ArticleInternational journal of epidemiology2021
Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations.
Article in International journal of epidemiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 7 of them syntheses that pooled it.
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Who cites it
72 citing papers in PubMed, 7 syntheses or guidelines pooled it.
- The influence of fetal sex on maternal blood pressure in pregnancy.BMC medicine · 2025Pooled it
- Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes.Nature genetics · 2023Pooled it
- Appraising the causal relationship between plasma caffeine levels and neuropsychiatric disorders through Mendelian randomization.BMC medicine · 2023Pooled it
- The influence of growth and sex hormones on risk of alzheimer's disease: a mendelian randomization study.European journal of epidemiology · 2023Pooled it
- Genetic association and causal inference between lung function and venous thromboembolism.Respiratory research · 2023Pooled it
- Blood copper and risk of cardiometabolic diseases: a Mendelian randomization study.Human molecular genetics · 2022Pooled it
- Systematic review and meta-analyses: What has the application of Mendelian randomization told us about the causal effect of adiposity on health outcomes?Wellcome open research · 2022Pooled it
- UK BioCoin: swift trait-specific summary statistics regression for UK Biobank.Nature communications · 2026Article
- Genetically mediated causal relationship between gut microbiota composition and childhood obesity.Pediatric research · 2026Article
- Assessing the impact of maternal blood pressure during pregnancy on perinatal health: a wide-angled Mendelian randomization study.BMC medicine · 2026Article
- Disentangling mature cow weight and body condition score: a comparative single-step GWAS of phenotypic pre-adjustment vs. recursive modeling.Journal of animal science · 2026Article
- Causal Effects of Atrial Fibrillation and Warfarin Use on Osteoporosis Risk: A Two-Sample Mendelian Randomization Analysis.International journal of genomics · 2026Article
- Phosphodiesterase-5 Inhibition and Alzheimer's Disease Risk: A Mendelian Randomisation Study.Aging cell · 2025Article
- Contribution of leukocyte telomere length to cardiovascular disease onset from genome-wide cross-trait analysis.Nature communications · 2025Article
- Obstructive sleep apnea mediates genetic risk of Diabetes Mellitus in Hispanic and Latino communities.Communications medicine · 2025Article
- A semi-empirical Bayes approach for calibrating weak instrumental bias in sex-specific Mendelian randomization studies.American journal of human genetics · 2025Article
- Plasma proteomic profiles reveal proteins and three characteristic patterns associated with osteoporosis: A prospective cohort study.Journal of advanced research · 2025Article
- Genetically proxied blood pressure, vascular brain injury, and Alzheimer's disease pathology.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Causal association of modifiable factors with cardiometabolic multimorbidity: an exposome-wide Mendelian randomization investigation.Cardiovascular diabetology · 2025Observational
- Causal Effects of Breast Cancer Risk Factors across Hormone Receptor Breast Cancer Subtypes: A Two-Sample Mendelian Randomization Study.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2025Article
12 more citing papers are in PubMed but not listed here.
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Funding
Abstract
backgroundTwo-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables.
methodsWe performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR.
resultsIn the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index.
conclusionsOur findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.
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