Background
Adiponectin is a protein hormone produced by adipocytes that may play an important role in obesity. However, the causal interrelation between plasma adiponectin and body mass index (BMI) is still uncertain. We tested the hypotheses that (a) plasma adiponectin and BMI are inversely associated observationally, (b) genetically high BMI is associated with lower plasma adiponectin, and (c) genetically high plasma adiponectin is associated with lower BMI.

Methods
Information on 108 896 individuals from the Copenhagen General Population Study was used in observational and bidirectional one-sample Mendelian randomization analyses, using 5 genetic variants for BMI and 3 for adiponectin. For independent confirmation, information on 322 154 individuals from the GIANT consortium, and 29 347 individuals from the ADIPOGen consortium was used in bidirectional two-sample Mendelian randomization analysis, using 68 genetic variants for BMI and 14 for adiponectin.

Results
In observational analyses, a 1 kg/m2 increase in BMI was associated with −0.44 µg/mL (95% confidence interval: −0.46, −0.42) in plasma adiponectin, whereas a 1 µg/mL increase in plasma adiponectin was associated with −0.11 kg/m2 (−0.12, −0.11) in BMI. In causal genetic analyses, no associations were observed between BMI and plasma adiponectin and vice versa. In one-sample Mendelian randomization analyses, a 1 kg/m2 genetically determined increase in BMI was associated with −0.13 µg/mL (−0.53, 0.28) in plasma adiponectin, whereas a 1 µg/mL genetically determined increase in plasma adiponectin was associated with 0.01 kg/m2 (−0.05, 0.07) in BMI. Corresponding estimates in the two-sample Mendelian randomization analyses were 0.03 µg/mL (−0.02, 0.07) and 0.03 kg/m2(−0.02, 0.07), respectively.

Conclusions
Observationally, plasma adiponectin and BMI are inversely associated. In contrast, genetically high plasma adiponectin is unlikely to influence BMI, and genetically high BMI is unlikely to influence plasma adiponectin.