Cited by 1,496Genetic Associations and EpidemiologyAdvanced Causal Inference TechniquesGenetics and Physical Performance

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Evaluating the potential role of pleiotropy in Mendelian randomization studies

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Hemani, Gibran, Bowden, Jack, Davey Smith, George·2018·Human Molecular Genetics

DOI 10.1093/hmg/ddy163PMC PMC6061876

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Abstract

Pleiotropy, the phenomenon of a single genetic variant influencing multiple traits, is likely widespread in the human genome. If pleiotropy arises because the single nucleotide polymorphism (SNP) influences one trait, which in turn influences another ('vertical pleiotropy'), then Mendelian randomization (MR) can be used to estimate the causal influence between the traits. Of prime focus among the many limitations to MR is the unprovable assumption that apparent pleiotropic associations are mediated by the exposure (i.e. reflect vertical pleiotropy), and do not arise due to SNPs influencing the two traits through independent pathways ('horizontal pleiotropy'). The burgeoning treasure trove of genetic associations yielded through genome wide association studies makes for a tantalizing prospect of phenome-wide causal inference. Recent years have seen substantial attention devoted to the problem of horizontal pleiotropy, and in this review we outline how newly developed methods can be used together to improve the reliability of MR.

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Figure 1. (A) The same SNP can associate with multiple traits due to vertical pleiotropy, horizontal pleiotropy and linkage disequilibrium with distinct causal variants depending on the analytical context. To estimate the causal influence of gene expression level (Gene) 1 on Trait 1, SNP 1 is a valid instrument that acts in a vertical pleiotropic manner. But SNP 1 has a horizontal pleiotropic effect when using it to estimate the causal influence of Gene 1 on Trait 2. If SNP 1 was used to instrument Gene 1 to test its effect on Trait 3, it would exhibit a pleiotropic association through linkage disequilibrium with SNP 2. (B) A directed acyclic graph (DAG) in which four SNPs instrument an exposure. The fourth SNP has a horizontal pleiotropic effect of magnitude α. The impact of the horizontal pleiotropic effect is shown in the scatter plot in (C), where the grey slope represents the true causal effect obtained from the three valid instruments, and the red slope represents the IVW estimate when all SNPs are used as instruments.CC BY · PubMed Central

Appendix figure 1. (A) Unobserved confounding (U) makes it impossible to be fully confident that an association between risk factor X and outcome Y represents a measure of causal effect of X on Y. (B) In a perfect RCT, randomization to treatment (T) removes the possibility of confounding, enabling the causal effect of T on Y to be estimated. (C) MR uses genetic variants (G) that explain some variation in the exposure X to estimate the causal effect of X on Y. G must satisfy the instrumental variable assumptions, encoded by the solid arrows (and the strict absence of the dotted arrows) in (C). (D) Instrumental variable methods can also be used in clinical trials when randomization is imperfect because some patients do not receive the treatment they were originally assigned. This is referred to as `non-compliance’. An MR analysis is conceptually and mathematically equivalent to the analysis of RCT data in the presence of non-compliance, where the SNP (G) and exposure (X) proxy for randomization (R) and treatment (T), respectively.CC BY · PubMed Central

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The use of negative control outcomes in Mendelian randomization to detect potential population stratification
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“A key assumption for MR to give consistent estimates of the causal effect of an exposure on the outcome is that the SNPs used as instruments are not associated with the outcome other than through the exposure.(3) One way in which this assumption may be violated is through population stratification, where structure in…”
BackgroundSelf-citation
C-Reactive Protein Levels and Risk of Cardiovascular Diseases: A Two-Sample Bidirectional Mendelian Randomization Study
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Coffee Consumption and Kidney Function: A Mendelian Randomization Study
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“Previous studies have suggested that significant MR outcomes may arise from a locus in which SNPs are in close linkage disequilibrium and in which the SNP-exposure and SNP-outcome associations arise from two different causal SNPs, and therefore may lead to inferred false positive results [44].”
Background
Genetics of substance use disorders in the era of big data
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“studies in the results presented here, such as biases due to pleiotropy or collider bias.[25, 31, 42] These results should therefore be taken as an illustration of the application and interpretation of the methods discussed.”
Method
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Thyroid function, sex hormones and sexual function: a Mendelian randomization study
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“Leave-one-SNP-out analysis was performed to assess if the overall effect was driven by any single SNP. MR-PRESSO was employedtodetectoutliersandweremovedtheseoutlierstogenerate reported estimates 70 .”
Tools for assessing quality and risk of bias in Mendelian randomization studies: a systematic review
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Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases
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Self-citation
Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
Hamel, A. R., Yan, W., Rouhana, J. M., Monavarfeshani, A., Jiang, X., Mehta, P. A., Advani, J., Luo, Y., Liang, Q., Rajasundaram, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44380-y · Cited by 100
“We provided additional support for three quarters of the colocalizing e/sGenes using Mendelian randomization 43,51,52 , which tests for horizontal pleiotropy, not accounted for by Bayesian colocalization analysis 53,54 .”
Method
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“We recommend care be taken in examining such pathways and suggest MRGxE be implemented as one component of a series of sensitivity analyses, as with other such approaches.(4)”
BackgroundMethodSelf-citation
Mendelian Randomization Studies of Coffee and Caffeine Consumption
Cornelis, M. C., & Munafo, M. R. (2018) · Nutrients · doi:10.3390/nu10101343 · Cited by 89
High blood pressure and risk of dementia: a two-sample mendelian randomization study in the UK Biobank
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The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study
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“This could be via, for example, a common causal basis (panel A in S1 Methods) or via vertical (mediating) pleiotropy [27] (panel B in S1 Methods).”
BackgroundInfluential
Physical activity, sedentary behavior and risk of coronary artery disease, myocardial infarction and ischemic stroke: a two-sample Mendelian randomization study
Bahls, M., Leitzmann, M. F., Karch, A., Teumer, A., Dörr, M., Felix, S. B., Meisinger, C., Baumeister, S. E., & Baurecht, H. (2021) · Clinical Research in Cardiology · doi:10.1007/s00392-021-01846-7 · Cited by 91
“To detect and correct for outliers of the IVW linear regression, we applied the MR-Pleiotropy RESidual Sum and Outlier (MRPRESSO) method [34, 38].”
BackgroundMethod
Mediators of the association between educational attainment and type 2 diabetes mellitus: a two-step multivariable Mendelian randomisation study
Zhang, J., Chen, Z., Pärna, K., van Zon, S. K. R., Snieder, H., & Thio, C. H. L. (2022) · Diabetologia · doi:10.1007/s00125-022-05705-6 · Cited by 90
“To evaluate potential directional horizontal pleiotropy, we performed MR-Egger regression to assess whether the mean value of the Egger intercept was non-zero, in which case pleiotropy could be directional [39].”
Method
The use of Mendelian randomisation to identify causal cancer risk factors: promise and limitations
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“The only current solution to this problem is to attain a better understanding of the way SNPs affect biological pathways that are linked to the outcome.”
BackgroundMethodInfluential
DNA methylation biomarkers of myocardial infarction and cardiovascular disease
Fernández‐Sanlés, A., Sayols-Baixeras, S., Subirana, I., Sentı́, M., Pérez-Fernández, S., Moura, M. D. C., Esteller, M., Marrugat, J., & Elosúa, R. (2021) · Clinical Epigenetics · doi:10.1186/s13148-021-01078-6 · Cited by 84
“Although a non-causal relationship was suggested, this must be interpreted with caution as there was a single genetic instrumental variable, and we cannot discard that the meQTL is in linkage disequilibrium with the causal variant for CHD, reverse causation or horizontal pleiotropy using this framework [28, 29].”
Method
Exploring and mitigating potential bias when genetic instrumental variables are associated with multiple non-exposure traits in Mendelian randomization
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“Without this understanding it is challenging to understand whether the outlying SNP is introducing horizontal pleiotropy (and might be best removed or down weighted) or is the most biologically reliable SNP and, therefore, the most credible instrument in the analysis [10].”
BackgroundMethodInfluential
A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome
Richardson, T. G., Hemani, G., Gaunt, T. R., Relton, C. L., & Smith, G. D. (2020) · Nature Communications · doi:10.1038/s41467-019-13921-9 · Cited by 84
“Firstly, we evaluate the relationship between gene expression across many tissues and pleiotropy; the phenomenon whereby a gene in ﬂ u-ences variation in multiple traits 16 .”
MethodSelf-citation
The Effect of Plasma Lipids and Lipid-Lowering Interventions on Bone Mineral Density: A Mendelian Randomization Study
Zheng, J., Brion, M., Kemp, J. P., Warrington, N. M., Borges, M. C., Hemani, G., Richardson, T. G., Rasheed, H., Qiao, Z., Haycock, P., et al. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3989 · Cited by 82
Self-citation
Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome
Baird, D. A., Liu, J. Z., Zheng, J., Sieberts, S. K., Perumal, T. M., Elsworth, B., Richardson, T. G., Chen, C., Carrasquillo, M. M., Allen, M., et al. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009224 · Cited by 80
“instrument is associated with risk factors that act through the same pathway, and does not violate the assumptions of MR [17,18].”
Self-citation
Two‐Sample Multivariable Mendelian Randomization Analysis Using R
Rasooly, D., & Peloso, G. M. (2021) · Current Protocols · doi:10.1002/cpz1.335 · Cited by 81
“In vertical pleiotropy, a genetic variant is associated with a risk factor that exerts a downstream causal effect on another, potentially closely related risk factor, which then exerts a causal effect on the outcome (Hemani et al., 2018; Fig.”
BackgroundMethodInfluential
Causal relationship between obesity, lifestyle factors and risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study
Wang, Y., Yang, L., Deng, Y.-Q., Yan, S., Luo, L.-S., Chen, P., & Zeng, X. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03722-y · Cited by 89
“05, and we used a random-effect inverse-variance weighted (IVW) model as the main analysis method [33].”
Method
Independent Associations of Education, Intelligence, and Cognition With Hypertension and the Mediating Effects of Cardiometabolic Risk Factors: A Mendelian Randomization Study
Wang, Y., Ye, C., Kong, L., Zheng, J., Xu, M., Xu, Y., Li, M., Zhao, Z., Lu, J., Chen, Y., et al. (2022) · Hypertension · doi:10.1161/hypertensionaha.122.20286 · Cited by 85
“…30643251 Coffee consumption SD (1% change) 375 833 European UK Biobank Zhong et al 2019 31046077 Total household income SD 397 751 European UK Biobank Hemani et al 2018 29846171 BF% indicates body fat percentage; BMI, body mass index; COGENT, Cognitive Genomics Consortium; DBP, diastolic blood…”
Background
Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study
Magnus, M. C., Guyatt, A. L., Lawn, R. B., Wyss, A. B., Trajanoska, K., Küpers, L. K., Rivadeneira, F., Tobin, M. D., London, S. J., Lawlor, D. A., et al. (2020) · BMC Medicine · doi:10.1186/s12916-020-01515-y · Cited by 81
“, presence of interactions or nonlinear effects) [41].”
BackgroundResultInfluential
Sex hormone–binding globulin: biomarker and hepatokine?
Simons, P. I. H. G., Valkenburg, O., Stehouwer, C. D. A., & Brouwers, M. C. G. J. (2021) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2021.05.002 · Cited by 82
Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis
Hazelwood, E., Sanderson, E. C. M., Tan, V. Y., Ruth, K. S., Frayling, T. M., Dimou, N. L., Gunter, M. J., Dossus, L., Newton, C. L., Ryan, N. A. J., et al. (2022) · BMC Medicine · doi:10.1186/s12916-022-02322-3 · Cited by 83
“For traits instrumented by a single SNP, the Wald ratio was used to generate effect estimates 172 and the delta method was used to approximate standard errors [45].”
Method
The role of cortisol in ischemic heart disease, ischemic stroke, type 2 diabetes, and cardiovascular disease risk factors: a bi-directional Mendelian randomization study
Kwok, M. K., Kawachi, I. I., Rehkopf, D. H., & Schooling, C. M. (2020) · BMC Medicine · doi:10.1186/s12916-020-01831-3 · Cited by 80
“However, these studies are Table 3 Association of genetically predicted cortisol (P value 5 × 10−6 and r2 0.001) based on 3 separate data sources (CORtisol NETwork (CORNET) consortium, Shin GWAS, and Long GWAS) with type 2 diabetes (T2DM) based on the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANT…”
BackgroundInfluential
Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids
Davyson, E., Shen, X., Gadd, D. A., Bernabeu, E., Hillary, R. F., McCartney, D. L., Adams, M. J., Marioni, R. E., & McIntosh, A. M. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.01.027 · Cited by 80
“This indicates that the instrumental variable in MR exhibits horizontal pleiotropy on the outcome (a direct violation of the exchangeability assumption for MR), thus weakening the evidence for causality (82,83).”
Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci
Gong, J., Wang, F., Xiao, B., Panjwani, N., Fan, L., Keenan, K., Avolio, J., Esmaeili, M., Zhang, L., He, G., et al. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1008007 · Cited by 79
Sex hormone binding globulin and risk of breast cancer: a Mendelian randomization study
Dimou, N. L., Papadimitriou, N., Gill, D., Christakoudi, S., Murphy, N., Gunter, M. J., Travis, R. C., Key, T. J., Fortner, R. T., Haycock, P., et al. (2019) · International Journal of Epidemiology · doi:10.1093/ije/dyz107 · Cited by 78
“rs12150660) has been also associated at a genome-wide significance level with testosterone concentrations in men,(55) but this variant is located in the SHBG gene, and will likely lead to vertical (not horizontal) pleiotropy, not violating thus the results of the present study.(56) In addition, most known genetic sign…”
Result
Searching for the causal effects of body mass index in over 300 000 participants in UK Biobank, using Mendelian randomization
Millard, L. A. C., Davies, N. M., Tilling, K. M., Gaunt, T. R., & Smith, G. D. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1007951 · Cited by 78
“The MR-Egger, weighted median and MBE approaches are complementary, each depending on distinct assumptions about instrument validity [73].”
Background
Association Between Plasma Proteome and Childhood Neurodevelopmental Disorders: A Two-Sample Mendelian Randomization Analysis
Yang, J., He, X., Li, Q., Zhao, B., Fan, Y., Gao, F., Yan, B., Zhu, F., & Ma, X. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2022.103948 · Cited by 77
Evaluating the impact of metformin targets on the risk of osteoarthritis: a mendelian randomization study
Zhang, Y., Li, D., Zhu, Z., Chen, S., Lu, M., Cao, P., Chen, T., Li, S., Xue, S., Zhang, Y., et al. (2022) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2022.06.010 · Cited by 77
Causal inference in health and disease: a review of the principles and applications of Mendelian randomization
Lovegrove, C. E., Howles, S., Furniss, D., & Holmes, M. V. (2024) · Journal of Bone and Mineral Research · doi:10.1093/jbmr/zjae136 · Cited by 80
“48 Balanced horizontal pleiotropy (the deviation of a variant’s estimate from the mean estimate is independent of its effect on the exposure) may be accounted for if the random effects do not systematically affect the outcome.”
Background
Testing the association between tobacco smoking, alcohol consumption, and risk of periodontitis: A Mendelian randomization study
Baumeister, S., Freuer, D., Nolde, M., Kocher, T., Baurecht, H., Khazaei, Y., Ehmke, B., & Holtfreter, B. (2021) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.13544 · Cited by 76
“…of the individual SNP effects using the Cochran Q and I GX2 statistics, applied the MR Egger intercept test of directional pleiotropy, the leave-one-out MR analysis to assess whether the MR estimate was driven by a single SNP, and applied various pleiotropy-robust MR methods (Hemani et al., 2018).”
Influential

Authors: Hemani, G., Bowden, J., & Davey Smith, G.
Affiliations: University of Bristol (GB)
MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol
Corresponding author: Hemani, Gibran
ORCID: Hemani, Gibran
Bowden, Jack
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2018-05-16
Volume: 27
Issue: R2
Pages: R195-R208
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddy163
PMC: PMC6061876
OpenAlex: W2810852503
Cited by: 1,496
References: 113
Citations by year: 2026: 129 · 2025: 266 · 2024: 422 · 2023: 209 · 2022: 169 · 2021: 131 · 2020: 101 · 2019: 62 · 2018: 7
FWCI: 10.71
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Human Molecular Genetics (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Bristol Research (University of Bristol) (submittedVersion, cc-by)
Funders: Wellcome Trust (208806/Z/17/Z)
Medical Research Council (MC_UU_12013/1)
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: pleiotropy, Mendelian randomization, horizontal pleiotropy, single nucleotide polymorphisms, causal inference, phenome-wide association study, genetic variants
MeSH terms: Animals, Humans, Phenotype, Genetic Variation, Reproducibility of Results, Genome, Human, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis, Genetic Pleiotropy

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Evaluating the potential role of pleiotropy in Mendelian randomization studies

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