Causal inference of the effect of adiposity on bone mineral density in adults

Abstract

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. Subjects consisted of 2154 adults aged 25-54years from a cross-sectional cohort of the employees of the Electricity Generating Authority of Thailand. Body composition was determined after at least 3h 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. 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 23·9kg/m(2) (SD=3·6), 17·9kg (SD=6·6) and 26·8% (SD=7·2), respectively. The FTO rs9939609 polymorphism was significantly correlated with BMI (coefficient=0·673kg/m(2) , P<0·001), body fat mass (coefficient=0·948kg, 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. Mendelian randomization analysis suggests that adiposity might be causally related to BMD at the femur but not at the spine.