Meta-Analysis

. 2020 Oct;13(5):387-395.

doi: 10.1161/CIRCGEN.119.002874. Epub 2020 Aug 21.

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Lu-Chen Weng^#^{1

2}, Amelia Weber Hall^#^{1

2}, Seung Hoan Choi², Sean J Jurgens², Jeffrey Haessler³, Nathan A Bihlmeyer⁴, Niels Grarup⁵, Honghuang Lin^{6

7}, Alexander Teumer^{8

9}, Ruifang Li-Gao¹⁰, Jie Yao¹¹, Xiuqing Guo^{11

12}, Jennifer A Brody¹³, Martina Müller-Nurasyid^{14

15

16}, Katharina Schramm^{14

15

16}, Niek Verweij^{17

18}, Marten E van den Berg¹⁹, Jessica van Setten²⁰, Aaron Isaacs^{21

22}, Julia Ramírez^{23

24}, Helen R Warren^{23

24}, Sandosh Padmanabhan²⁵, Jan A Kors²⁶, Rudolf A de Boer¹⁸, Peter van der Meer¹⁸, 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 Kanters³³, Man Li³⁴, Alvaro Alonso³⁵, Marco V Perez³⁶, Ilonca Vaartjes³⁷, Michiel L Bots³⁷, Paul L Huang¹, Susan R Heckbert³⁸, Henry J Lin^{11

12}, Jelena Kornej⁶, 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 Sotoodehnia¹³, 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 Hansen⁵, Dan E Arking⁴, Charles Kooperberg³, Emelia J Benjamin^{6

54

55}, Kathryn L Lunetta^{6

56}, Patrick T Ellinor^{1

57

2}, Steven A Lubitz^{57

2}

Affiliations

¹ Cardiovascular Research Center (L.-C.W., A.W.H., P.L.H., P.T.E.), MGH, Boston.
² 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.).
³ Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA (J.H., C.K.).
⁴ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (N.A.B., D.E.A.).
⁵ Novo Nordisk Foundation Center for Basic Metabolic Research (N.G., T.H.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
⁶ Boston University & NHLBI's Framingham Heart Study, Framingham, MA (H.L., J.K., E.J.B., K.L.L.).
⁷ Section of Computational Biomedicine, Department of Medicine (H.L.), Boston University School of Medicine, Boston, MA.
⁸ DZHK (German Center for Cardiovascular Research), partner site Greifswald, Germany (A.T., U.V., M.D., S.B.F.).
⁹ Institute for Community Medicine (A.T.), University Medicine Greifswald, Germany.
¹⁰ Department of Clinical Epidemiology (R.L.-G., D.O.M.-K.), Leiden University Medical Center, the Netherlands.
¹¹ 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.).
¹² Department of Pediatrics (X.G., K.D.T., H.J.L.), David Geffen School of Medicine at UCLA, Los Angeles, CA.
¹³ Cardiovascular Health Research Unit, Department of Medicine (J.A.B., N.S.), University of Washington.
¹⁴ Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany (M.M.-N., K.S.).
¹⁵ 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.).
¹⁶ Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany (M.M.-N., K.S.).
¹⁷ Genomics plc, Oxford, United Kingdom (N.V.).
¹⁸ Department of Cardiology (N.V., R.A.d.B., P.v.d.M., P.v.d.H.), University of Groningen & University Medical Center.
¹⁹ Department of Epidemiology (M.E.v.d.B.).
²⁰ 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.).
²¹ CARIM School for Cardiovascular Diseases (A.I.), Maastricht University, the Netherlands.
²² Department of Physiology (A.I.), Maastricht University, the Netherlands.
²³ National Institute for Health Research, Barts Cardiovascular Biomedical Research Center (J.R., H.R.W., P.B.M.), Queen Mary University of London, London.
²⁴ 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.
²⁵ Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, United Kingdom (S.P.).
²⁶ Department of Medicine Informatics (J.A.K.), Erasmus University Medical Center, Rotterdam, the Netherlands.
²⁷ DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance (M.F.S., M.W., S.K., A.P.).
²⁸ Institute of Epidemiology (M.W., A.P.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ Research Unit of Molecular Epidemiology (M.W.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
³⁰ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology & Health Services (B.M.P.), University of Washington.
³¹ Kaiser Permanente Washington Health Research Institute, Seattle, WA (B.M.P.).
³² Interfaculty Institute for Genetics & Functional Genomics (U.V.), University Medicine Greifswald, Germany.
³³ Lab of Experimental Cardiology (J.K.K.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
³⁴ Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT (M.L.).
³⁵ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).
³⁶ Department of Medicine, Stanford University, Palo Alto, CA (M.V.P.).
³⁷ Julius Center for Health Sciences & Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands (I.V., M.L.B.).
³⁸ Cardiovascular Health Research Unit, Department of Epidemiology (S.R.H.), University of Washington.
³⁹ Department of Epidemiology (C.M.v.D.), Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴⁰ Nuffield Department of Population Health, Medical Sciences Division, St. Cross College, Oxford University (C.M.v.D.).
⁴¹ Health Data Research UK & Institute of Health Informatics (F.W.A.), University College London, United Kingdom.
⁴² Institute of Cardiovascular Science, Faculty of Population Health Sciences (F.W.A.), University College London, United Kingdom.
⁴³ Department of Internal Medicine (B.H.S.).
⁴⁴ Department of Medicine Informatics (B.H.S.).
⁴⁵ Inspectorate of Health Care (B.H.S.), ICIN-Netherlands Heart Institute, Utrecht.
⁴⁶ Department of Genetics (P.v.d.H.), University of Groningen & University Medical Center.
⁴⁷ Durrer Center for Cardiogenetic Research (P.v.d.H.), ICIN-Netherlands Heart Institute, Utrecht.
⁴⁸ German Center for Diabetes Research, Neuherberg, Germany (A.P.).
⁴⁹ Departments of Pediatrics & Human Genetics (J.I.R.), David Geffen School of Medicine at UCLA, Los Angeles, CA.
⁵⁰ Department of Public Health & Primary Care (D.O.M.-K.), Leiden University Medical Center, the Netherlands.
⁵¹ Department of Internal Medicine B (M.D., S.B.F.), University Medicine Greifswald, Germany.
⁵² Department of Clinical Medicine (A.L.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
⁵³ Center for Clinical Research & Prevention, Bispebjerg & Frederiksberg Hospital, Copenhagen, Denmark (A.L.).
⁵⁴ Department of Medicine (E.J.B.), Boston University School of Medicine, Boston, MA.
⁵⁵ Department of Epidemiology (E.J.B.), Boston University School of Public Health, Boston, MA.
⁵⁶ Department of Biostatistics (K.L.L.), Boston University School of Public Health, Boston, MA.
⁵⁷ Cardiac Arrhythmia Service (P.T.E, S.A.L.), MGH, Boston.

^# Contributed equally.

PMID: 32822252
PMCID: PMC7578098
DOI: 10.1161/CIRCGEN.119.002874

Meta-Analysis

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Lu-Chen Weng et al. Circ Genom Precis Med. 2020 Oct.

. 2020 Oct;13(5):387-395.

doi: 10.1161/CIRCGEN.119.002874. Epub 2020 Aug 21.

Authors

Affiliations

¹ Cardiovascular Research Center (L.-C.W., A.W.H., P.L.H., P.T.E.), MGH, Boston.
² 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.).
³ Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA (J.H., C.K.).
⁴ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (N.A.B., D.E.A.).
⁵ Novo Nordisk Foundation Center for Basic Metabolic Research (N.G., T.H.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
⁶ Boston University & NHLBI's Framingham Heart Study, Framingham, MA (H.L., J.K., E.J.B., K.L.L.).
⁷ Section of Computational Biomedicine, Department of Medicine (H.L.), Boston University School of Medicine, Boston, MA.
⁸ DZHK (German Center for Cardiovascular Research), partner site Greifswald, Germany (A.T., U.V., M.D., S.B.F.).
⁹ Institute for Community Medicine (A.T.), University Medicine Greifswald, Germany.
¹⁰ Department of Clinical Epidemiology (R.L.-G., D.O.M.-K.), Leiden University Medical Center, the Netherlands.
¹¹ 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.).
¹² Department of Pediatrics (X.G., K.D.T., H.J.L.), David Geffen School of Medicine at UCLA, Los Angeles, CA.
¹³ Cardiovascular Health Research Unit, Department of Medicine (J.A.B., N.S.), University of Washington.
¹⁴ Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany (M.M.-N., K.S.).
¹⁵ 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.).
¹⁶ Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany (M.M.-N., K.S.).
¹⁷ Genomics plc, Oxford, United Kingdom (N.V.).
¹⁸ Department of Cardiology (N.V., R.A.d.B., P.v.d.M., P.v.d.H.), University of Groningen & University Medical Center.
¹⁹ Department of Epidemiology (M.E.v.d.B.).
²⁰ 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.).
²¹ CARIM School for Cardiovascular Diseases (A.I.), Maastricht University, the Netherlands.
²² Department of Physiology (A.I.), Maastricht University, the Netherlands.
²³ National Institute for Health Research, Barts Cardiovascular Biomedical Research Center (J.R., H.R.W., P.B.M.), Queen Mary University of London, London.
²⁴ 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.
²⁵ Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, United Kingdom (S.P.).
²⁶ Department of Medicine Informatics (J.A.K.), Erasmus University Medical Center, Rotterdam, the Netherlands.
²⁷ DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance (M.F.S., M.W., S.K., A.P.).
²⁸ Institute of Epidemiology (M.W., A.P.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ Research Unit of Molecular Epidemiology (M.W.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
³⁰ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology & Health Services (B.M.P.), University of Washington.
³¹ Kaiser Permanente Washington Health Research Institute, Seattle, WA (B.M.P.).
³² Interfaculty Institute for Genetics & Functional Genomics (U.V.), University Medicine Greifswald, Germany.
³³ Lab of Experimental Cardiology (J.K.K.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
³⁴ Division of Nephrology & Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT (M.L.).
³⁵ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.).
³⁶ Department of Medicine, Stanford University, Palo Alto, CA (M.V.P.).
³⁷ Julius Center for Health Sciences & Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands (I.V., M.L.B.).
³⁸ Cardiovascular Health Research Unit, Department of Epidemiology (S.R.H.), University of Washington.
³⁹ Department of Epidemiology (C.M.v.D.), Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴⁰ Nuffield Department of Population Health, Medical Sciences Division, St. Cross College, Oxford University (C.M.v.D.).
⁴¹ Health Data Research UK & Institute of Health Informatics (F.W.A.), University College London, United Kingdom.
⁴² Institute of Cardiovascular Science, Faculty of Population Health Sciences (F.W.A.), University College London, United Kingdom.
⁴³ Department of Internal Medicine (B.H.S.).
⁴⁴ Department of Medicine Informatics (B.H.S.).
⁴⁵ Inspectorate of Health Care (B.H.S.), ICIN-Netherlands Heart Institute, Utrecht.
⁴⁶ Department of Genetics (P.v.d.H.), University of Groningen & University Medical Center.
⁴⁷ Durrer Center for Cardiogenetic Research (P.v.d.H.), ICIN-Netherlands Heart Institute, Utrecht.
⁴⁸ German Center for Diabetes Research, Neuherberg, Germany (A.P.).
⁴⁹ Departments of Pediatrics & Human Genetics (J.I.R.), David Geffen School of Medicine at UCLA, Los Angeles, CA.
⁵⁰ Department of Public Health & Primary Care (D.O.M.-K.), Leiden University Medical Center, the Netherlands.
⁵¹ Department of Internal Medicine B (M.D., S.B.F.), University Medicine Greifswald, Germany.
⁵² Department of Clinical Medicine (A.L.), Faculty of Health & Medicine Sciences, University of Copenhagen, Denmark.
⁵³ Center for Clinical Research & Prevention, Bispebjerg & Frederiksberg Hospital, Copenhagen, Denmark (A.L.).
⁵⁴ Department of Medicine (E.J.B.), Boston University School of Medicine, Boston, MA.
⁵⁵ Department of Epidemiology (E.J.B.), Boston University School of Public Health, Boston, MA.
⁵⁶ Department of Biostatistics (K.L.L.), Boston University School of Public Health, Boston, MA.
⁵⁷ Cardiac Arrhythmia Service (P.T.E, S.A.L.), MGH, Boston.

^# Contributed equally.

PMID: 32822252
PMCID: PMC7578098
DOI: 10.1161/CIRCGEN.119.002874

Abstract

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.

Keywords: atrial fibrillation; electrophysiology; exome; genetic; genome-wide association studies; population.

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Figures

**Figure 1.**
P-wave duration loci and atrial fibrillation risk. The x-axis represents the association between the top P-wave duration (PWD) loci and PWD in -log₁₀ scale. The y-axis represents the association P-value between the top PWD loci and atrial fibrillation (AF) risk (-log₁₀ scale). Variants above y=0 refer to loci associated with longer PWD and higher AF risk (colored in yellow). Variants below y=0 refer to loci associated with longer PWD but lower AF risk (colored in blue). Displayed results are from the multi-ethnic meta-analysis of PWD residuals. Associations with AF were derived from a recent AF GWAS. Dashed lines show the significance threshold for the current exome-wide analysis (vertical; P-value<1.9×10⁻⁶) and for prior genome-wide analyses of AF (horizontal; P-value<5×10⁻⁸). The dotted line represents the significance cutoff after Bonferroni correction (horizontal; P-value<2.4×10⁻³=0.05/21 PWD loci).

**Figure 2:**
Identified P-wave duration associated genes highlight multiple biological pathways for atrial fibrillation risk. Gene with *increasing* risk of AF coupled with prolonged PWD are listed at the right. Gene with *decreasing* risk of AF coupled with prolonged PWD are listed at the left. Each gene is accompanied by a diagram representing the biological function of the gene, indicating how the gene may affect PWD.

See this image and copyright information in PMC

References

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Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Affiliations

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical