title: FTO association and interaction with time spent sitting.
abstract: OBJECTIVE
  Multiple studies have revealed an interaction between a variant in the FTO gene and self-reported physical activity on body mass index (BMI). Physical inactivity, such as time spent sitting (TSS) has recently gained attention as an important risk factor for obesity and related diseases. It is possible that FTO interacts with TSS to affect BMI, and/or that FTO's putative effect on BMI is mediated through TSS.
  
  
  METHODS
  We tested these hypotheses in two cohorts of the Framingham Heart Study (FHS) (Offspring: n=3430 and Third Generation: n=3888), and attempted to replicate our results in the Women's Health Initiative (WHI; n=4756). Specifically, we examined whether an association exists between FTO and self-reported TSS, and whether an interaction exists between FTO and TSS on BMI, while adjusting for several important covariates such as physical activity.
  
  
  RESULTS
  In FHS, we find a significant positive association between the BMI-increasing FTO allele and TSS. We find a similar trend in WHI. Mediation analyses suggest that the effect of FTO on BMI is mediated through TSS. In FHS, we find a significant interaction of FTO and TSS on BMI, whereby the association of TSS with BMI is greatest among those with more FTO risk alleles. In WHI, we also find a significant interaction, although the direction is opposite to that in FHS. In a meta-analysis of the two data sets, there is no net interaction of FTO with TSS on BMI.
  
  
  CONCLUSIONS
  Our study suggests that FTO exerts its effect on BMI, at least partly, through energy expenditure mechanisms such as TSS. Further research into the intersection of genetics, sedentary behavior and obesity-related outcomes is warranted.
authors.affiliation: Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Klimentidis
authors.affiliation: Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Arora
authors.affiliation: Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Chougule
authors.affiliation: Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Anthropology, University of Arizona, Tucson, AZ, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Raichlen
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics / Q000378:metabolism*; D015992:Body Mass Index; D002149:Energy Intake / Q000235:genetics*; D015444:Exercise; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D057185:Sedentary Behavior
chemical_list: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human