Meta-Analysis

. 2016 Nov 8:6:35371.

doi: 10.1038/srep35371.

Gene-gene Interaction Analyses for Atrial Fibrillation

Honghuang Lin^{1

2}, Martina Mueller-Nurasyid^{3

4

5}, Albert V Smith^{6

7}, Dan E Arking⁸, John Barnard⁹, Traci M Bartz¹⁰, Kathryn L Lunetta^{1

11}, Kurt Lohman¹², Marcus E Kleber¹³, Steven A Lubitz^{14

15}, Bastiaan Geelhoed¹⁶, Stella Trompet^{17

18}, Maartje N Niemeijer¹⁹, Tim Kacprowski^{20

21}, Daniel I Chasman²², Derek Klarin^{23

24

25

26}, Moritz F Sinner⁴, Melanie Waldenberger^{5

13

27}, Thomas Meitinger^{5

28

29}, Tamara B Harris³⁰, Lenore J Launer³⁰, Elsayed Z Soliman³¹, Lin Y Chen³², Jonathan D Smith⁹, David R Van Wagoner⁹, Jerome I Rotter³³, Bruce M Psaty^{34

35}, Zhijun Xie², Audrey E Hendricks^{1

36}, Jingzhong Ding³⁷, Graciela E Delgado¹³, Niek Verweij¹⁶, Pim van der Harst¹⁶, Peter W Macfarlane³⁸, Ian Ford³⁹, Albert Hofman¹⁹, André Uitterlinden⁴⁰, Jan Heeringa¹⁹, Oscar H Franco¹⁹, Jan A Kors⁴¹, Stefan Weiss^{20

21}, Henry Völzke^{21

42}, Lynda M Rose²², Pradeep Natarajan^{15

23

24

26}, Sekar Kathiresan^{15

23

24

26}, Stefan Kääb^{4

5}, Vilmundur Gudnason^{6

7}, Alvaro Alonso⁴³, Mina K Chung⁹, Susan R Heckbert^{35

44}, Emelia J Benjamin^{1

45

46}, Yongmei Liu⁴⁷, Winfried März^{48

49

50}, Michiel Rienstra¹⁶, J Wouter Jukema¹⁷, Bruno H Stricker^{40

51}, Marcus Dörr^{21

52}, Christine M Albert²², Patrick T Ellinor¹⁵

Affiliations

¹ National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.
² Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
³ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁴ Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.
⁵ DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
⁶ Icelandic Heart Association, Kopavogur, Iceland.
⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Cleveland Clinic, Cleveland, OH, USA.
¹⁰ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹² Department of Biostatistical Sciences, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹³ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
¹⁴ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁷ Department of Cardiology, Leiden University Medical Center, the Netherlands.
¹⁸ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
¹⁹ Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
²⁰ Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
²¹ DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
²² Division of Preventive Medicine, Brigham and Women's Hospital, Boston MA, USA.
²³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
²⁴ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
²⁶ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
²⁷ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁸ Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ Institute of Human Genetics, Technische Universität München, Munich, Germany.
³⁰ National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³¹ Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC, USA.
³² Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
³³ Institute for Translational Genomics and Population Sciences (J.I.R.), Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
³⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
³⁵ Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
³⁶ Mathematical and Statistical Sciences, University of Colorado, Denver, Denver, CO, USA.
³⁷ Department of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁸ Institute of Health and Wellbeing, College of Veterinary, Medical and Life Sciences, University of Glasgow, United Kingdom.
³⁹ Robertson Center for Biostatistics, University of Glasgow, United Kingdom.
⁴⁰ Department of Epidemiology &Internal Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁴¹ Department of Medical Informatics, Erasmus MC - University Medical Center Rotterdam, the Netherlands.
⁴² Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁴⁴ Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
⁴⁵ Section of Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁴⁶ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁴⁷ Department of Epidemiology &Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁴⁸ Synlab Academy, Synlab Services, GmbH P5,7, 68161 Mannheim, Germany.
⁴⁹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
⁵⁰ Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁵¹ Inspectorate of Health Care, Utrecht, the Netherlands.
⁵² Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.

PMID: 27824142
PMCID: PMC5099695
DOI: 10.1038/srep35371

Meta-Analysis

Gene-gene Interaction Analyses for Atrial Fibrillation

Honghuang Lin et al. Sci Rep. 2016.

. 2016 Nov 8:6:35371.

doi: 10.1038/srep35371.

Authors

Affiliations

¹ National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.
² Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
³ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁴ Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.
⁵ DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
⁶ Icelandic Heart Association, Kopavogur, Iceland.
⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Cleveland Clinic, Cleveland, OH, USA.
¹⁰ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹² Department of Biostatistical Sciences, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹³ Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
¹⁴ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁷ Department of Cardiology, Leiden University Medical Center, the Netherlands.
¹⁸ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
¹⁹ Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
²⁰ Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
²¹ DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
²² Division of Preventive Medicine, Brigham and Women's Hospital, Boston MA, USA.
²³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
²⁴ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
²⁶ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
²⁷ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁸ Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ Institute of Human Genetics, Technische Universität München, Munich, Germany.
³⁰ National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³¹ Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC, USA.
³² Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
³³ Institute for Translational Genomics and Population Sciences (J.I.R.), Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
³⁴ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
³⁵ Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
³⁶ Mathematical and Statistical Sciences, University of Colorado, Denver, Denver, CO, USA.
³⁷ Department of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁸ Institute of Health and Wellbeing, College of Veterinary, Medical and Life Sciences, University of Glasgow, United Kingdom.
³⁹ Robertson Center for Biostatistics, University of Glasgow, United Kingdom.
⁴⁰ Department of Epidemiology &Internal Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁴¹ Department of Medical Informatics, Erasmus MC - University Medical Center Rotterdam, the Netherlands.
⁴² Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁴⁴ Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
⁴⁵ Section of Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁴⁶ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁴⁷ Department of Epidemiology &Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁴⁸ Synlab Academy, Synlab Services, GmbH P5,7, 68161 Mannheim, Germany.
⁴⁹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
⁵⁰ Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁵¹ Inspectorate of Health Care, Utrecht, the Netherlands.
⁵² Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.

PMID: 27824142
PMCID: PMC5099695
DOI: 10.1038/srep35371

Abstract

Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 × 10^-8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10^-7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.

PubMed Disclaimer

Conflict of interest statement

Dr. Ellinor serves as the principal investigator on a grant from Bayer HealthCare to the Broad Institute related to atrial fibrillation. Dr. Psaty serves on the DSMB of a clinical trial funded by the device manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.

Figures

**Figure 1. Regional plot of the interaction between rs7164883 and SNPs close to rs4980345.**
Each dot represents one SNP. The x-axis represents the chromosomal position, whereas the y-axis represents the −log₁₀(P) of the association of the interaction between rs7164883 and each SNP with AF.

**Figure 2. Forest plot of the association of interaction between rs7164883 and rs4980345 with AF in each study.**
Each line represents the 95% confidence interval, and the size is proportional to the number of cases. OR: odds ratio.

See this image and copyright information in PMC

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Gene-gene Interaction Analyses for Atrial Fibrillation

Affiliations

Gene-gene Interaction Analyses for Atrial Fibrillation

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