Polygenic risk score approach

A method which combines multiple genetic instrumental variables (IVs) into a single univariate score, which can then be used as a single IV.

Traditionally used with individual-level data to generate the polygenic risk score (PRS) and combined using one-sample MR methodology (e.g., two-stage least squares (TSLS)). If summary statistics from the associations between the PRS and exposure and the PRS and outcome can be obtained, these can used to derive MR estimates with two-sample MR methodology (e.g., Wald ratio). Importantly, the univariate score must be a valid IV. This method is more robust to weak instrument bias than TSLS but it is hard to test for IV validity.

References

• Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Statistics in medicine 2016; 35: 1880-1906.

Other terms in 'One-sample MR methods':

• Generalized Method of Moments (GMM) estimator
• MR with a time-to-event outcome
• Non-parametric methods with bounds of causal effect
• Structural Mean Models (SMMs)
• Two-stage least squares (TSLS)
• Two-stage least squares (TSLS) with binary outcomes
• Two-stage predictor substitution estimators
• Two-stage residual inclusion estimators
• Within-family MR