Selecting instruments for Mendelian randomization in the wake of genome-wide association studies.
Open accessAbstract
Mendelian randomization (MR) studies typically assess the pathogenic relevance of environmental exposures or disease biomarkers, using genetic variants that instrument these exposures. The approach is gaining popularity-our systematic review reveals a greater than 10-fold increase in MR studies published between 2004 and 2015. When the MR paradigm was first proposed, few biomarker- or exposure-related genetic variants were known, most having been identified by candidate gene studies. However, genome-wide association studies (GWAS) are now providing a rich source of potential instruments for MR analysis. Many early reviews covering the concept, applications and analytical aspects of the MR technique preceded the surge in GWAS, and thus the question of how best to select instruments for MR studies from the now extensive pool of available variants has received insufficient attention. Here we focus on the most common category of MR studies-those concerning disease biomarkers. We consider how the selection of instruments for MR analysis from GWAS requires consideration of: the assumptions underlying the MR approach; the biology of the biomarker; the genome-wide distribution, frequency and effect size of biomarker-associated variants (the genetic architecture); and the specificity of the genetic associations. Based on this, we develop guidance that may help investigators to plan and readers interpret MR studies.
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Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.
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Self-citationExperiments in Plant Hybridisation
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Secretory Phospholipase A2-IIA and Cardiovascular Disease
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Self-citationGenome-wide Association Studies and Human Disease
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Using Multivariable Mendelian Randomization to Disentangle the Causal Effects of Lipid Fractions
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Hepatic nuclear factor 1-α: inflammation, genetics, and atherosclerosis
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Human C-reactive protein (CRP) 1059G/C polymorphism
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Genome-Wide Association Study of Lp-PLA2 Activity and Mass in the Framingham Heart Study
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Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates
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Mendelian randomisation: a new spin or real progress?
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Genome-Wide Association Study of Height and Body Mass Index in Australian Twin Families
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Estimation of Bias in Nongenetic Observational Studies Using “Mendelian Triangulation”
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Self-citationApolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study
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Bayesian Meta-Analysis of Genetic Association Studies with Different Sets of Markers
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Association of a Fasting Glucose Genetic Risk Score With Subclinical Atherosclerosis
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Relation of Age-related Cataract With Obesity and Obesity Genes in an Asian Population
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Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease
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Stillbirth and slow metabolizers of caffeine: comparison by genotypes
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Circulating β-carotene levels and type 2 diabetes—cause or effect?
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The MR-Base platform supports systematic causal inference across the human phenome
Hemani, G., Zheng, J., Elsworth, B., Wade, K. H., Haberland, V., Baird, D., Laurin, C., Burgess, S., Bowden, J., Langdon, R., et al. (2018) · eLife · doi:10.7554/elife.34408 · Cited by 7,959 · see citing works
Facing up to the global challenges of ageing
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Guidelines for performing Mendelian randomization investigations
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Self-citationMendelian randomization in cardiometabolic disease: challenges in evaluating causality
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Self-citationAssociation of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes
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Self-citationThe <i>MS4A</i> gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
Deming, Y., Filipello, F., Cignarella, F., Cantoni, C., Hsu, S., Mikesell, R., Li, Z., Del-Aguila, J. L., Dube, U., Farias, F. G., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau2291 · Cited by 271 · see citing works
“Mendelian randomization uses genetic variation as instrumental variables to analyze whether a specific variable, which can be a treatment or a protein (57), is associated with a specific outcome (AD risk in this case) independently of reverse causation or confounding effects.”
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Lipid lowering and Alzheimer disease risk: A mendelian randomization study
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Pleiotropy-robust Mendelian randomization.
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Maternal psychological distress during pregnancy and childhood health outcomes: a narrative review
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Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers
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“Proteins represent a particularly appealing application of MR as the blood concentrations of manyproteinsareregulatedbygeneticvariants,manyofwhichlieinor near a protein ’ s cognate gene (variants known as cis protein quantitative trait loci [cis-pQTL]) 16 .”
BackgroundLor, G. C. Y., Risch, H. A., Fung, W. T., Au Yeung, S. L., Wong, I. O. L., Zheng, W., & Pang, H. (2019) · Cancer Epidemiology · doi:10.1016/j.canep.2019.101577 · Cited by 27 · see citing works
- Authors
- Swerdlow, D. I., Kuchenbaecker, K. B., Shah, S., Sofat, R., Holmes, M. V., White, J., Mindell, J. S., Kivimaki, M., Brunner, E. J., Whittaker, J. C., Casas, J. P., & Hingorani, A. D.
- Affiliations
- University College London (GB)
- University of Cambridge (GB)
- University of Oxford (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- London School of Hygiene & Tropical Medicine (GB)
- Corresponding author
- Swerdlow, Daniel I
- ORCID
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-06-24
- Volume
- 45
- Issue
- 5
- Pages
- 1600-1616
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- PMC
- PMC5100611
- OpenAlex
- W2462634178
- Cited by
- 387
- References
- 127
- Citations by year
- 2026: 20 · 2025: 56 · 2024: 91 · 2023: 65 · 2022: 39 · 2021: 24 · 2020: 27 · 2019: 26 · 2018: 22 · 2017: 11 · 2016: 5
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- International Journal of Epidemiology (publishedVersion, public-domain)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research (613598, NF-SI-0515-10091, ACF-2015-21-003)
- British Heart Foundation (G0802432, HL036310, 613598, K013351, RG/10/12/28456, FS/07/011, PG/11/63/29011, RG/13/2/30098)
- University College London
- NordForsk (613598, K013351)
- Medical Research Council (HL036310, MR/K013351/1, MR/K006584/1, K013351, 613598, G0802432)
- National Institute on Aging (AG034454, R01AG034454, HL036310, K013351, 613598)
- National Heart, Lung, and Blood Institute (R01HL036310)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- Mendelian randomization, instrument selection, genome-wide association study, disease biomarkers, genetic variants, genetic architecture, genetic specificity
- MeSH terms
- Humans, Genetic Variation, Biomarkers, Causality, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis
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