Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches.
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Authors
Zuber, Verena
Grinberg, Nastasiya F
Gill, Dipender
Manipur, Ichcha
Slob, Eric AW
Patel, Ashish
Wallace, Chris
Publication Date
2022-05-05Journal Title
Am J Hum Genet
ISSN
0002-9297
Publisher
Elsevier BV
Volume
109
Issue
5
Pages
767-782
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Zuber, V., Grinberg, N. F., Gill, D., Manipur, I., Slob, E. A., Patel, A., Wallace, C., & et al. (2022). Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches.. Am J Hum Genet, 109 (5), 767-782. https://doi.org/10.1016/j.ajhg.2022.04.001
Abstract
Mendelian randomization and colocalization are two statistical approaches that can be applied to summarized data from genome-wide association studies (GWASs) to understand relationships between traits and diseases. However, despite similarities in scope, they are different in their objectives, implementation, and interpretation, in part because they were developed to serve different scientific communities. Mendelian randomization assesses whether genetic predictors of an exposure are associated with the outcome and interprets an association as evidence that the exposure has a causal effect on the outcome, whereas colocalization assesses whether two traits are affected by the same or distinct causal variants. When considering genetic variants in a single genetic region, both approaches can be performed. While a positive colocalization finding typically implies a non-zero Mendelian randomization estimate, the reverse is not generally true: there are several scenarios which would lead to a non-zero Mendelian randomization estimate but lack evidence for colocalization. These include the existence of distinct but correlated causal variants for the exposure and outcome, which would violate the Mendelian randomization assumptions, and a lack of strong associations with the outcome. As colocalization was developed in the GWAS tradition, typically evidence for colocalization is concluded only when there is strong evidence for associations with both traits. In contrast, a non-zero estimate from Mendelian randomization can be obtained despite only nominally significant genetic associations with the outcome at the locus. In this review, we discuss how the two approaches can provide complementary information on potential therapeutic targets.
Keywords
Causal inference, Genetic epidemiology, phenome-wide association study, post-GWAS investigations, shared heritability, Causality, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Phenotype
Sponsorship
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MC_UU_00002/4)
Medical Research Council (MC_UU_00002/7)
National Institute for Health Research (IS-BRC-1215-20014)
Wellcome Trust (220788/Z/20/Z)
Identifiers
35452592, PMC7612737
External DOI: https://doi.org/10.1016/j.ajhg.2022.04.001
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337446
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