title: Causal inference of the effect of adiposity on bone mineral density in adults.
abstract: OBJECTIVE
  The causal effect of adipose tissue on bone mass and the direction of its net influence have not been directly assessed in adult humans. Using the Mendelian randomization analysis, we assessed the causality of adiposity in measurements of bone mass in adult males and females.
  
  
  METHODS
  Subjects consisted of 2154 adults aged 25-54 years from a cross-sectional cohort of the employees of the Electricity Generating Authority of Thailand. Body composition was determined after at least 3 h of fasting using multifrequency bioelectrical impedance analysis. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry. A polymorphism in the fat mass and obesity-associated gene (FTO rs9939609) was used as an instrument in the Mendelian randomization analysis.
  
  
  RESULTS
  The genotype distribution of the FTO rs9939609 polymorphism was 61·1% TT, 33·9% AT and 5·0% AA. The average body mass index (BMI), body fat mass and percentage body fat were 23·9 kg/m(2) (SD = 3·6), 17·9 kg (SD = 6·6) and 26·8% (SD = 7·2), respectively. The FTO rs9939609 polymorphism was significantly correlated with BMI (coefficient = 0·673 kg/m(2) , P < 0·001), body fat mass (coefficient = 0·948 kg, P < 0·001) and percentage body fat (coefficient = 0·759%, P < 0·01). An instrumental variable (IV) regression model, using BMI as the intermediate phenotype, suggested that FTO was a strong IV. Also, the FTO-BMI polymorphism was significantly associated with total hip and femoral neck BMD but was not correlated with total spine BMD, with estimated correlation coefficients of 0·0189 (95% CI: 0·0046, 0·0332), 0·0149 (95% CI: 0·0030, 0·0268) and 0·0025 (95% CI: -0·0131, 0·0136) g/cm(2) , respectively. The variances of BMDs explained by the FTO-BMI were 19·0%, 21·3% and 1·1%, respectively. Similar trends were also observed for the FTO-body fat mass and FTO-percentage body fat correlations.
  
  
  CONCLUSIONS
  Mendelian randomization analysis suggests that adiposity might be causally related to BMD at the femur but not at the spine.
authors.affiliation: Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Daruneewan
authors.initials: D
authors.lastname: Warodomwichit
authors.forename: Chanika
authors.initials: C
authors.lastname: Sritara
authors.forename: Ammarin
authors.initials: A
authors.lastname: Thakkinstian
authors.forename: La-Or
authors.initials: LO
authors.lastname: Chailurkit
authors.forename: Sukit
authors.initials: S
authors.lastname: Yamwong
authors.forename: Wipa
authors.initials: W
authors.lastname: Ratanachaiwong
authors.forename: Boonsong
authors.initials: B
authors.lastname: Ongphiphadhanakul
authors.forename: Piyamitr
authors.initials: P
authors.lastname: Sritara
mesh_terms: D015502:Absorptiometry, Photon; D050154:Adiposity / Q000502:physiology*; D000328:Adult; D001823:Body Composition / Q000502:physiology; D015992:Body Mass Index; D015519:Bone Density / Q000502:physiology*; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged