Gene-gene Interaction Analyses for Atrial Fibrillation.
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.
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Honghuang
H
Lin
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
Martina
M
Mueller-Nurasyid
Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Albert V
AV
Smith
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Dan E
DE
Arking
Cleveland Clinic, Cleveland, OH, USA.
John
J
Barnard
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Traci M
TM
Bartz
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Kathryn L
KL
Lunetta
Department of Biostatistical Sciences, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Kurt
K
Lohman
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
Marcus E
ME
Kleber
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Steven A
SA
Lubitz
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Bastiaan
B
Geelhoed
Department of Cardiology, Leiden University Medical Center, the Netherlands.|Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Stella
S
Trompet
Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
Maartje N
MN
Niemeijer
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Tim
T
Kacprowski
Division of Preventive Medicine, Brigham and Women's Hospital, Boston MA, USA.
Daniel I
DI
Chasman
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Derek
D
Klarin
Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.
Moritz F
MF
Sinner
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.|Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Melanie
M
Waldenberger
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
Thomas
T
Meitinger
National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Tamara B
TB
Harris
National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Lenore J
LJ
Launer
Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC, USA.
Elsayed Z
EZ
Soliman
Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
Lin Y
LY
Chen
Cleveland Clinic, Cleveland, OH, USA.
Jonathan D
JD
Smith
Cleveland Clinic, Cleveland, OH, USA.
David R
DR
Van Wagoner
Institute for Translational Genomics and Population Sciences (J.I.R.), Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
Jerome I
JI
Rotter
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
Bruce M
BM
Psaty
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Zhijun
Z
Xie
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Mathematical and Statistical Sciences, University of Colorado, Denver, Denver, CO, USA.
Audrey E
AE
Hendricks
Department of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Jingzhong
J
Ding
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
Graciela E
GE
Delgado
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Niek
N
Verweij
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Pim
P
van der Harst
Institute of Health and Wellbeing, College of Veterinary, Medical and Life Sciences, University of Glasgow, United Kingdom.
Peter W
PW
Macfarlane
Robertson Center for Biostatistics, University of Glasgow, United Kingdom.
Ian
I
Ford
Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
Albert
A
Hofman
Department of Epidemiology &Internal Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
André
A
Uitterlinden
Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
Jan
J
Heeringa
Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.
Oscar H
OH
Franco
Department of Medical Informatics, Erasmus MC - University Medical Center Rotterdam, the Netherlands.
Jan A
JA
Kors
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
Stefan
S
Weiss
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Henry
H
Völzke
Division of Preventive Medicine, Brigham and Women's Hospital, Boston MA, USA.
Lynda M
LM
Rose
Harvard Medical School, Boston, MA, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Pradeep
P
Natarajan
Harvard Medical School, Boston, MA, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Sekar
S
Kathiresan
Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
Stefan
S
Kääb
Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Vilmundur
V
Gudnason
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
Alvaro
A
Alonso
Cleveland Clinic, Cleveland, OH, USA.
Mina K
MK
Chung
Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.|Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
Susan R
SR
Heckbert
National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.|Section of Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.|Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
Emelia J
EJ
Benjamin
Department of Epidemiology &Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Yongmei
Y
Liu
Synlab Academy, Synlab Services, GmbH P5,7, 68161 Mannheim, Germany.|Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.|Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Winfried
W
März
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Michiel
M
Rienstra
Department of Cardiology, Leiden University Medical Center, the Netherlands.
J Wouter
JW
Jukema
Department of Epidemiology &Internal Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands.|Inspectorate of Health Care, Utrecht, the Netherlands.
Bruno H
BH
Stricker
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
Marcus
M
Dörr
Division of Preventive Medicine, Brigham and Women's Hospital, Boston MA, USA.
Christine M
CM
Albert
Harvard Medical School, Boston, MA, USA.
Patrick T
PT
Ellinor
D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics*; D015331:Cohort Studies; D004843:Epistasis, Genetic; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009124:Muscle Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics
C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D026901:Membrane Transport Proteins; D009124:Muscle Proteins; D015221:Potassium Channels; C065171:cif nucleoside transporter