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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Yang, X., Wang, J., Hong, H., Xing, F., Zhang, X., & Song, J. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1398101 · Cited by 10
Integrating DNA sequencing and transcriptomic data for association analyses of low-frequency variants and lipid traits
Yang, T., Wu, C., Wei, P., & Pan, W. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz314 · Cited by 8
“Regarding aim (2), it was pointed out that the assumptions underlying TWAS or 2SLS may not hold exactly due to that the constructed weights may not be precise with often small sample sizes of reference eQTL data, likely widespread horizontal pleiotropy, measurement error in expression quantification and cell-type hete…”
Background
Colocalization of association signals at nicotinic acetylcholine receptor genes between schizophrenia and smoking traits
Al‐Soufi, L., & Costas, J. (2021) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2021.108517 · Cited by 9
Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020
Tobias, J. H., Duncan, E. L., Kague, É., Hammond, C. L., Gregson, C. L., Bassett, D., Williams, G. R., Min, J. L., Gaunt, T. R., Karasik, D., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.630875 · Cited by 9
“To improve reliability of MR, multiple independent genetic variants influencing a molecular trait can be employed, which should exhibit consistent causal effects (53).”
Background
Mendelian randomization analyses reveal novel drug targets for anorexia nervosa
Yang, J., Fan, Y., Yan, B., Zhao, B., Qian, L., Gao, F., Ma, Q., Yang, L., Wang, W., Bai, L., et al. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110427 · Cited by 9
Modifiable risk factors for ectopic pregnancy: a Mendelian randomization study
Rogne, T., Liew, Z., Hernáez, Á., Brumpton, B. M., & Magnus, M. C. (2022) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2022.03.063 · Cited by 15
An Overview of Methods and Exemplars of the Use of Mendelian Randomisation in Nutritional Research
Bennett, D., & Du, H. (2022) · Nutrients · doi:10.3390/nu14163408 · Cited by 9
Causal effects of systemic lupus erythematosus on endometrial cancer: A univariable and multivariable Mendelian randomization study
Wan, A., Zhao, W., & Tao, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.930243 · Cited by 7
“Recent advances in MR approaches such as weighted median MR and MR-Egger enabled us to assess the robustness of the causal estimates in the presence of pleiotropy (15).”
Background
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
“Additionally, the effects of the genetic variants on the exposure are present since conception, which means MR can assess the effect of lifetime exposure of an exposure on the risk of an outcome [16].”
Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study
Hernáez, Á., Lee, Y., Page, C. M., Skåra, K. H., Håberg, S. E., Magnus, P. M., Njølstad, P. R., Andreassen, O. A., Corfield, E. C., Havdahl, A., et al. (2023) · Human Reproduction · doi:10.1093/humrep/dead234 · Cited by 10
Intergenerational effects of parental educational attainment on parenting and childhood educational outcomes: Evidence from MoBa using within-family Mendelian randomizationPreprint
Havdahl, A., Hughes, A., Sanderson, E. C. M., Ask, H., Cheesman, R., Reichborn‐Kjennerud, T., Andreassen, O. A., Corfield, E. C., Hannigan, L. J., Magnus, P. M., et al. (2023) · medRxiv · doi:10.1101/2023.02.22.23285699 · Cited by 9
Physical activity and the risk of periodontitis: an instrumental variable study
Baumeister, S., Reckelkamm, S. L., Ehmke, B., Nolde, M., & Baurecht, H. (2023) · Clinical Oral Investigations · doi:10.1007/s00784-023-05109-9 · Cited by 8
“The MR Egger intercept test was used to test for directional pleiotropy [26].”
BackgroundMethod
Causal effect of gallstone disease on the risk of coronary heart disease or acute myocardial infarction: a Mendelian randomization study
Fu, Q., Shen, T., Yu, Q., Jiang, L., & Yang, R. (2023) · Scientific Reports · doi:10.1038/s41598-023-46117-9 · Cited by 9
“It has been suggested that the significance of MR results may be derived from SNPs in a state of linkage disequilibrium and that the associated SNPs for exposure and outcome are different causal SNPs, which may lead to false-positive inferred results 32 .”
Background
The impact of obesity and sexual behavior on prostate cancer risk is mediated by testosterone levels: a mendelian randomization study and mediation analysis
Di, H., Wen, Y., Wang, J., Wang, J., Wang, Y., Li, Y., & Sun, F. (2024) · Prostate International · doi:10.1016/j.prnil.2024.03.003 · Cited by 8
Mendelian randomization and colocalization analysis reveal novel drug targets for myasthenia gravis
Ouyang, Y., Chen, Y., Chen, K., Tang, Z., Shi, G., Qu, C., Zhang, K.-Y., & Yang, H. (2024) · Human Genomics · doi:10.1186/s40246-024-00607-7 · Cited by 8
“The close linkage disequilibrium also leads to inaccurate MR results because of the horizontal pleiotropy, where the associations of SNP-exposure and SNP-outcome fall on distinct causal SNPs [26].”
Background
The effect of depression status on osteoarthritis: A powerful two-step Mendelian randomization study
Yan, Z., Yang, J., Zhang, H., Li, Z., Zheng, W., Li, S., & Huang, W. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.08.009 · Cited by 8
Causality between neuroticism personality clusters and female reproductive diseases in European population: a two-sample bidirectional mendelian randomization study
Kong, X., Jin, F., Tang, G., Qin, Y., Liu, D., & Sun, J. (2024) · BMC Women s Health · doi:10.1186/s12905-024-03347-x · Cited by 8
“Leave-one-out (LOO) analysis was used to recalculate and visualize the overall effect in the IVW analysis by sequentially omitting each SNP, and assess whether the observed causality depends on any individual SNP [37].”
Method
Triangulated evidence provides no support for bidirectional causal pathways between diet/physical activity and depression/anxiety
van Hooijdonk, K. J. M., Reed, Z. E., van den Broek, N., Singh, M., Sallis, H., Gillespie, N. A., Munafo, M. R., & Vink, J. M. (2025) · Psychological Medicine · doi:10.1017/s0033291724003349 · Cited by 8
“…discordance definitions or confounding by non-shared factors in Study 2 (Frisell, Öberg, Kuja-Halkola, & Sjölander, 2012) and potential violations of the MR assumptions (e.g., horizontal pleiotropy 10 ) in Study 3 (Davies et al., 2019; Hemani, Bowden, & Davey Smith, 2018; Spiga et al., 2023).”
White blood cell traits and lung cancer risk: a two-sample mendelian randomization analysis
Long, K., Zhu, Z., Zheng, X., Xu, G., Chen, C. Y., & Ke, X. (2025) · Scientific Reports · doi:10.1038/s41598-025-88366-w · Cited by 9
“Additionally, leave-one-out analyses were conducted to evaluate whether the results were influenced by any single SNP 37 .”
Schizophrenia, bipolar disorder and major depressive disorder are probably not risk factors for cardiovascular disease: A Mendelian randomized study
Chen, J., Duan, W., Liu, P., Cui, L., Li, A., Zhang, X., & Zuo, X. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.02.069 · Cited by 9
Sleep traits causally affect epigenetic age acceleration: a Mendelian randomization study
Zhao, W., Yu, S., Xu, Y., Liao, H., Chen, D., Lu, T., Ren, Z., Ge, L., Liu, J., & Sun, J. (2025) · Scientific Reports · doi:10.1038/s41598-024-84957-1 · Cited by 9
“As part of the analysis, the “leave-one-out” analysis was applied to screen out the SNP that independently drove the direction of estimation 41 .”
Genome-wide analyses of variance in blood cell phenotypes provide new insights into complex trait biology and prediction
Xiang, R., Ben-Eghan, C., Liu, Y., Roberts, D. J., Ritchie, S. C., Lambert, S. A., Xu, Y., Takeuchi, F., & Inouye, M. (2025) · Nature Communications · doi:10.1038/s41467-025-59525-4 · Cited by 9
Characterizing causal relationships of visceral fat and body shape on multiple sclerosis risk
Misicka, E., Gunzler, D. D., Albert, J. M., & Briggs, F. B. S. (2023) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2023.104964 · Cited by 8
Causal effects of genetically determined blood metabolites on multiple myeloma: a Mendelian randomization study
Ren, J.-L., & Wu, M. (2023) · Scientific Reports · doi:10.1038/s41598-023-45801-0 · Cited by 8
“The default fixed-effects model was employed if no substantial heterogeneity ( P > 0.05) was observed; otherwise, the random-effects model was utilized 26 .”
MethodInfluential
Sjögren’s Disease and Oral Health: A Genetic Instrumental Variable Analysis
Reckelkamm, S. L., Alayash, Z., Holtfreter, B., Nolde, M., & Baumeister, S. (2024) · Journal of Dental Research · doi:10.1177/00220345231218903 · Cited by 11
“A non-zero MR Egger intercept points toward the presence of directional (nonmean zero) horizontal pleiotropy (Hemani et al. 2018).”
Background
Heartache and Heartbreak: An Observational and Mendelian Randomization Study
Cai, D., Xia, M., Chen, X., Yagi, K., Xu, L., Wang, B., Wang, Y., Zhou, Y., & Liu, J. (2024) · Global Heart · doi:10.5334/gh.1302 · Cited by 10
“(c ) The influence of IVs on the risk of outcomes is just through exposure [19].”
Background
Estimating the direct effects of the genetic liabilities to bipolar disorder, schizophrenia, and behavioral traits on suicide attempt using a multivariable Mendelian randomization approach
Cabrera‐Mendoza, B., Aydin, N., Fries, G. R., Docherty, A. R., Walss‐Bass, C., & Polimanti, R. A. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-01833-2 · Cited by 9
“Unless otherwise noted, here we reported IVW effect estimates, as this method provides the highest statistical power [54].”
Appraising associations between signature lipidomic biomarkers and digestive system cancer risk: novel evidences from a prospective cohort study of UK Biobank and Mendelian randomization analyses
Sun, Y., Cao, D.-H., Zhang, Y., Wu, Y.-H., Jia, Z.-F., Cui, Y., Li, D., Cao, X.-Y., & Jiang, J. (2024) · Lipids in Health and Disease · doi:10.1186/s12944-024-02053-9 · Cited by 9
“Secondly, the deviation of causal effects caused by horizontal pleiotropy often interferes with the causal effects of exposures on outcomes in MR analysis [48].”
Background
Association of coffee intake with bone mineral density: a Mendelian randomization study
Yang, Y., Zhong, R., Xiong, X.-M., & Wang, C. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1328748 · Cited by 8
A Mendelian randomization study on the causal effects of circulating cytokines on the risk of vitiligo
Liu, C., Liu, X., Xin, H., & Li, X. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1375339 · Cited by 8
Do iron homeostasis biomarkers mediate the associations of liability to type 2 diabetes and glycemic traits in liver steatosis and cirrhosis: a two-step Mendelian randomization study
Liang, Y., Luo, S., Bell, S., Mo, J. M. Y., He, B., Zhou, Y., Bai, X., & Au Yeung, S. L. (2024) · BMC Medicine · doi:10.1186/s12916-024-03486-w · Cited by 8
“…arguably the downstream effects of glucose level variation (i.e., vertical pleiotropy and hence valid), given its high relevance in glucose metabolism, the increased circulating lipids could also arguably as an effect independent of glucose (i.e., horizontal pleiotropy and hence invalid) [60, 61].”
Background
Genetic landscape of atopic dermatitis
Paternoster, L. (2024) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000001005 · Cited by 8
“This should be investigated in studies and Steiger filtering is one approach to avoid this pitfall [55].”
Association of ankylosing spondylitis with cardiovascular disease: a bidirectional two-sample mendelian randomization study
Liu, P., Shang, J., Qi, Z., Qiu, S., Lai, X., Shi, L., Zhang, Z., Li, M., & Yang, L. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1260247 · Cited by 9
Vexed causal inferences in nutritional epidemiology—call for genetic help
Ohukainen, P., Virtanen, J. K., & Ala‐Korpela, M. (2021) · International Journal of Epidemiology · doi:10.1093/ije/dyab152 · Cited by 8
“The obstacle of (horizontal) pleiotropy has been tackled extensively in the literature and readers are referred to a recent review by Hemani et al.20 for further details.”
Background
Impact of nonrandom selection mechanisms on the causal effect estimation for two-sample Mendelian randomization methods
Yu, Y., Hou, L., Shi, X., Sun, X., Liu, X., Yu, Y., Yuan, Z., Li, H., & Xue, F. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010107 · Cited by 8
Using genetic designs to identify likely causal environmental contributions to psychopathology
Sellers, R., Riglin, L., Harold, G. T., & Thapar, A. (2022) · Development and Psychopathology · doi:10.1017/s0954579422000906 · Cited by 8
“One common type of MR method is a two-sample MR that utilizes summary SNP-exposure and SNP-outcome data from different GWAS (Hemani et al., 2018).”
Method
The causal relationship between physical activity, sedentary time and idiopathic pulmonary fibrosis risk: a Mendelian randomization study
Lei, W., Yang, M., Yuan, Z., Feng, R., Kuang, X., Liu, Z., Deng, Z., Hu, X., & Tai, W. (2023) · Respiratory Research · doi:10.1186/s12931-023-02610-3 · Cited by 8
“Cochran’s Q test initially evaluated heterogeneity among the IVs [37].”
Method
A genetic model of ivabradine recapitulates results from randomized clinical trials
Legault, M., Sandoval, J., Provost, S., Barhdadi, A., Perreault, L. L., Shah, S. H., Lumbers, R. T., de Denus, S., Tyl, B., Tardif, J., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0236193 · Cited by 7
Identification of 370 genetic loci for age at first sex and birth linked to externalising behaviourPreprint
Mills, M. C., Tropf, F. C., Brazel, D. M., van Zuydam, N. R., Vaez, A., Pers, T. H., Snieder, H., Perry, J. R. B., Ong, K. K., den Hoed, M., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.06.081273 · Cited by 8
Associations of computer gaming with incident dementia, cognitive functions, and brain structure: a prospective cohort study and Mendelian randomization analysis
Jia, Y., Shi, M., Yang, P., Wang, R., Sun, L., Wang, Y., Xu, Q., Zhang, J., Zhang, Q., Guo, D., et al. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01496-7 · Cited by 11
“…median method [28], the maximum likelihood method [14], the MR-Robust Adjusted Profile Scoring (MR-RAPS) method [29], the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) method [30], the MR-Egger regression method [31], and the leave-one-out method were used in the sensitivity MR analyses [32].”
Method
Plasma proteome mediate the impact of PM2.5 on stroke: A 2-step Mendelian randomization study
Yang, H., Shi, P., Li, M., Liu, S., Mou, B., Xia, Y., & Sun, J. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2024.116624 · Cited by 7
An exploration of the causal relationship between 731 immunophenotypes and osteoporosis: a bidirectional Mendelian randomized study
Zhou, D., Zi, C., Gan, G., Tang, S., & Qiu, C. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1341002 · Cited by 7
Shared genetic architecture and causality between autism spectrum disorder and irritable bowel syndrome, multisite pain, and fatigue
Li, Y., Xie, T., Vos, M., Snieder, H., & Hartman, C. A. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03184-4 · Cited by 8
An atlas of the shared genetic architecture between atopic and gastrointestinal diseases
Qi, C., Li, A., Su, F., Wang, Y., Zhou, L., Tang, C., Feng, R., Mao, R., Chen, M., Chen, L., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-07416-7 · Cited by 8
“Shared genetic factors have been shown to be involved in cross-disease causality which was related to the comorbidities 30,38 .”
Association of cancers with the occurrence and 28-day mortality of sepsis: a mendelian randomization and mediator analysis
Cheng, D., Pan, S., Fang, X., Wang, S., Zou, X., Shu, H., Yang, X., Xu, J., & Shang, Y. (2025) · Scientific Reports · doi:10.1038/s41598-025-89354-w · Cited by 7
Breaking the winner’s curse in Mendelian randomization: Rerandomized inverse variance weighted estimator
Ma, X., Wang, J., & Wu, C. (2023) · The Annals of Statistics · doi:10.1214/22-aos2247 · Cited by 8
“Balanced pleiotropy (also known as systematic pleiotropy) refers to the scenario that the exclusion restriction assumption breaks down and the genetic variants have equal chances to affect the outcome either positively or negatively [17, 38].”
Background

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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