title: Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke.
abstract: OBJECTIVE
  Atrial fibrillation (AF) is prevalent and there is a clinical need for biomarkers to identify individuals at higher risk for AF. Fixed throughout a life course and assayable early in life, genetic biomarkers may meet this need. Here, we investigate whether multiple single nucleotide polymorphisms together as an AF genetic risk score (AF-GRS) can improve prediction of one's risk for AF.
  
  
  METHODS
  In 27 471 participants of the Malmö Diet and Cancer Study, a prospective, community-based cohort, we used Cox models that adjusted for established AF risk factors to assess the association of AF-GRS with incident AF and ischemic stroke. Median follow-up was 14.4 years for incident AF and 14.5 years for ischemic stroke. The AF-GRS comprised 12 single nucleotide polymorphisms that had been previously shown to be associated with AF at genome-wide significance.
  
  
  RESULTS
  During follow-up, 2160 participants experienced a first AF event and 1495 had a first ischemic stroke event. Participants in the top AF-GRS quintile were at increased risk for incident AF (hazard ratio, 2.00; 95% confidence interval, 1.73-2.31; P=2.7×10(-21)) and ischemic stroke (hazard ratio, 1.23; 95% confidence interval, 1.04-1.46; P=0.02) when compared with the bottom quintile. Addition of the AF-GRS to established AF risk factors modestly improved both discrimination and reclassification (P<0.0001 for both).
  
  
  CONCLUSIONS
  An AF-GRS can identify 20% of individuals who are at ≈2-fold increased risk for incident AF and at 23% increased risk for ischemic stroke. Targeting diagnostic or therapeutic interventions to this subset may prove clinically useful.
authors.affiliation: Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.|Broad Institute, Program in Medical and Population Genetics, Cambridge, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.affiliation: Celera, A Quest Diagnostics Company, Alameda, California.
authors.forename: Dov
authors.initials: D
authors.lastname: Shiffman
authors.affiliation: Department of Cardiology, Lund University, Lund, Sweden.
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Marketa
authors.initials: M
authors.lastname: Sjögren
authors.affiliation: Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.|Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.affiliation: Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.affiliation: Celera, A Quest Diagnostics Company, Alameda, California.
authors.forename: Judy Z
authors.initials: JZ
authors.lastname: Louie
authors.affiliation: Celera, A Quest Diagnostics Company, Alameda, California.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Catanese
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Engström
authors.affiliation: Celera, A Quest Diagnostics Company, Alameda, California.
authors.forename: James J
authors.initials: JJ
authors.lastname: Devlin
authors.affiliation: Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.|Broad Institute, Program in Medical and Population Genetics, Cambridge, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*
keywords: atrial fibrillation; polymorphism, single nucleotide; stroke