Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

doi:10.1016/j.jacc.2013.12.015

. 2014 Apr 1;63(12):1200-1210.

doi: 10.1016/j.jacc.2013.12.015. Epub 2014 Jan 30.

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

Steven A Lubitz^#^{1

2}, Kathryn L Lunetta^#^{3

4}, Honghuang Lin^#^{3

5}, Dan E Arking^#⁶, Stella Trompet^#^{7

8}, Guo Li^#⁹, Bouwe P Krijthe^#^{10

11}, Daniel I Chasman^#^{12

13}, John Barnard^#¹⁴, Marcus E Kleber^#¹⁵, Marcus Dörr^#^{16

17}, Kouichi Ozaki^#¹⁸, Albert V Smith^#¹⁹, Martina Müller-Nurasyid^#^{20

21

22}, Stefan Walter^#²³, Sunil K Agarwal²⁴, Joshua C Bis⁹, Jennifer A Brody⁹, Lin Y Chen²⁵, Brendan M Everett^{12

26}, Ian Ford²⁷, Oscar H Franco^{10

11}, Tamara B Harris²⁸, Albert Hofman^{10

11}, Stefan Kääb^{20

29}, Saagar Mahida³⁰, Sekar Kathiresan³¹, Michiaki Kubo³², Lenore J Launer²⁸, Peter W MacFarlane³³, Jared W Magnani^{3

34}, Barbara McKnight³⁵, David D McManus³⁶, Annette Peters^{29

37}, Bruce M Psaty^{9

38

39

40}, Lynda M Rose⁴¹, Jerome I Rotter⁴², Guenther Silbernagel⁴³, Jonathan D Smith⁴⁴, Nona Sotoodehnia^{9

45}, David J Stott⁴⁶, Kent D Taylor⁴⁷, Andreas Tomaschitz⁴⁸, Tatsuhiko Tsunoda⁴⁹, Andre G Uitterlinden^{10

11

50}, David R Van Wagoner⁵¹, Uwe Völker^{17

52}, Henry Völzke^{17

53}, Joanne M Murabito^#^{3

54}, Moritz F Sinner^#²⁰, Vilmundur Gudnason^#¹⁹, Stephan B Felix^#^{16

17}, Winfried März^#^{15

55

56}, Mina Chung^#^{51

57}, Christine M Albert^#^{12

26

41}, Bruno H Stricker^#^{10

11

50

58}, Toshihiro Tanaka^#^{18

59}, Susan R Heckbert^#^{9

39

40}, J Wouter Jukema^#⁶⁰, Alvaro Alonso^#⁶¹, Emelia J Benjamin^#^{3

34

62

63}, Patrick T Ellinor^#^{1

2}

Affiliations

¹ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
³ Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
⁴ Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.
⁵ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
⁶ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁷ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
⁸ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁰ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹¹ Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.
¹² Harvard Medical School, Boston, Massachusetts, USA.
¹³ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁴ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁵ Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
¹⁶ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
¹⁷ DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
¹⁸ Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁹ Icelandic Heart Association, Kopavogur Iceland and University of Iceland Reykjavik, Iceland.
²⁰ Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
²¹ Institute of Genetic Epidemiology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.
²² Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians University, Munich, Germany.
²³ Department of Society, Human Development & Health, Harvard School of Public Health, Boston, Massachusetts, USA.
²⁴ Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.
²⁵ Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
²⁶ Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
²⁷ Robertson Center for Biostatistics, University of Glasgow, United Kingdom.
²⁸ Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
²⁹ Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner site Munich Heart Alliance, Munich, Germany.
³⁰ Leeds General Infirmary, Great George Street, Leeds, UK.
³¹ Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
³² Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³³ Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom.
³⁴ Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
³⁵ Department of Biostatistics, University of Washington, Seattle, Washington, USA.
³⁶ Departments of Medicine and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
³⁷ Institute of Epidemiology II, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.
³⁸ Department of Health Services, University of Washington, Seattle, Washington, USA.
³⁹ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
⁴⁰ Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
⁴¹ Division of Preventive Medicine, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁴² Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif, USA.
⁴³ Department of Angiology, Swiss Cardiovascular Centre, Bern University Hospital, Bern, Switzerland.
⁴⁴ Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁴⁵ Division of Cardiology, University of Washington, Seattle, Washington, USA.
⁴⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
⁴⁷ Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁴⁸ Department of Cardiology, Medical University of Graz, Graz, Austria.
⁴⁹ Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁵⁰ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁵¹ Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁵² Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
⁵³ Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
⁵⁴ Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
⁵⁵ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
⁵⁶ Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
⁵⁷ Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁵⁸ Inspectorate for Health Care, the Hague, The Netherlands.
⁵⁹ Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁶⁰ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
⁶¹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, USA.
⁶² Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.
⁶³ Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

^# Contributed equally.

PMID: 24486271
PMCID: PMC4009240
DOI: 10.1016/j.jacc.2013.12.015

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

Steven A Lubitz et al. J Am Coll Cardiol. 2014.

. 2014 Apr 1;63(12):1200-1210.

doi: 10.1016/j.jacc.2013.12.015. Epub 2014 Jan 30.

Authors

Affiliations

¹ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
³ Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
⁴ Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.
⁵ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
⁶ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁷ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
⁸ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁰ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹¹ Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.
¹² Harvard Medical School, Boston, Massachusetts, USA.
¹³ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁴ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹⁵ Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
¹⁶ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
¹⁷ DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
¹⁸ Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁹ Icelandic Heart Association, Kopavogur Iceland and University of Iceland Reykjavik, Iceland.
²⁰ Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
²¹ Institute of Genetic Epidemiology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.
²² Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians University, Munich, Germany.
²³ Department of Society, Human Development & Health, Harvard School of Public Health, Boston, Massachusetts, USA.
²⁴ Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.
²⁵ Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
²⁶ Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
²⁷ Robertson Center for Biostatistics, University of Glasgow, United Kingdom.
²⁸ Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
²⁹ Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner site Munich Heart Alliance, Munich, Germany.
³⁰ Leeds General Infirmary, Great George Street, Leeds, UK.
³¹ Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
³² Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³³ Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom.
³⁴ Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
³⁵ Department of Biostatistics, University of Washington, Seattle, Washington, USA.
³⁶ Departments of Medicine and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
³⁷ Institute of Epidemiology II, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.
³⁸ Department of Health Services, University of Washington, Seattle, Washington, USA.
³⁹ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
⁴⁰ Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
⁴¹ Division of Preventive Medicine, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁴² Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif, USA.
⁴³ Department of Angiology, Swiss Cardiovascular Centre, Bern University Hospital, Bern, Switzerland.
⁴⁴ Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁴⁵ Division of Cardiology, University of Washington, Seattle, Washington, USA.
⁴⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
⁴⁷ Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁴⁸ Department of Cardiology, Medical University of Graz, Graz, Austria.
⁴⁹ Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁵⁰ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁵¹ Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁵² Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
⁵³ Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
⁵⁴ Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
⁵⁵ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
⁵⁶ Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
⁵⁷ Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁵⁸ Inspectorate for Health Care, the Hague, The Netherlands.
⁵⁹ Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁶⁰ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
⁶¹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, USA.
⁶² Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.
⁶³ Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

^# Contributed equally.

PMID: 24486271
PMCID: PMC4009240
DOI: 10.1016/j.jacc.2013.12.015

Abstract

Objectives: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

Background: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

Methods: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

Results: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

Conclusions: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Keywords: atrial fibrillation; atrial flutter; genetic; prognosis; risk.

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Figures

**Figure 1. Genome-wide and conditional associations between genetic variants and atrial fibrillation**
Associations between genetic variants and atrial fibrillation are displayed (A) across the genome in marginal association analyses as previously reported (12) and (B) at each genome-wide significant susceptibility locus after adjustment for the genotype of the most significantly associated SNP at that locus.

**Figure 2. Regional association between variants on chromosome 4q25 and atrial fibrillation after adjustment for the top SNP at the locus in the AFGen sample**
Associations between SNPs and atrial fibrillation at the chromosome 4q25 locus (A) before and (B) after adjustment for the genotype of the top SNP (rs6817105) are displayed. Additional distinct susceptibility signals discovered in this analysis are represented by purple circles and are labeled. The strength of linkage disequilibrium between genetic variants in relation to rs6817105 is indicated by the color gradient as denoted in the legend. The region displayed is limited to a 310 kb segment containing the associated non-redundant signals. Linkage data and recombination rates are derived from the HapMap phase II CEU panel.

**Figure 3. Graded relative risk of atrial fibrillation stratified by the number of susceptibility alleles in Europeans and Japanese**
The risk of atrial fibrillation is plotted according to the unweighted number of estimated distinct atrial fibrillation risk alleles, relative to that among individuals with the most common number of estimated risk alleles for (A) chromosome 4q25, and (B) all genome-wide significant atrial fibrillation susceptibility loci in individuals of European ancestry from AFGen. Replicated associations in the BioBank Japan sample are displayed in (C) and (D), respectively. The distribution of risk alleles in the sample is displayed in the bar graph to the left of the risk plots. The AF risk alleles are listed in Table 3.

See this image and copyright information in PMC

Comment in

Atrial fibrillation genomics: time to take the next step.
Roden DM. Roden DM. J Am Coll Cardiol. 2014 Apr 1;63(12):1211-1213. doi: 10.1016/j.jacc.2013.12.016. Epub 2014 Jan 30. J Am Coll Cardiol. 2014. PMID: 24486270 No abstract available.

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References

1. Fox CS, Parise H, D'Agostino RB, Sr., et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004;291:2851–5. - PubMed
1. Ellinor PT, Yoerger DM, Ruskin JN, MacRae CA. Familial aggregation in lone atrial fibrillation. Hum Genet. 2005;118:179–84. - PubMed
1. Arnar DO, Thorvaldsson S, Manolio TA, et al. Familial aggregation of atrial fibrillation inIceland. Eur Heart J. 2006;27:708–12. - PubMed
1. Marcus GM, Smith LM, Vittinghoff E, et al. A first-degree family history in lone atrial fibrillation patients. Heart Rhythm. 2008;5:826–30. - PMC - PubMed
1. Christophersen IE, Ravn LS, Budtz-Joergensen E, et al. Familial aggregation of atrial fibrillation: a study in Danish twins. Circ Arrhythm Electrophysiol. 2009;2:378–83. - PMC - PubMed

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[1] Fox CS, Parise H, D'Agostino RB, Sr., et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004;291:2851–5. - PubMed

[2] Fox CS, Parise H, D'Agostino RB, Sr., et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004;291:2851–5. - PubMed

[3] Ellinor PT, Yoerger DM, Ruskin JN, MacRae CA. Familial aggregation in lone atrial fibrillation. Hum Genet. 2005;118:179–84. - PubMed

[4] Ellinor PT, Yoerger DM, Ruskin JN, MacRae CA. Familial aggregation in lone atrial fibrillation. Hum Genet. 2005;118:179–84. - PubMed

[5] Arnar DO, Thorvaldsson S, Manolio TA, et al. Familial aggregation of atrial fibrillation inIceland. Eur Heart J. 2006;27:708–12. - PubMed

[6] Arnar DO, Thorvaldsson S, Manolio TA, et al. Familial aggregation of atrial fibrillation inIceland. Eur Heart J. 2006;27:708–12. - PubMed

[7] Marcus GM, Smith LM, Vittinghoff E, et al. A first-degree family history in lone atrial fibrillation patients. Heart Rhythm. 2008;5:826–30. - PMC - PubMed

[8] Marcus GM, Smith LM, Vittinghoff E, et al. A first-degree family history in lone atrial fibrillation patients. Heart Rhythm. 2008;5:826–30. - PMC - PubMed

[9] Christophersen IE, Ravn LS, Budtz-Joergensen E, et al. Familial aggregation of atrial fibrillation: a study in Danish twins. Circ Arrhythm Electrophysiol. 2009;2:378–83. - PMC - PubMed

[10] Christophersen IE, Ravn LS, Budtz-Joergensen E, et al. Familial aggregation of atrial fibrillation: a study in Danish twins. Circ Arrhythm Electrophysiol. 2009;2:378–83. - PMC - PubMed

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Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

Affiliations

Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese

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