Using Mendelian Randomization to Improve the Design of Randomized Trials

Ference, Brian A.; Holmes, Michael V.; Smith, George Davey

doi:10.1101/cshperspect.a040980

Cited by 339Genetic Associations and EpidemiologyAdvanced Causal Inference TechniquesStatistical Methods in Clinical Trials

Using Mendelian Randomization to Improve the Design of Randomized Trials

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Ference, Brian A., Holmes, Michael V., Smith, George Davey·2021·Cold Spring Harbor Perspectives in Medicine

DOI 10.1101/cshperspect.a040980PMC PMC8247560

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Abstract

Randomized controlled trials and Mendelian randomization studies are two study designs that provide randomized evidence in human biological and medical research. Both exploit the power of randomization to provide unconfounded estimates of causal effect. However, randomized trials and Mendelian randomization studies have very different study designs and scientific objectives. As a result, despite sometimes being referred to as "nature's randomized trial," a Mendelian randomization study cannot be used to replace a randomized trial but instead provides complementary information. In this review, we explain the similarities and differences between randomized trials and Mendelian randomization studies, and suggest several ways that Mendelian randomization can be used to directly inform and improve the design of randomized trials illustrated with practical examples. We conclude by describing how Mendelian randomization studies can employ the principles of trial design to be framed as "naturally randomized trials" that can provide a template for the design of future randomized trials evaluating therapies directed against genetically validated targets.

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Mendelian Randomization Studies in Stroke: Exploration of Risk Factors and Drug Targets With Human Genetic Data
Georgakis, M. K., & Gill, D. (2021) · Stroke · doi:10.1161/strokeaha.120.032617 · Cited by 97 · see citing works
Role of the Microbiome in Regulating Bone Metabolism and Susceptibility to Osteoporosis
Cronin, O., Lanham-New, S. A., Corfe, B. M., Gregson, C. L., Darling, A. L., Ahmadi, K. R., Gibson, P. S., Tobias, J. H., Ward, K. A., Τράκα, Μ., et al. (2021) · Calcified Tissue International · doi:10.1007/s00223-021-00924-2 · Cited by 58 · see citing works
A Large Genetic Causal Analysis of the Gut Microbiota and Urological Cancers: A Bidirectional Mendelian Randomization Study
Yin, Z., Liu, B., Feng, S., He, Y., Tang, C., Chen, P., Wang, X., & Wang, K. (2023) · Nutrients · doi:10.3390/nu15184086 · Cited by 57 · see citing works
Low vitamin D concentrations and BMI are causal factors for primary biliary cholangitis: A mendelian randomization study
Xu, H., Wu, Z., Feng, F., Li, Y., & Zhang, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1055953 · Cited by 50 · see citing works
Lipoprotein(a) and cardiovascular disease: sifting the evidence to guide future research
Kamstrup, P. R., Neely, R. D. G., Nissen, S. E., Landmesser, U., Haghikia, A., Costa‐Scharplatz, M., Abbas, C. A., & Nordestgaard, B. G. (2024) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwae032 · Cited by 48 · see citing works
The association between immune cells and breast cancer: insights from Mendelian randomization and meta‐analysis
Xu, W., Zhang, T., Zhu, Z., & Yang, Y. (2024) · International Journal of Surgery · doi:10.1097/js9.0000000000001840 · Cited by 42 · see citing works
TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro
Duan, Q., Wang, H., Su, W., Gu, X., Shen, X., Jiang, Z., Ren, Y., Cao, B., Li, G., Wang, Y., et al. (2024) · BMC Medicine · doi:10.1186/s12916-024-03314-1 · Cited by 41 · see citing works
Human Genomics and Drug DevelopmentPreprint
Schmidt, A. F., Hingorani, A. D., & Finan, C. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a039230 · Cited by 36 · see citing works
PCSK9 Inhibition and Risk of Diabetes: Should We Worry?
Carugo, S., Sirtori, C. R., Corsini, A., Tokgözoğlu, L. S., & Ruscica, M. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01074-y · Cited by 39 · see citing works
Crosstalk between Statins and Cancer Prevention and Therapy: An Update
Grabarek, B. O., Boroń, D., Morawiec, E., Michalski, P., Palazzo-Michalska, V., Pach, Ł., Dziuk, B., Świder, M., & Zmarzły, N. (2021) · Pharmaceuticals · doi:10.3390/ph14121220 · Cited by 34 · see citing works
Association of remnant cholesterol with frailty: findings from observational and Mendelian randomization analyses
Hu, Y., Wang, X., Lin, L., Huan, J.-M., Li, Y., Zhang, L., & Li, Y. (2023) · Lipids in Health and Disease · doi:10.1186/s12944-023-01882-4 · Cited by 32 · see citing works
Review of Mendelian Randomization Studies on Endometrial Cancer
Guo, J.-Z., Wu, Q., Liu, F.-H., Gao, C., Gong, T., & Li, G. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.783150 · Cited by 30 · see citing works
Effect of coffee consumption on thyroid function: NHANES 2007-2012 and Mendelian randomization
Zhao, G., Wang, Z., Ji, J., & Cui, R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1188547 · Cited by 24 · see citing works
Systematic comparison of Mendelian randomisation studies and randomised controlled trials using electronic databases
Sobczyk, M., Zheng, J., Smith, G. D., & Gaunt, T. R. (2023) · BMJ Open · doi:10.1136/bmjopen-2023-072087 · Cited by 24 · see citing works
Self-citation
Identification of Circulating Plasma Proteins as a Mediator of Hypertension-Driven Cardiac Remodeling: A Mediation Mendelian Randomization Study
Hu, Y., Lin, L., Zhang, L., Li, Y., Cui, X., Lu, M., Zhang, Z., Guan, X., Zhang, M., Hao, J., et al. (2024) · Hypertension · doi:10.1161/hypertensionaha.123.22504 · Cited by 23 · see citing works
Causal relationships between CD25 on immune cells and hip osteoarthritis
Luo, H., Zhu, Y., Guo, B., Ruan, Z., Liu, Z., Fan, Z., & Zhao, S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1247710 · Cited by 22 · see citing works
Genetic analysis of the causal relationship between gut microbiota and intervertebral disc degeneration: a two-sample Mendelian randomized study
Zheng, D., Wu, Z., Li, L., Cheng, S., & Chang, J. (2023) · European Spine Journal · doi:10.1007/s00586-023-08059-8 · Cited by 21 · see citing works
Causal Inference with Genetic Data: Past, Present, and FuturePreprint
Pingault, J., Richmond, R. C., & Smith, G. D. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041271 · Cited by 22 · see citing works
Self-citation
B4GALNT3 regulates glycosylation of sclerostin and bone mass
Movérare‐Skrtic, S., Voelkl, J. G. J., Nilsson, K. H., Nethander, M., Luong, T. T. D., Alesutan, I., Li, L., Wu, J., Horkeby, K., Lagerquist, M. K., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104546 · Cited by 22 · see citing works
Causal relationship between Gut Microbiota and Obstructive sleep apnea
Wei, Y., Huang, L., Liu, C., & Qi, M. (2023) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2023.105052 · Cited by 20 · see citing works
Efficacy and safety of PCSK9 inhibitors in patients with diabetes: A systematic review and meta-analysis
Chen, T., Wang, Z., Xie, J., Xiao, S., Li, W., & Liu, N. (2023) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2023.05.033 · Cited by 20 · see citing works
Mendelian randomization in hepatology: A review of principles, opportunities, and challenges
Song, Y., Ye, T., Roberts, L. R., Larson, N. B., & Winham, S. J. (2023) · Hepatology · doi:10.1097/hep.0000000000000649 · Cited by 17 · see citing works
Role of gut microbiota and inflammatory factors in acute respiratory distress syndrome: a Mendelian randomization analysis
Ma, J., Zhu, Z., Yishajiang, Y., Alarjani, K. M., Hong, L., & Luo, L. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1294692 · Cited by 18 · see citing works
A Mendelian randomization study between chronic periodontitis and non‐alcoholic fatty liver disease
Tan, L., He, Y., Wang, T., Gao, X., Fan, W., & Fan, B. (2023) · Journal of Periodontal Research · doi:10.1111/jre.13218 · Cited by 17 · see citing works
Neuropsychiatric disorders, chronotype and sleep: A narrative review of GWAS findings and the application of Mendelian randomization to investigate causal relationships
Crinion, S., Morris, D. W., & Lopez, L. M. (2024) · Genes Brain & Behavior · doi:10.1111/gbb.12885 · Cited by 16 · see citing works
Causal relationship between gut microbiota and chronic renal failure: a two-sample Mendelian randomization study
Liu, X., Mo, J., Yang, X., Peng, L., Zeng, Y., Zheng, Y., & Song, G. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1356478 · Cited by 15 · see citing works
Causal insights into major risk factors for diabetic kidney disease: a comprehensive meta-analysis and Mendelian randomization study
Zhou, Y., Liu, Y., Wu, L., Zhang, Y., Wen, H., Hu, J., Huo, Z., Ju, S., & Sheng, R. (2025) · Renal Failure · doi:10.1080/0886022x.2025.2468741 · Cited by 14 · see citing works
Blood pressure, plasma proteins, and cardiovascular diseases: a network Mendelian randomization and observational study
Meena, D., Huang, J., Smith, A., Yarmolinsky, J., Wu, S., Koskeridis, F., Ko, Y.-H., Dib, M., Antonatos, C., Vasilopoulos, Y., et al. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf725 · Cited by 12 · see citing works
Alcohol drinking, smoking, and cutaneous melanoma risk: Mendelian randomization analysis
Xu, J., Liu, W., Liu, X., Zhou, X., & Li, G. (2023) · Gaceta Sanitaria · doi:10.1016/j.gaceta.2023.102351 · Cited by 13 · see citing works
Treg cells as a protective factor for Hashimoto`s thyroiditis: a Mendelian randomization study
Guo, J., Si, G., & Si, F. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1347695 · Cited by 12 · see citing works
Gut Microbiota and Respiratory Infections: Insights from Mendelian Randomization
Huang, S., Li, J., Zhu, Z., Liu, X., Shen, T., Wang, Y., Ma, Q., Wang, X., Yang, G., Guo, G., et al. (2023) · Microorganisms · doi:10.3390/microorganisms11082108 · Cited by 12 · see citing works
Mendelian Randomization Methods for Causal Inference: Estimands, Identification and Inference
Yao, M., Wang, A., Li, X., & Liu, Z. (2026) · Statistics in Medicine · doi:10.1002/sim.70394 · Cited by 11 · see citing works
Causal relationship between hypertension and ischemic stroke: A two-sample Mendelian randomization study
Zhang, W., Li, Y., Pang, M., & Yue, X. (2024) · Brain Circulation · doi:10.4103/bc.bc_105_23 · Cited by 11 · see citing works
Linking ambient air pollution to mental health: evidence based on the two-sample Mendelian randomization and colocalization study
Fan, H., Li, J., Dou, Y., Yan, Y., Wang, M., Yang, X. Q., & Ma, X. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03196-0 · Cited by 11 · see citing works
Non-Steroidal Anti-Inflammatory Drug Target Gene Associations with Major Depressive Disorders: A Mendelian Randomisation Study Integrating GWAS, eQTLand mQTL Data
He, Q., Wu, K. C. H., Bennett, A. N., Fan, B., Liu, J., Huang, R., Kong, A. P. S., Tian, X. Y., Kwok, M. K., & Chan, K. H. K. (2022) · The Pharmacogenomics Journal · doi:10.1038/s41397-023-00302-1 · Cited by 11 · see citing works
Associations between Serum Mineral Nutrients, Gut Microbiota, and Risk of Neurological, Psychiatric, and Metabolic Diseases: A Comprehensive Mendelian Randomization Study
Li, W., Lv, B., Quan, Y., Zhu, Q., & Zhang, H. (2024) · Nutrients · doi:10.3390/nu16020244 · Cited by 11 · see citing works
Mendelian Randomization Analysis Reveals Causal Factors behind Alzheimer’s Disease Risk: Evidence, Opportunities, and Challenges
Feng, X., Zhang, L., Hou, Y., Ma, W., Ma, J., Chang, X., & Yang, L. (2024) · The journal of prevention of Alzheimer's disease · doi:10.14283/jpad.2024.30 · Cited by 9 · see citing works
Association of sleep traits with male fertility: a two-sample Mendelian randomization study
Lu, S., Ma, Z., Zhou, W., Zeng, H., Ma, J., Deng, H., & Zhang, P. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1353438 · Cited by 11 · see citing works
Association between periodontitis and endometriosis: a bidirectional Mendelian randomization study
Jin, B., Wang, P., Liu, P., Wang, Y., Guo, Y., Wang, C., Jia, Y., Zou, R., Dong, S., & Niu, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1271351 · Cited by 10 · see citing works
Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer’s disease models
Yu, Y., Chen, C. Z.-Y., Celardo, I., Tan, B. W. Z., Hurcomb, J. D., Leal, N. S., Popovic, R., Loh, S. H. Y., & Martins, L. M. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07179-3 · Cited by 11 · see citing works
Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization
Aman, A., Slob, E. A. W., Ward, J., Cullen, B., Graham, N., Lyall, D. M., Sattar, N. A., & Strawbridge, R. J. (2022) · PLoS ONE · doi:10.1371/journal.pone.0279381 · Cited by 10 · see citing works
Association between nonalcoholic fatty liver disease and type 2 diabetes: A bidirectional two-sample mendelian randomization study
Ni, X., Tong, C., Halengbieke, A., Cao, T., Tang, J., Tao, L., Zheng, D., Han, Y., Li, Q., & Yang, X. (2023) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2023.110993 · Cited by 10 · see citing works
Microbiome and its implications in oncogenesis: a Mendelian randomization perspective.
Feng, K., Ren, F., Xing, Z., Zhao, Y., Yang, C., Liu, J., Shang, Q., Wang, X., & Wang, X. (2023) · PubMed Central · Cited by 10 · see citing works
RETRACTED: Genetic link between gut microbiota, immune cells, and rheumatoid arthritis: Mechanism of action of CD28 proteins
Wu, R. T., Cheng, J. L., Qi, Y., & Jiang, X. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.137212 · Cited by 9 · see citing works
Retracted
The mitochondrial DNA copy number and ovary‐related reproductive disorders: A bidirectional two‐sample Mendelian randomization study
Peng, K., Han, X., Wu, C., Lu, Q., & Gao, S. (2024) · International Journal of Gynecology & Obstetrics · doi:10.1002/ijgo.16057 · Cited by 9 · see citing works
Novel insights into immune-gut microbiota interactions in colorectal cancer: a Mendelian randomization study
Liu, Z., Zhou, X., Kuang, L., Chen, Q., Zhao, J., Yin, H., Zhou, Z., Liu, X., Liu, D., Wu, S.-G., et al. (2025) · Infectious Agents and Cancer · doi:10.1186/s13027-025-00653-3 · Cited by 9 · see citing works
Integrating the Biology of Cardiovascular Disease into the Epidemiology of Economic Decision Modelling via Mendelian Randomisation
Ademi, Z., Morton, J. I., Liew, D., Nicholls, S. J., Zoungas, S., & Ference, B. A. (2022) · PharmacoEconomics · doi:10.1007/s40273-022-01183-1 · Cited by 9 · see citing works
Self-citation
Vitamin D Levels and Risk of Male Factor Infertility: A Mendelian Randomization Study
Chi, Y., Xiang, L., Jian, Z., & Liao, B. (2023) · The World Journal of Men s Health · doi:10.5534/wjmh.220109 · Cited by 9 · see citing works
Socioeconomic status, obesity, individual behaviors, diabetes, and risk for frozen shoulder: A Mendelian randomization study
Yang, W., Yang, Y., & Han, B. (2023) · Medicine · doi:10.1097/md.0000000000036470 · Cited by 8 · see citing works
Circulating cytokines and vascular dementia: A bi-directional Mendelian randomization study
Xia, Y., Xu, Z., Zhang, Y., Jiang, D., Zhu, Y., Liang, X., & Sun, R. (2024) · Experimental Gerontology · doi:10.1016/j.exger.2024.112394 · Cited by 8 · see citing works
Association between gut microbiota and acute pancreatitis: a bidirectional Mendelian randomization study
Zhou, F., Liu, Y., Shi, Y., Wu, N., Xie, Y., & Zhou, X. (2024) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.16658 · Cited by 8 · see citing works
Causal associations between disorders of lipoprotein metabolism and ten cardiovascular diseases
Gao, Q., Tan, J., Fan, L., Wang, X., Hua, L., & Cai, J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1023006 · Cited by 8 · see citing works
Starting the journey: Understanding the roles of complement proteins in liver diseases through mendelian randomization
Zavareh, M. S. R., Kim, N., & Yang, J. D. (2024) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0116 · Cited by 8 · see citing works
Cross-sectional studies of the causal link between asthma and osteoporosis: insights from Mendelian randomization and bioinformatics analysis
Chen, L., Li, C., Chen, H., Xie, Y., Su, N. Y., Luo, F., Huang, J., Zhang, R., Chen, L., Chen, B., et al. (2024) · Osteoporosis International · doi:10.1007/s00198-024-07037-0 · Cited by 7 · see citing works
Lipid-lowering drugs and inflammatory bowel disease’s risk: a drug-target Mendelian randomization study
Zhao, J., Chen, R., Luo, M., Gong, H., Li, K., & Zhao, Q. (2024) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-023-01252-1 · Cited by 7 · see citing works
Drug repurposing opportunities for chronic kidney disease
Chen, X., Shen, R., Zhu, D., Luo, S., You, G., Li, R., Hong, X., Li, R., Wu, J., Huang, Y., et al. (2024) · iScience · doi:10.1016/j.isci.2024.109953 · Cited by 7 · see citing works
SGLT2 inhibition, circulating proteins, and insomnia: A mendelian randomization study
Luo, J., Tu, L., Zhou, C., Li, G., Shi, L., & Hu, S. (2024) · Sleep Medicine · doi:10.1016/j.sleep.2024.05.036 · Cited by 7 · see citing works
Gut microbiome and peritoneal inflammation: a new perspective on peritoneal dialysis-associated peritonitis
Xu, P., Zhang, M., Cui, S., Wang, L., Li, Y., Li, Y., & Jiang, C. (2025) · Renal Failure · doi:10.1080/0886022x.2025.2542532 · Cited by 6 · see citing works
Genetically supported causality between gut microbiota, immune cells, and ischemic stroke: a two-sample Mendelian randomization study
Han, S., Wang, Z., Xiao, Y., Ge, Y., Mao, H., & Gao, J. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1402718 · Cited by 6 · see citing works
Particulate matter 2.5 causally increased genetic risk of autism spectrum disorder
Jin, T., Pang, Q., Huang, W., Xing, D., He, Z., Zheng, C., & Zhang, T. (2024) · BMC Psychiatry · doi:10.1186/s12888-024-05564-y · Cited by 6 · see citing works
Inflammatory bowel disease and risk of ophthalmic inflammation-related diseases: a two-sample Mendelian randomization study
Ren, S., Xu, M., Shi, W., Chen, X., Fan, R., Yu, Z., & Li, X. (2024) · International Journal of Ophthalmology · doi:10.18240/ijo.2024.11.17 · Cited by 6 · see citing works
Techniques for randomization and allocation for clinical trials
Miola, A. C., Espósito, A. C. C., & Miot, H. A. (2024) · Jornal Vascular Brasileiro · doi:10.1590/1677-5449.202400462 · Cited by 5 · see citing works
Associations of Education Attainment With Postpartum Depression and the Mediating Exploration: A Mendelian Randomization Study
Wang, X., Zhou, F., Hao, Y., Wu, J., Su, K., Chen, S.-Y., Yu, W., Zhang, C., Wu, Y., & Huang, H. (2025) · Depression and Anxiety · doi:10.1155/da/8835118 · Cited by 5 · see citing works
Implications of Glucagon-like Peptide-1 Receptor Agonists on Thyroid Function and Thyroid Nodules: A Drug Target Mendelian Randomization and Cohort Study
Zhang, Z., Yang, J., & Gao, L. (2025) · Endocrine Practice · doi:10.1016/j.eprac.2025.07.013 · Cited by 5 · see citing works
Causal Relationship Between Serum Zinc Levels and Diabetic Kidney Disease (DKD): A Plasma Proteomics Mediation Study
Zhao, C., Pan, T., Liu, W., Cheng, F., Zhao, X., Yu, S., Yang, Y., Zhang, R., & Sun, W. (2025) · Biological Trace Element Research · doi:10.1007/s12011-025-04782-z · Cited by 7 · see citing works
Heavy metal exposure and cancer risk: Findings from a Mendelian randomization study
Qin, S., Xie, L., Lan, J., Yang, Y., Diao, W., & Ning, Y. (2026) · Toxicology Letters · doi:10.1016/j.toxlet.2026.111848 · Cited by 5 · see citing works
Identifying effects of genetic obesity exposure on leukocyte telomere length using Mendelian randomization
Wan, B., Ma, N., & Lv, C. (2023) · PeerJ · doi:10.7717/peerj.15085 · Cited by 5 · see citing works
Associations between 25-hydroxyvitamin D/calcium/alkaline phosphatase levels and the risk of developing kidney stones: Results from NHANES (2013–2018)-based and Mendelian randomization studies
Ran, Y., Liu, Z., Ma, H., Li, C., Zhou, J., Li, D., Guo, Z., Dan, L., Zhao, Z., Zou, Z., et al. (2025) · Medicine · doi:10.1097/md.0000000000041323 · Cited by 5 · see citing works
THE RELATIONSHIP BETWEEN CIRCULATING IMMUNE CELL PHENOTYPES AND SEPSIS: A MENDELIAN RANDOMIZATION STUDY
Liu, H., Hai, L., Zhou, L., Wen, S., Liu, T. T., Ju, L., & Liu, Y. (2024) · Shock · doi:10.1097/shk.0000000000002334 · Cited by 5 · see citing works
A Mendelian randomization study on the causal effects of cigarette smoking on liver fibrosis and cirrhosis
Guo, L., An, Y., Huang, X., Liu, W., Chen, F., Fan, Y., Gao, S., Han, L., & Wang, K. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1390049 · Cited by 5 · see citing works
Causal relationships between immune cell phenotypes and lung adenocarcinoma: A bidirectional two‐sample Mendelian randomization study
Li, B., Huang, Z., Wang, Y., Guo, C., Liang, N., Yang, H., & Li, S. (2024) · Thoracic Cancer · doi:10.1111/1759-7714.15394 · Cited by 5 · see citing works
Causal impact of statins on susceptibility to osteoarthritis: insights from a two-sample Mendelian randomization analysis
Yu, K., Li, Z., Shi, W., Zhao, Z., & Li, Y. (2024) · International Journal of Clinical Pharmacy · doi:10.1007/s11096-024-01754-6 · Cited by 5 · see citing works
No causal relationship serum lipids on age-related hearing loss based on Mendelian randomized evidence
Ni, T., Shen, Z., Lu, X., Shi, H., Xie, H., Yang, S., Zhuang, W., Liu, Y., & Han, Z. (2024) · Hearing Research · doi:10.1016/j.heares.2024.109128 · Cited by 5 · see citing works
The association between lipid parameters and erectile dysfunction: a two-sample Mendelian randomization and case-control study
Ke, M.-H., Bao, B., Ke, Z., Ma, W., Guo, J., Zhang, L., Wen, H., Ma, L.-R., Fan, G., & Liu, B. (2023) · Endocrine · doi:10.1007/s12020-023-03653-8 · Cited by 4 · see citing works
Multiscale crosstalk between oral-gut microbiome and brain structure
Yang, L., Xu, W., Wang, X., Huang, S., & Liu, J. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120420 · Cited by 4 · see citing works
Addressing confounders in observational comparative effectiveness research: Methods, software, and reporting standards
Wang, Y., Li, W., Wang, L., Wei, Y., Zhao, Y., Feng, G., & Huang, L. (2026) · The Innovation Medicine · doi:10.59717/j.xinn-med.2026.100187 · Cited by 4 · see citing works
Unveiling causal relationships between inflammatory cytokines and neurite orientation dispersion and density imaging phenotypes: Insights from bidirectional Mendelian randomization and bibliometric analysis
Yang, L., Xu, W., Tang, Y., Wu, B., Wang, X., & Liu, J. (2026) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.70025 · Cited by 4 · see citing works
Causal effects of dietary habits on COVID-19 susceptibility, hospitalisation and severity: a comprehensive Mendelian randomisation study
Li, X., Wang, N., Wang, C., Chen, X., Chen, S., & Jiang, W. (2023) · British Journal Of Nutrition · doi:10.1017/s0007114523002556 · Cited by 4 · see citing works
Uncovering Druggable Targets in Aortic Dissection: An Association Study Integrating Mendelian Randomization, pQTL, and Protein–Protein Interaction Network
Jiang, D., Zheng, S., Xu, X., Yue, H., Liang, W., & Wu, Z. (2024) · Biomedicines · doi:10.3390/biomedicines12061204 · Cited by 4 · see citing works
Genetic insight into dissecting the immunophenotypes and inflammatory profiles in the pathogenesis of Sjogren syndrome
Xu, J., Si, S., Han, Y., Zeng, L., & Zhao, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-024-05993-z · Cited by 5 · see citing works
RNA interference versus antibody-based PCSK9 inhibition for the prevention of cardiovascular disease: a drug-target Mendelian randomization study
Gagnon, É., Gill, D., Bourgault, J., Gobeil, É., Mitchell, P. L., Girard, A. S., Paulin, A., Couture, C., Bossé, Y., Thériault, S., et al. (2025) · Cardiovascular Research · doi:10.1093/cvr/cvaf078 · Cited by 4 · see citing works
Insight into the relationship between resting heart rate and atrial fibrillation: a Mendelian randomization study
Klevjer, M., Rasheed, H., Romundstad, P., Madssen, E., Brumpton, B. M., & Bye, A. (2023) · EP Europace · doi:10.1093/europace/euad292 · Cited by 4 · see citing works
Causal associations between leisure sedentary behaviors and sleep status with frailty: insight from Mendelian randomization study
Li, C., Li, N., Huang, H., Li, Y., & Zhuang, Y. (2024) · BMC Geriatrics · doi:10.1186/s12877-024-04758-z · Cited by 5 · see citing works
The Application of Mendelian Randomization in Cardiovascular Disease Risk Prediction: Current Status and Future Prospects
Jin, Y.-J., Wu, X.-Y., & An, Z. (2024) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2507262 · Cited by 5 · see citing works
Causal influence of immune factors on the risk of diabetic retinopathy: a mendelian randomization study
Li, Y., Xiang, Y., Mou, B., & Song, X. (2024) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-024-01441-6 · Cited by 4 · see citing works
Multiple sclerosis and abnormal spermatozoa: A bidirectional two-sample mendelian randomization study
Li, B., Zhang, L., Li, Q., Zhang, J., Wang, W., & Quan, J. (2024) · PLoS ONE · doi:10.1371/journal.pone.0308815 · Cited by 4 · see citing works
Mendelian Randomization Studies: Opening a New Window in the Study of Metabolic Diseases and Chronic Kidney Disease
Liang, N., Ma, X., Cao, Y., Liu, T., Fang, J., & Zhang, X. (2024) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/0118715303288685240808073238 · Cited by 4 · see citing works
Understanding the Genetic Architecture of Vitamin Status Biomarkers in the Genome-Wide Association Study Era: Biological Insights and Clinical Significance
Reay, W. R., Clarke, E. D., Albiñana, C., & Hwang, L. (2024) · Advances in Nutrition · doi:10.1016/j.advnut.2024.100344 · Cited by 4 · see citing works
Genetic Biomarkers and Circulating White Blood Cells in Osteoarthritis: A Bioinformatics and Mendelian Randomization Analysis
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Causal relationship between gut microbiota and hepatocellular carcinoma: a two-sample Mendelian randomization and case–control study
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Mood instability and low back pain: a mendelian randomization study
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RETRACTED: Association between cathepsins and skin cancers: A bidirectional two‐sample Mendelian randomization study
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Retracted
Causal relationship between atherosclerosis and inflammatory bowel disease risk: a two-sample Mendelian randomization study
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Can a Mendelian Randomization Study Predict the Results of a Clinical Trial? Yes and No
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Special Article Limits to Causal Inference based on Mendelian Randomization: A Comparison with Randomized Controlled Trials
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Nature as a Trialist?: Deconstructing the Analogy Between Mendelian Randomization and Randomized Trials
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Limits to Causal Inference based on Mendelian Randomization: A Comparison with Randomized Controlled Trials
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COMMON PITFALLS IN MENDELIAN RANDOMIZATION STUDIES AND HOW TO AVOID THEM
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Authors: Ference, B. A., Holmes, M. V., & Smith, G. D.
Affiliations: University of Cambridge (GB)
University of Oxford (GB)
University of Bristol (GB)
ORCID: Holmes, Michael V.
Smith, George Davey
Venue: Cold Spring Harbor Perspectives in Medicine
Publisher: Cold Spring Harbor Laboratory
Published: 2021-01-11
Volume: 11
Issue: 7
Pages: a040980
ISSN: 2157-1422 (ISSN-L)
DOI: 10.1101/cshperspect.a040980
PMC: PMC8247560
OpenAlex: W3121012153
Semantic Scholar: ca6a57ef2bff6e618ed580877c5ffce37afc62c2
Cited by: 338
References: 80
Citations by year: 2026: 59 · 2025: 117 · 2024: 106 · 2023: 39 · 2022: 9 · 2021: 7
Type: posted content
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cold Spring Harbor Perspectives in Medicine (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Explore Bristol Research (acceptedVersion, other-oa)
Funders: Cancer Research UK (16896)
Medical Research Council (MC_UU_00011/1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Keywords: Mendelian randomization, randomized controlled trials, trial design, causal inference, genetic variants as instrumental variables
MeSH terms: Humans, Research Design, Randomized Controlled Trials as Topic, Mendelian Randomization Analysis, Quality Improvement

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Using Mendelian Randomization to Improve the Design of Randomized Trials

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