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Lookup NU author(s): Dr Karina PatasovaORCiD, Professor Rachel Knevel, Professor Heather CordellORCiD, Dr Arthur PrattORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). Genetic Epidemiology published by Wiley Periodicals LLC.In the last decade, genome-wide association studies (GWAS) have identified tens of thousands of common variants associated with a wide array of complex traits and diseases. Integration of GWAS with molecular data has informed the development of statistical tools for causal gene discovery. In this paper, we give an overview of commonly used causal inference methods and discuss the strengths and limitations of colocalization, Mendelian randomization (MR) and network-based approaches. Colocalization is often used to assess whether the genetic association signals for two traits arise from the same causal variant, thereby strengthening inferred causal associations. MR was developed to tackle issues of confounding and reverse causality, providing a rigorous approach to causal inference and demonstrating improved false discovery rates. Unlike MR, network-based analyses employ a discovery approach and model complex relationships between multiple variables. All causal inference methods are, to varying degrees, susceptible to spurious associations due to genetic confounding, pleiotropy and linkage disequilibrium. Here, we discuss the latest developments in the field of causal gene inference and limitations of these methods. We give an overview of interplay between different approaches as well as practical applications with reference to published examples in context of heart disease.
Author(s): Patasova K, Sedaghati-Khayat B, Knevel R, Cordell HJ, Pratt AG
Publication type: Review
Publication status: Published
Journal: Genetic Epidemiology
Year: 2026
Volume: 50
Issue: 3
Print publication date: 01/04/2026
Online publication date: 02/03/2026
Acceptance date: 23/02/2026
ISSN (print): 0741-0395
ISSN (electronic): 1098-2272
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/gepi.70037
DOI: 10.1002/gepi.70037
