title: Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization.
abstract: BACKGROUND
  Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI.
  
  
  METHODS
  We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used:FTOgenotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis.
  
  
  RESULTS
  In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32-0.54] kg/m2per A-allele,P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m2per 1-U increase,P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02-1.11] per A-allele,P=0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase,P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m2,P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m2,P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m2,P<0.001). Multivariable adjustment did not significantly change findings.
  
  
  CONCLUSIONS
  Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Neal A
authors.initials: NA
authors.lastname: Chatterjee
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Franco
authors.initials: F
authors.lastname: Giulianini
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Geelhoed
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA; Cardiology and Preventive Medicine Sections, Boston University School of Medicine, Epidemiology Department, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Misialek
authors.affiliation: Department of Epidemiology, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maartje N
authors.initials: MN
authors.lastname: Niemeijer
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Rienstra
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Rose
authors.affiliation: Icelandic Heart Association, Research Institute, Kpoavogur, Iceland and University of Iceland, Reykjavik, Iceland.
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.affiliation: Cardiovascular Research Center and Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA and Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.affiliation: Department of Epidemiology, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Heeringa
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA; Cardiology and Preventive Medicine Sections, Boston University School of Medicine, Epidemiology Department, Boston University School of Public Health, Boston, MA, USA.|Computational Biomedicine Section, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: Cardiovascular Research Center and Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA and Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.affiliation: Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
authors.forename: Elsayed Z
authors.initials: EZ
authors.lastname: Soliman
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Niek
authors.initials: N
authors.lastname: Verweij
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alonso
authors.affiliation: The Framingham Heart Study, Framingham, MA, USA; Cardiology and Preventive Medicine Sections, Boston University School of Medicine, Epidemiology Department, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Icelandic Heart Association, Research Institute, Kpoavogur, Iceland and University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Department of Epidemiology, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Bruno H C
authors.initials: BHC
authors.lastname: Stricker
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: Van Der Harst
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Albert
mesh_terms: D000368:Aged; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics; D001281:Atrial Fibrillation / Q000453:epidemiology / Q000209:etiology*; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011897:Random Allocation; D012307:Risk Factors
chemical_list: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human
keywords: atrial fibrillation; epidemiology; genetics; obesity; prevention & control