MR Dictionary

Vertical Pleiotropy

Also known as “spurious” or “false” pleiotropy. This is when a genetic variant affects other traits (which influence the outcome) via its effect on the exposure. 

This is the very phenomenon that MR seeks to detect (i.e., the chain of traits to the outcome is what gives rise to an unbiased non-null causal effect estimate). 

Vertical and Horizontal Pleiotropy. Adapted from Hemani et al.  and Holmes et al.  (A) Classic horizontal pleiotropy, whereby the instrument (Z) for the exposure of interest (X) is independently associated with the outcome (Y) either directly or indirectly through other trait(s) – denoted “?”. Here, this would violate the third assumption of MR and would bias results from an MR study. (B) Indirect horizontal pleiotropy, whereby another SNP (Z2) in linkage disequilibrium (LD) with the instrument (Z1) for the exposure of interest (X) is associated with the outcome (Y) and, due to this correlation between SNPs, the instrument is therefore not independent of the outcome of interest. This is another reason to use independent genetic variants as instruments in an MR analysis and to have some biological knowledge about the mechanisms by which the SNPs are associated with the exposure. (C) A depiction of vertical pleiotropy, whereby the genetic instrument (Z) for the exposure (X) is associated with other trait(s) – denoted “?” – however, this reflects the downstream effects of the exposure that is likely on the causal pathway linking the exposure to the outcome (Y). This is the very essence of MR and is not something that needs to be accounted for in analyses. Measured and unmeasured confounders in all diagrams as represented by “U”, “U1” and “U2”.
Figure 4.2 - Vertical and Horizontal Pleiotropy. Adapted from Hemani et al. and Holmes et al. (A) Classic horizontal pleiotropy, whereby the instrument (Z) for the exposure of interest (X) is independently associated with the outcome (Y) either directly or indirectly through other trait(s) – denoted “?”. Here, this would violate the third assumption of MR and would bias results from an MR study. (B) Indirect horizontal pleiotropy, whereby another SNP (Z2) in linkage disequilibrium (LD) with the instrument (Z1) for the exposure of interest (X) is associated with the outcome (Y) and, due to this correlation between SNPs, the instrument is therefore not independent of the outcome of interest. This is another reason to use independent genetic variants as instruments in an MR analysis and to have some biological knowledge about the mechanisms by which the SNPs are associated with the exposure. (C) A depiction of vertical pleiotropy, whereby the genetic instrument (Z) for the exposure (X) is associated with other trait(s) – denoted “?” – however, this reflects the downstream effects of the exposure that is likely on the causal pathway linking the exposure to the outcome (Y). This is the very essence of MR and is not something that needs to be accounted for in analyses. Measured and unmeasured confounders in all diagrams as represented by “U”, “U1” and “U2”.

References

Other terms in 'Sources of bias and limitations in MR':