Genetic associations represent the average change in the risk factor or the outcome per additional copy of the reference allele. There is no biological rationale why associations should be expressed with respect to either the major (wildtype) or the minor (variant) allele. In the univariable and multivariable IVW methods, the estimate is not affected by the choice of orientation, as the intercept is fixed at zero. However, in the univariable and multivariable MR‐Egger methods, changing the orientation of the variant affects the intercept term and the causal estimate as the orientation affects the definition of the pleiotropy terms α j and αj′. Consequently, for each choice of orientation, there is a different version of the InSIDE assumption.
