Figure 1. Possible explanations for associations of SNPs and intelligence, education and outcomes later in life.

(A) Vertical pleiotropy: SNPs associated with intelligence and educational attainment could be vertically pleiotropic. This could occur if all of the effect of the SNPs on the outcomes is mediated via their effects on intelligence, the effect of intelligence on educational attainment, and the effect of educational attainment on the outcome. Confounders omitted from this figure for clarity. (B) Horizontal pleiotropy: The SNPs could be associated with the outcome via intelligence and educational attainment because of horizontal pleiotropy. This would occur if the SNPs had effects on the outcome via intelligence or education that were not mediated via the other trait. (C) Confounding pleiotropy: The SNPs could be associated with the outcomes, intelligence and educational attainment because of the effect of the SNPs on intelligence, and hence education, but that education had no direct effect on the outcome (i.e. the effects of the SNPs were entirely mediated via intelligence. This would occur if the SNPs had effects on the outcome via intelligence or education that were not mediated via the other trait (or vice versa). Multivariable Mendelian randomization does not overcome bias due to other pleiotropic effects by pathways other than intelligence or education.