Fig. 1

Directed acyclic graph (DAG) depicting Mendelian randomization and correlated pleiotropy. A Genetic variants (Z) act as proxies or instruments to investigate if an exposure (X) is associated with a disease outcome (Y). Causal inference can be made between X and Y if the following conditions are upheld: (1) Z is a valid instrument, reliably associated with X (‘relevance’); (2) Z is independent of any measured or unmeasured confounding factors (U) (‘exchangeability’) and (3) there is no independent association between Z and Y except through X (‘exclusion restriction’). B DAG depicting correlated pleiotropy (C) whereby the genetic variant (Z) can affect the exposure (X) and the outcome (Y) via a shared heritable factor (C), for example here through smoking, alcohol, or risk tolerance