Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.
BACKGROUND
Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.


OBJECTIVE
To study the association of genetic variants with AF at GWAS top loci.


METHODS
In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.


RESULTS
One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).


CONCLUSIONS
We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; The NHLBI's Framingham Heart Study, Framingham, Massachusetts. Electronic address: hhlin@bu.edu.
Honghuang
H
Lin
The NHLBI's Framingham Heart Study, Framingham, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Moritz F
MF
Sinner
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
Jennifer A
JA
Brody
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Dan E
DE
Arking
The NHLBI's Framingham Heart Study, Framingham, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
Kathryn L
KL
Lunetta
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Michiel
M
Rienstra
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
Steven A
SA
Lubitz
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; The NHLBI's Framingham Heart Study, Framingham, Massachusetts.
Jared W
JW
Magnani
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Division of Cardiology, University of Washington, Seattle, Washington.
Nona
N
Sotoodehnia
Department of Biostatistics, University of Washington, Seattle, Washington.
Barbara
B
McKnight
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
David D
DD
McManus
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas.
Eric
E
Boerwinkle
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington; Department of Health Services, University of Washington, Seattle, Washington.
Bruce M
BM
Psaty
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
Jerome I
JI
Rotter
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
Joshua C
JC
Bis
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
Richard A
RA
Gibbs
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
Donna
D
Muzny
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
Christie L
CL
Kovar
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas.
Alanna C
AC
Morrison
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
Mayetri
M
Gupta
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
Aaron R
AR
Folsom
Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany; Munich Heart Alliance, Munich, Germany.
Stefan
S
Kääb
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington.
Susan R
SR
Heckbert
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
Alvaro
A
Alonso
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Patrick T
PT
Ellinor
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; The NHLBI's Framingham Heart Study, Framingham, Massachusetts.
Emelia J
EJ
Benjamin
D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics*
D018398:Homeodomain Proteins; C082157:PRRX1 protein, human; D019947:Receptors, Interleukin-6
Arrhythmia; Atrial fibrillation; Epidemiology; Genetics