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

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Foley, Christopher N 

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? Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see for revised estimates.

causal inference, drug discovery, genetic epidemiology, instrumental variable, target validation, Causality, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Risk Factors
Journal Title
Annual Review of Genomics and Human Genetics
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Annual Reviews, Inc.
Medical Research Council (MR/L003120/1)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)