Mendelian Randomization: New Applications in the Coming Age of Hypothesis-Free Causality.
Mendelian randomization (MR) is an approach that uses genetic variants associated with a modifiable exposure or biological intermediate to estimate the causal relationship between these variables and a medically relevant outcome. Although it was initially developed to examine the relationship between modifiable exposures/biomarkers and disease, its use has expanded to encompass applications in molecular epidemiology, systems biology, pharmacogenomics, and many other areas. The purpose of this review is to introduce MR, the principles behind the approach, and its limitations. We consider some of the new applications of the methodology, including informing drug development, and comment on some promising extensions, including two-step, two-sample, and bidirectional MR. We show how these new methods can be combined to efficiently examine causality in complex biological networks and provide a new framework to data mine high-dimensional studies as we transition into the age of hypothesis-free causality.
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia; email: d.evans1@uq.edu.au.
David M
DM
Evans
George
G
Davey Smith
D001794:Blood Pressure / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D055808:Drug Discovery; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D057182:Mendelian Randomization Analysis; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011897:Random Allocation; D016032:Randomized Controlled Trials as Topic
C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins
causal analysis; genetic epidemiology; mining the phenome; pharmacogenomics; structural equation modeling