Fig. 4.

Directed acyclic graph illustrating the concept of multivariable Mendelian randomization. Including additional instruments for body mass index (BMI) in the analysis accounts for the horizontal pleiotropy acting via BMI and gives an estimate of the direct effect of bone mineral density (BMD) on hip osteoarthitis (OA) and BMI on hip OA. However, if there is another pleiotropic pathway via an unknown or unmeasured variable (Exposure₃), the effect estimates will still be biased. GRS = genetic risk score.