Mendelian randomization with proxy exposures: challenges and opportunities.

ABSTRACT: A key challenge in human genetics is the discovery of modifiable causal risk factors for complex traits and diseases. Mendelian randomization (MR) using molecular traits as exposures is a particularly promising approach for identifying such risk factors. Despite early successes with the application of MR to biomarkers such as low-density lipoprotein cholesterol and C-reactive protein, recent studies have revealed a more nuanced picture, with widespread horizontal pleiotropy. Using data from the UK Biobank, we illustrate the issue of horizontal pleiotropy with 2 case studies, one involving glycolysis and the other involving vitamin D synthesis. We demonstrate that, although the measured metabolites (pyruvate or histidine, respectively) do not have a direct causal effect on the outcomes of i

SUBMITTER: Rahu I 

PROVIDER: S-EPMC12693524 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature