (S.R.H.), University of Washington.
Department of Epidemiology (C.M.v.D.), Erasmus University Medical Center, Rotterdam, the Netherlands.
Nuffield Department of Population Health, Medical Sciences Division, St. Cross College, Oxford University (C.M.v.D.).
Health Data Research UK & Institute of Health Informatics (F.W.A.), University College London, United Kingdom.
Institute of Cardiovascular Science, Faculty of Population Health Sciences (F.W.A.), University College London, United Kingdom.
Department of Internal Medicine (B.H.S.).
Department of Medicine Informatics (B.H.S.).
Inspectorate of Health Care (B.H.S.), ICIN-Netherlands Heart Institute, Utrecht.
Department of Genetics (P.v.d.H.), University of Groningen & University Medical Center.
Durrer Center for Cardiogenetic Research (P.v.d.H.), ICIN-Netherlands Heart Institute, Utrecht.
German Center for Diabetes Research, Neuherberg, Germany (A.P.).
Departments of Pediatrics & Human Genetics (J.I.R.), David Geffen School of Medicine at UCLA, Los Angeles, CA.
Department of Public Health & Primary Care (D.O.M.-K.), Leiden University Medical Center, the Netherlands.
Department of Internal Medicine B (M.D., S.B.F.), University Medicine Greifswald, Germany.
Department of Clinical Medicine (A.L.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
Center for Clinical Research & Prevention, Bispebjerg & Frederiksberg Hospital, Copenhagen, Denmark (A.L.).
Department of Medicine (E.J.B.), Boston University School of Medicine, Boston, MA.
Department of Epidemiology (E.J.B.), Boston University School of Public Health, Boston, MA.
Department of Biostatistics (K.L.L.), Boston University School of Public Health, Boston, MA.
Cardiac Arrhythmia Service (P.T.E, S.A.L.), MGH, Boston.

Background:The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.Methods:Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.Results:We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk.Conclusions:Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

中文翻译：

心电图 P 波持续时间的遗传决定因素及其与心房颤动的关系。

背景：P 波持续时间 (PWD) 是一种心电图测量，代表心房的心脏传导。 PWD 缩短或延长与心房颤动 (AF) 相关。我们使用外显子组芯片数据来检查常见和罕见变异与 PWD 之间的关联。方法：使用 15 项研究，包括 64 440 名个体（56 943 名欧洲人、5 681 名非洲人、1 186 名西班牙裔、630 名亚洲人）和约 230 000 个变异来检查关联12 导联 ECG 上具有最大 PWD。荟萃分析总结了常见变异的关联结果；基于基因的负担和序列核关联测试检查了低频变异-PWD 关联。此外，我们利用之前的 AF 全基因组关联研究检查了 PWD 基因座与 AF 之间的关联。结果：我们鉴定了 21 个与最大 PWD 相关的常见和低频遗传位点（14 个新基因位点），包括几个 AF 基因座（ TTN 、 CAND2 、 SCN10A 、 PITX2 、 CAV1 、 SYNPO2L 、 SOX5 、 TBX5、MYH6、RPL3L ）。已知肌节基因（ TTN、MYH6 ）的主要变异与更长的 PWD 和增加的 AF 风险相关。然而，其他基因座（例如PITX2和SCN10A ）的顶级变异与较长的 PWD 但较低的 AF 风险相关。结论：我们的结果强调了与 PWD 相关的多个新基因位点，并强调了心房传导和 AF 的共同机制。长时间的 PWD 可能是 AF 几种不同遗传机制的内表型。

更新日期：2020-10-20

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