ArticlePLoS genetics2022
A practical problem with Egger regression in Mendelian randomization.
Article in PLoS genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 4 of them syntheses that pooled it.
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25 citing papers in PubMed, 4 syntheses or guidelines pooled it, 27 citations in OpenAlex.
- Elevated C-reactive protein to albumin ratio is a promising predictive biomarker for prognosis in patients with renal cell carcinoma.Annals of medicine · 2026Pooled it
- Disentangling the inverse relationship between cancer and Alzheimer's or Parkinson's disease: A systematic review on Mendelian randomization studies.Neurobiology of disease · 2025Pooled it
- Efficacy of traditional Chinese medicineFrontiers in medicine · 2024Pooled it
- Significant association between high neutrophil-lymphocyte ratio and poor prognosis in patients with hepatocellular carcinoma: a systematic review and meta-analysis.Frontiers in immunology · 2023Pooled it
- Decoding causal m6A: a bioinformatics roadmap for psychiatric disorders.Briefings in bioinformatics · 2026Review
- Single-cell RNA sequencing reveals immune regulatory mechanisms and molecular therapeutic strategies in the microenvironment of multiple myeloma.International journal of surgery (London, England) · 2026Article
- Getting to GRIPS with MR-Egger: Modelling directional pleiotropy independently of allele coding.PLoS genetics · 2025Article
- Bioinformatics analysis of IFI6 as a novel prognostic biomarker and its correlation with immune infiltration in breast cancer.Scientific reports · 2025Article
- KAZN methylation as a potential diagnostic and prognostic marker in non-small cell lung cancer.iScience · 2025Article
- Celiac Disease Increases the Risk of Multiple Sclerosis: Evidence from Mendelian Randomization and the Role of CCL19.Experimental neurobiology · 2025Article
- Genetically predicted inflammatory proteins mediate the association between gut microbiota and renal cell carcinoma.Discover oncology · 2025Article
- Causal role of oxidative stress in age-related macular degeneration: a bidirectional Mendelian randomization study.International journal of ophthalmology · 2025Article
- Causal relationship between inflammatory bowel disease and cardiovascular disease: a two-sample Mendelian randomized study.Archives of medical science : AMS · 2025Article
- The Impact of Triglycerides on Rheumatoid Arthritis: Risk Factor and Mendelian Randomization Study.Open access rheumatology : research and reviews · 2025Article
- Omega-3 Polyunsaturated Fatty Acids as a Protective Factor for Myopia.American journal of ophthalmology · 2024Article
- Article
- A robust cis-Mendelian randomization method with application to drug target discovery.Nature communications · 2024Article
- Mendelian randomisation and mediation analysis of self-reported walking pace and coronary artery disease.Scientific reports · 2024Article
- Collider bias correction for multiple covariates in GWAS using robust multivariable Mendelian randomization.PLoS genetics · 2024Article
- The causality between use of glucocorticoids and risk of pancreatitis: a Mendelian randomization study.Frontiers in immunology · 2024Article
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Authors and funding
3 authors at 2 institutions in 1 country.
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Abstract
Mendelian randomization (MR) is an instrumental variable (IV) method using genetic variants such as single nucleotide polymorphisms (SNPs) as IVs to disentangle the causal relationship between an exposure and an outcome. Since any causal conclusion critically depends on the three valid IV assumptions, which will likely be violated in practice, MR methods robust to the IV assumptions are greatly needed. As such a method, Egger regression stands out as one of the most widely used due to its easy use and perceived robustness. Although Egger regression is claimed to be robust to directional pleiotropy under the instrument strength independent of direct effect (InSIDE) assumption, it is known to be dependent on the orientations/coding schemes of SNPs (i.e. which allele of an SNP is selected as the reference group). The current practice, as recommended as the default setting in some popular MR software packages, is to orientate the SNPs to be all positively associated with the exposure, which however, to our knowledge, has not been fully studied to assess its robustness and potential impact. We use both numerical examples (with both real data and simulated data) and analytical results to demonstrate the practical problem of Egger regression with respect to its heavy dependence on the SNP orientations. Under the assumption that InSIDE holds for some specific (and unknown) coding scheme of the SNPs, we analytically show that other coding schemes would in general lead to the violation of InSIDE. Other related MR and IV regression methods may suffer from the same problem. Cautions should be taken when applying Egger regression (and related MR and IV regression methods) in practice.
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