Mendelian randomization

Mendelian randomization (MR) uses germline genetic variants — typically single-nucleotide polymorphisms associated with an exposure in a genome-wide association study — as instrumental variables to estimate the causal effect of that exposure on an outcome, exploiting the random allocation of alleles at conception as a natural experiment. The method relies on three core assumptions: the instrument is robustly associated with the exposure (relevance), affects the outcome only through that exposure (exclusion restriction), and is independent of confounders (independence). Violations — through pleiotropy, population stratification, or weak instruments — are major pitfalls; sensitivity analyses including MR-Egger, weighted-median, and CAUSE help detect and partially correct for horizontal pleiotropy. In longevity research, MR has been widely used to test causal links between biomarkers such as LDL-C, CRP, IGF-1, or BMI and lifespan outcomes without requiring decades-long randomized trials.