Mind the gap: characterizing bias due to population mismatch in two-sample Mendelian randomization.

ABSTRACT: Mendelian randomization (MR) is a statistical method for estimating causal effects using genetic variants as instrumental variables. In two sample MR (2SMR), different study samples are used to estimate genetic associations with the exposure and outcome. For valid inference, these studies must include individuals from the same population. Using studies from different populations may bias the 2SMR estimate due to differences in linkage disequilibrium or genetic effects on the exposure trait. We show that violation of the same-population assumption leads to bias in the causal estimate towards zero on average, and does not increase the rate of false positives. We verify this result in a broad survey of 2SMR estimates, comparing estimates made with matching and mismatching populations across 5

SUBMITTER: Li J 

PROVIDER: S-EPMC12324648 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature