Fig 1.

Examples of Mendelian randomisation and potential violations of assumptions. (A) A simplified causal diagram depicting confounding of the association of alcohol consumption and blood pressure by existing disease or social deprivation. The instrumental variable assumptions are that the genetic variants are associated with the risk factor, that theyhave no other influence on the outcome, except through alcohol, and that there are no confounders of the genetic variants-outcome association. (B) Confounding by ancestry could occur if variants associated with alcohol consumption had different frequencies in different ethnic groups in the population sampled and if cultural differences affected blood pressure between ethnic groups. This would violate the second instrumental variable assumption— the independence assumption. (C) An example of horizontal pleiotropy, in which the genetic variants associated with alcohol consumption also affect tobacco consumption (violating the third assumption— the exclusion restriction assumption). (D) An example of vertical pleiotropy, in which the effect of ALDH2 on coronary heart disease is mediated by blood pressure. This example does not violate the Mendelian randomisation assumptions and does not cause bias.