Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.
OBJECTIVE
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.
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Steven A
SA
Lubitz
Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.|Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.
Kathryn L
KL
Lunetta
Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.|Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Honghuang
H
Lin
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Dan E
DE
Arking
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.|Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Stella
S
Trompet
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Guo
G
Li
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.
Bouwe P
BP
Krijthe
Harvard Medical School, Boston, Massachusetts, USA.|Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Daniel I
DI
Chasman
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
John
J
Barnard
Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
Marcus E
ME
Kleber
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
Marcus
M
Dörr
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Kouichi
K
Ozaki
Icelandic Heart Association, Kopavogur Iceland and University of Iceland Reykjavik, Iceland.
Albert V
AV
Smith
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.|Institute of Genetic Epidemiology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians University, Munich, Germany.
Martina
M
Müller-Nurasyid
Department of Society, Human Development & Health, Harvard School of Public Health, Boston, Massachusetts, USA.
Stefan
S
Walter
Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.
Sunil K
SK
Agarwal
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Joshua C
JC
Bis
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Jennifer A
JA
Brody
Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Lin Y
LY
Chen
Harvard Medical School, Boston, Massachusetts, USA.|Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Brendan M
BM
Everett
Robertson Center for Biostatistics, University of Glasgow, United Kingdom.
Ian
I
Ford
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.
Oscar H
OH
Franco
Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Tamara B
TB
Harris
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.
Albert
A
Hofman
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.|Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner site Munich Heart Alliance, Munich, Germany.
Stefan
S
Kääb
Leeds General Infirmary, Great George Street, Leeds, UK.
Saagar
S
Mahida
Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Sekar
S
Kathiresan
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Michiaki
M
Kubo
Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Lenore J
LJ
Launer
Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom.
Peter W
PW
MacFarlane
Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.|Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Jared W
JW
Magnani
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
Barbara
B
McKnight
Departments of Medicine and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
David D
DD
McManus
Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner site Munich Heart Alliance, Munich, Germany.|Institute of Epidemiology II, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.
Annette
A
Peters
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Health Services, University of Washington, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
Bruce M
BM
Psaty
Division of Preventive Medicine, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Lynda M
LM
Rose
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif, USA.
Jerome I
JI
Rotter
Department of Angiology, Swiss Cardiovascular Centre, Bern University Hospital, Bern, Switzerland.
Guenther
G
Silbernagel
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Jonathan D
JD
Smith
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.|Division of Cardiology, University of Washington, Seattle, Washington, USA.
Nona
N
Sotoodehnia
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
David J
DJ
Stott
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Kent D
KD
Taylor
Department of Cardiology, Medical University of Graz, Graz, Austria.
Andreas
A
Tomaschitz
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Tatsuhiko
T
Tsunoda
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Andre G
AG
Uitterlinden
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
David R
DR
Van Wagoner
DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.|Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
Uwe
U
Völker
DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.|Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
Henry
H
Völzke
Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.|Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Joanne M
JM
Murabito
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Moritz F
MF
Sinner
Icelandic Heart Association, Kopavogur Iceland and University of Iceland Reykjavik, Iceland.
Vilmundur
V
Gudnason
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.|DZHK (German Centre for Cardiovascular Research), Partner site Greifswald, Germany.
Stephan B
SB
Felix
Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.|Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.|Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
Winfried
W
März
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Mina
M
Chung
Harvard Medical School, Boston, Massachusetts, USA.|Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Preventive Medicine, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Christine M
CM
Albert
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.|Inspectorate for Health Care, the Hague, The Netherlands.
Bruno H
BH
Stricker
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.|Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Toshihiro
T
Tanaka
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.
Susan R
SR
Heckbert
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
J Wouter
JW
Jukema
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, USA.
Alvaro
A
Alonso
Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.|Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.|Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.|Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Emelia J
EJ
Benjamin
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Patrick T
PT
Ellinor
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D001281:Atrial Fibrillation / Q000235:genetics*; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4; D005060:Europe; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics; D000097577:Homeobox Protein PITX2
D005819:Genetic Markers; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
atrial fibrillation; atrial flutter; genetic; prognosis; risk