ArticleGenetic epidemiology2022
Disentangling the effects of traits with shared clustered genetic predictors using multivariable Mendelian randomization.
Article in Genetic epidemiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- Multivariable Mendelian Randomization With Weak Instruments: A Comparison of Bayesian and Frequentist Methods.Statistics in medicine · 2026Article
- Integrating immune-cell transcriptomic data with Mendelian randomisation reveals novel causal genes for type 2 diabetes and its complications.Diabetologia · 2026Article
- Article
- Human genetics suggests differing causal pathways from HMGCR inhibition to coronary artery disease and type 2 diabetes.International journal of epidemiology · 2026Article
- A flexible machine learning Mendelian randomization estimator applied to predict the safety and efficacy of sclerostin inhibition.American journal of human genetics · 2025Article
- Association between CKD and Kidney Stones: A Reliable Relationship?Journal of the American Society of Nephrology : JASN · 2025Article
- A multivariable cis-Mendelian randomization method robust to weak instrument bias and horizontal pleiotropy bias.Briefings in bioinformatics · 2025Article
- Estimating Causal Effects on a Disease Progression Trait Using Bivariate Mendelian Randomisation.Genetic epidemiology · 2025Article
- A novel multivariable Mendelian randomization framework to disentangle highly correlated exposures with application to metabolomics.American journal of human genetics · 2024Article
- Robust use of phenotypic heterogeneity at drug target genes for mechanistic insights: Application of cis-multivariable Mendelian randomization to GLP1R gene region.Genetic epidemiology · 2024Article
- Mendelian randomization for cardiovascular diseases: principles and applications.European heart journal · 2023Review
- Using genetic association data to guide drug discovery and development: Review of methods and applications.American journal of human genetics · 2023Review
- MendelianRandomization v0.9.0: updates to an R package for performing Mendelian randomization analyses using summarized data.Wellcome open research · 2023Article
- Disentangling the effects of traits with shared clustered genetic predictors using multivariable Mendelian randomization.Genetic epidemiology · 2022Article
- Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches.American journal of human genetics · 2022Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
When genetic variants in a gene cluster are associated with a disease outcome, the causal pathway from the variants to the outcome can be difficult to disentangle. For example, the chemokine receptor gene cluster contains genetic variants associated with various cytokines. Associations between variants in this cluster and stroke risk may be driven by any of these cytokines. Multivariable Mendelian randomization is an extension of standard univariable Mendelian randomization to estimate the direct effects of related exposures with shared genetic predictors. However, when genetic variants are clustered, due to being located in a single genetic region, a Goldilocks dilemma arises: including too many highly-correlated variants in the analysis can lead to ill-conditioning, but pruning variants too aggressively can lead to imprecise estimates or even lack of identification. We propose multivariable methods that use principal component analysis to reduce many correlated genetic variants into a smaller number of orthogonal components that are used as instrumental variables. We show in simulations that these methods result in more precise estimates that are less sensitive to numerical instability due to both strong correlations and small changes in the input data. We apply the methods to demonstrate the most likely causal risk factor for stroke at the chemokine gene cluster is monocyte chemoattractant protein-1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.