title: Whole Exome Sequencing in Atrial Fibrillation.
abstract: Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.
authors: Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, The Broad Insitute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Steven A
authors: SA
authors: Lubitz
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors: Jennifer A
authors: 0000-0001-8509-148X
authors: JA
authors: Brody
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Nathan A
authors: 0000-0002-4415-7419
authors: NA
authors: Bihlmeyer
authors: Program in Medical and Population Genetics, The Broad Insitute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Carolina
authors: 0000-0001-5267-6756
authors: C
authors: Roselli
authors: Program in Medical and Population Genetics, The Broad Insitute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Lu-Chen
authors: LC
authors: Weng
authors: Program in Medical and Population Genetics, The Broad Insitute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America.|Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Bærum, Norway.
authors: Ingrid E
authors: IE
authors: Christophersen
authors: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.
authors: Alvaro
authors: 0000-0002-2225-8323
authors: A
authors: Alonso
authors: Human Genetics Center, UTHealth, Houston, Texas, United States of America.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Eric
authors: E
authors: Boerwinkle
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Richard A
authors: RA
authors: Gibbs
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors: Joshua C
authors: 0000-0002-3409-1110
authors: JC
authors: Bis
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.|Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors: L Adrienne
authors: LA
authors: Cupples
authors: Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors: Peter J
authors: PJ
authors: Mohler
authors: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors: Deborah A
authors: DA
authors: Nickerson
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Donna
authors: D
authors: Muzny
authors: Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Marco V
authors: 0000-0003-2746-0202
authors: MV
authors: Perez
authors: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, United States of America.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
authors: Bruce M
authors: BM
authors: Psaty
authors: Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors: Elsayed Z
authors: EZ
authors: Soliman
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Division of Cardiology, University of Washington, Seattle, Washington, United States of America.
authors: Nona
authors: N
authors: Sotoodehnia
authors: Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors: Kathryn L
authors: KL
authors: Lunetta
authors: Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.|Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.|Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, United States of America.|Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Emelia J
authors: 0000-0003-4076-2336
authors: EJ
authors: Benjamin
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors: Susan R
authors: SR
authors: Heckbert
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Dan E
authors: DE
authors: Arking
authors: Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, United States of America.|Program in Medical and Population Genetics, The Broad Insitute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Patrick T
authors: PT
authors: Ellinor
authors: Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America.|Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Honghuang
authors: 0000-0003-3043-3942
authors: H
authors: Lin
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D008840:Microfilament Proteins; C551862:SYNPO2L protein, human