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Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data

Authors
  • Burgess, Stephen
  • Foley, Christopher N.
  • Zuber, Verena
Type
Published Article
Journal
Annual Review of Genomics and Human Genetics
Publisher
Annual Reviews
Publication Date
Aug 31, 2018
Volume
19
Pages
303–327
Identifiers
DOI: 10.1146/annurev-genom-083117-021731
Source
Annual Reviews
Keywords
License
Green

Abstract

An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious. We review the Mendelian randomization paradigm for making causal inferences using genetic variants. We consider monogenic analysis, in which genetic variants are taken from a single gene region, and polygenic analysis, which includes variants from multiple regions. We focus on answering two questions: When can Mendelian randomization be used to make reliable causal inferences, and when can it be used to make relevant causal inferences?

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