60 Mediation Analysis with Mendelian Randomization and Efficient Multiple GWAS Integration

Oregon Convention Center 

Mediation analysis is a powerful tool for studying causal pathways between exposure, mediator, and outcome variables of interest. While classical mediation analysis using observational data often requires strong and sometimes unrealistic assumptions, such as unconfoundedness, Mendelian Randomization (MR) avoids unmeasured confounding bias by employing genetic variants as instrumental variables. We develop a novel MR framework for mediation analysis with
genome-wide associate study (GWAS) summary data, and provide solid statistical guarantees. Our framework efficiently integrates information stored in three independent GWAS summary data and mitigates not only the commonly encountered winner's curse and measurement error bias in MR, but also the loser's
curse and the imperfect IV selection issue, which are tailored to mediation analysis. Our method is also immune to measurement error bias as the estimating equations are carefully adjusted by incorporating estimated conditional variances of the Rao-Blackwellized association effects. Through our theoretical investigations, we show that the proposed method delivers consistent and asymptotically normally distributed effect estimates.

Inverse Variance Weighting

Post-selection Inference

Instrumental Variable

Causal Mediation Analysis

Multivariable Mendelian Randomization 

Section on Statistics in Genomics and Genetics