Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions

Am J Epidemiol. 2012 Feb 15;175(4):332-9. doi: 10.1093/aje/kwr323. Epub 2012 Jan 12.


As with other instrumental variable (IV) analyses, Mendelian randomization (MR) studies rest on strong assumptions. These assumptions are not routinely systematically evaluated in MR applications, although such evaluation could add to the credibility of MR analyses. In this article, the authors present several methods that are useful for evaluating the validity of an MR study. They apply these methods to a recent MR study that used fat mass and obesity-associated (FTO) genotype as an IV to estimate the effect of obesity on mental disorder. These approaches to evaluating assumptions for valid IV analyses are not fail-safe, in that there are situations where the approaches might either fail to identify a biased IV or inappropriately suggest that a valid IV is biased. Therefore, the authors describe the assumptions upon which the IV assessments rely. The methods they describe are relevant to any IV analysis, regardless of whether it is based on a genetic IV or other possible sources of exogenous variation. Methods that assess the IV assumptions are generally not conclusive, but routinely applying such methods is nonetheless likely to improve the scientific contributions of MR studies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Bias
  • Body Mass Index
  • Causality*
  • Confounding Factors, Epidemiologic
  • Data Interpretation, Statistical
  • Epidemiologic Research Design*
  • Evaluation Studies as Topic
  • Genetic Markers
  • Humans
  • Mendelian Randomization Analysis / methods*
  • Mendelian Randomization Analysis / standards
  • Mendelian Randomization Analysis / statistics & numerical data
  • Mental Disorders / genetics
  • Obesity / complications
  • Proteins / genetics
  • Reproducibility of Results


  • Genetic Markers
  • Proteins
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human