ArticleGenetic epidemiology2024
Robust use of phenotypic heterogeneity at drug target genes for mechanistic insights: Application of cis-multivariable Mendelian randomization to GLP1R gene region.
Article in Genetic epidemiology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Integrating immune-cell transcriptomic data with Mendelian randomisation reveals novel causal genes for type 2 diabetes and its complications.Diabetologia · 2026Article
- Glucagon-like peptide-1 receptor activation and mental health: a drug-target mendelian randomization study.Translational psychiatry · 2026Article
- Observational
- Article
- Integrating genetic data with biological insight: A practical guide to cis-Mendelian randomization.American journal of human genetics · 2026Review
- Mendelian randomization study of GLP-1R effects on ovarian cancer subtypes mediated by metabolic factors.Communications medicine · 2026Article
- Human genetics suggests differing causal pathways from HMGCR inhibition to coronary artery disease and type 2 diabetes.International journal of epidemiology · 2026Article
- Article
- Investigating the association between GLP-1 receptor agonists and mood disorders: A study integrating real-world data and Mendelian randomization.European psychiatry : the journal of the Association of European Psychiatrists · 2025Article
- Deliberating the striking effect of dual GLP-1R and GIPR agonists on "Diabesity" in light of precision medicine and pharmacogenomics.Metabolism open · 2025Review
- Genetically modeled GLP1R and GIPR agonism reduce binge drinking and alcohol-associated phenotypes: a multi-ancestry drug-target Mendelian randomization study.Molecular psychiatry · 2025Article
- A flexible machine learning Mendelian randomization estimator applied to predict the safety and efficacy of sclerostin inhibition.American journal of human genetics · 2025Article
- Evaluating the Impact of Oral Contraceptives on Pancreatic Cancer Risk: A Two-Sample Mendelian Randomization Analysis.Biomedicines · 2025Article
- A multivariable cis-Mendelian randomization method robust to weak instrument bias and horizontal pleiotropy bias.Briefings in bioinformatics · 2025Article
- Instrumental Variable Methods to Target Hypothetical Estimands With Longitudinal Repeated Measures Data: Application to the STEP 1 Trial.Statistics in medicine · 2025Article
- Causal association of long COVID with brain structure changes: Findings from a 2-sample Mendelian randomization study.medRxiv : the preprint server for health sciences · 2025Article
- Leveraging multimodal neuroimaging and GWAS for identifying modality-level causal pathways to Alzheimer's disease.Imaging neuroscience (Cambridge, Mass.) · 2025Article
- Review
- Extensive co-regulation of neighboring genes complicates the use of eQTLs in target gene prioritization.HGG advances · 2024Article
- Drug-target Mendelian randomisation applied to metabolic dysfunction-associated steatotic liver disease: opportunities and challenges.eGastroenterology · 2024Review
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7 authors.
Funding
Abstract
Phenotypic heterogeneity at genomic loci encoding drug targets can be exploited by multivariable Mendelian randomization to provide insight into the pathways by which pharmacological interventions may affect disease risk. However, statistical inference in such investigations may be poor if overdispersion heterogeneity in measured genetic associations is unaccounted for. In this work, we first develop conditional F statistics for dimension-reduced genetic associations that enable more accurate measurement of phenotypic heterogeneity. We then develop a novel extension for two-sample multivariable Mendelian randomization that accounts for overdispersion heterogeneity in dimension-reduced genetic associations. Our empirical focus is to use genetic variants in the GLP1R gene region to understand the mechanism by which GLP1R agonism affects coronary artery disease (CAD) risk. Colocalization analyses indicate that distinct variants in the GLP1R gene region are associated with body mass index and type 2 diabetes (T2D). Multivariable Mendelian randomization analyses that were corrected for overdispersion heterogeneity suggest that bodyweight lowering rather than T2D liability lowering effects of GLP1R agonism are more likely contributing to reduced CAD risk. Tissue-specific analyses prioritized brain tissue as the most likely to be relevant for CAD risk, of the tissues considered. We hope the multivariable Mendelian randomization approach illustrated here is widely applicable to better understand mechanisms linking drug targets to diseases outcomes, and hence to guide drug development efforts.
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