Background
Cis-Mendelian randomization (cis-MR) uses genetic variants near a gene to estimate the causal effect of molecular traits (e.g., proteins) on disease. It is widely used for drug target validation but is prone to bias from linkage disequilibrium, weak instruments, and confounding within gene regions.
Findings
Robust instrument selection, colocalization analysis, and sensitivity testing are essential to ensure valid cis-MR results, while interpretation must consider biological context, as the method is powerful for drug target evaluation but sensitive to misuse.
Conclusions
Cis-MR is a valuable tool for causal inference and therapeutic target validation, but requires careful design and interpretation. Best practice includes combining MR with colocalization and complementary evidence to ensure reliable conclusions.