Mendelian randomization studies: a review of the approaches used and the quality of reporting

Boef, A. G. C.; Dekkers, O. M.; le Cessie, S.

doi:10.1093/ije/dyv071

Cited by 610Genetic Associations and EpidemiologyAdvanced Causal Inference TechniquesMeta-analysis and systematic reviews

Mendelian randomization studies: a review of the approaches used and the quality of reporting

Boef, A. G. C., Dekkers, O. M., le Cessie, S.·2015·International Journal of Epidemiology

DOI 10.1093/ije/dyv071

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Abstract

BACKGROUND: Mendelian randomization (MR) studies investigate the effect of genetic variation in levels of an exposure on an outcome, thereby using genetic variation as an instrumental variable (IV). We provide a meta-epidemiological overview of the methodological approaches used in MR studies, and evaluate the discussion of MR assumptions and reporting of statistical methods. METHODS: We searched PubMed, Medline, Embase and Web of Science for MR studies up to December 2013. We assessed (i) the MR approach used; (ii) whether the plausibility of MR assumptions was discussed; and (iii) whether the statistical methods used were reported adequately. RESULTS: Of 99 studies using data from one study population, 32 used genetic information as a proxy for the exposure without further estimation, 44 performed a formal IV analysis, 7 compared the observed with the expected genotype-outcome association, and 1 used both the latter two approaches. The 80 studies using data from multiple study populations used many different approaches to combine the data; 52 of these studies used some form of IV analysis; 44% of studies discussed the plausibility of all three MR assumptions in their study. Statistical methods used for IV analysis were insufficiently described in 14% of studies. CONCLUSIONS: Most MR studies either use the genotype as a proxy for exposure without further estimation or perform an IV analysis. The discussion of underlying assumptions and reporting of statistical methods for IV analysis are frequently insufficient. Studies using data from multiple study populations are further complicated by the combination of data or estimates. We provide a checklist for the reporting of MR studies.

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Published evidence from Mendelian randomisation studies is often hampered by inadequate reporting.
“but the published evidence is often hampered by inadequate reporting”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [22]
Many reports of Mendelian randomisation studies do not clearly state or examine the various assumptions of Mendelian randomisation methods.
“Empirical evidence22 23 24 indicates that many reports of MR studies do not clearly state or examine the various assumptions of MR methods”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [22]
The quality of reporting of Mendelian randomisation studies has been inconsistent.
“As a result, the quality of reporting of these studies has been inconsistent.”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [22]
Little consensus exists around the reporting of Mendelian randomisation studies.
“Despite the growth in MR applications and methods and the increasing relevance of MR findings, little consensus exists around the reporting of MR studies.”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [22]
Many reports of Mendelian randomisation studies report insufficient details on the data sources.
“and report insufficient details on the data sources”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [22]

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Abdominal obesity and lower gray matter volume: a Mendelian randomization study
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The causal effect of malaria on stunting: a Mendelian randomization and matching approach
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Usefulness of Mendelian Randomization in Observational Epidemiology
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The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study
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The causal role of smoking in anxiety and depression: a Mendelian randomization analysis of the HUNT study
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Evaluation of Moderate Alcohol Use and Cognitive Function Among Men Using a Mendelian Randomization Design in the Guangzhou Biobank Cohort Study
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Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population
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A Prospective Study of Leukocyte Telomere Length and Risk of Type 2 Diabetes in Postmenopausal Women
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Vitamin D Status, Filaggrin Genotype, and Cardiovascular Risk Factors: A Mendelian Randomization Approach
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Moderate Alcohol Use and Cardiovascular Disease from Mendelian Randomization
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Apolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study
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Systemic inflammation, genetic susceptibility and lung function
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Mendelian randomization: A novel test of the gateway hypothesis and models of gene–environment interplay
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Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults
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C-reactive protein-associated genetic variants and cancer risk: Findings from FINRISK 1992, FINRISK 1997 and Health 2000 studies
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Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk
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Mendelian randomization suggests non‐causal associations of testosterone with cardiometabolic risk factors and mortality
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Instrumental Variable Estimation of the Causal Effect of Plasma 25-Hydroxy-Vitamin D on Colorectal Cancer Risk: A Mendelian Randomization Analysis
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Association of interleukin-6 circulating levels with coronary artery disease: A meta-analysis implementing mendelian randomization approach
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Polymorphisms of the insulin receptor and the insulin receptor substrates genes in polycystic ovary syndrome: A Mendelian randomization meta-analysis
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Extreme Bilirubin Levels as a Causal Risk Factor for Symptomatic Gallstone Disease
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Genetically predicted testosterone and cardiovascular risk factors in men: a Mendelian randomization analysis in the Guangzhou Biobank Cohort Study
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Smoking Is Associated with, but Does Not Cause, Depressed Mood in Pregnancy – A Mendelian Randomization Study
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Association of a Fasting Glucose Genetic Risk Score With Subclinical Atherosclerosis
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Body mass index and depressive symptoms: instrumental‐variables regression with genetic risk score
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Association between CFH Y402H Polymorphism and Age Related Macular Degeneration in North Indian Cohort
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Genetic Susceptibility to Type 2 Diabetes Is Associated with Reduced Prostate Cancer Risk
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Does High C-reactive Protein Concentration Increase Atherosclerosis? The Whitehall II Study
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Gene variants influencing measures of inflammation or predisposing to autoimmune and inflammatory diseases are not associated with the risk of type 2 diabetes
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Causal Relevance of Blood Lipid Fractions in the Development of Carotid Atherosclerosis
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Association Between C677T Polymorphism of Methylene Tetrahydrofolate Reductase and Congenital Heart Disease
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Vitamin D and Mortality: A Mendelian Randomization Study
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Genetic variation in the lactase gene, dairy product intake and risk for prostate cancer in the European prospective investigation into cancer and nutrition
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RBP4 variants are significantly associated with plasma RBP4 levels and hypertriglyceridemia risk in Chinese Hans
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Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes
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Authors: Boef, A. G. C., Dekkers, O. M., & le Cessie, S.
Affiliations: Leiden University Medical Center (NL)
Corresponding author: Boef, A. G. C.
ORCID: Boef, A. G. C.
Dekkers, O. M.
Venue: International Journal of Epidemiology
Publisher: Oxford University Press (OUP)
Published: 2015-04-01
Volume: 44
Issue: 2
Pages: 496-511
ISSN: 0300-5771 (ISSN-L)
1464-3685
DOI: 10.1093/ije/dyv071
OpenAlex: W2265865881
Cited by: 610
References: 201
Citations by year: 2026: 40 · 2025: 116 · 2024: 241 · 2023: 86 · 2022: 33 · 2021: 23 · 2020: 13 · 2019: 14 · 2018: 9 · 2017: 15 · 2016: 13 · 2015: 6
FWCI: 1.85
Type: journal article
Language: en
Open access: closed
Locations: International Journal of Epidemiology (publishedVersion)
PubMed (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Leiden Repository (Leiden University) (submittedVersion)
Funders: ZonMw (152002040)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
Keywords: Mendelian randomization, instrumental variables, genetic instruments, reporting quality, meta-epidemiology, methodological approaches, reporting checklist
MeSH terms: Genotype, Humans, Research Design, Statistics as Topic, Bias, Causality, Mendelian Randomization Analysis

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Mendelian randomization studies: a review of the approaches used and the quality of reporting

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