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Evaluating the potential role of pleiotropy in Mendelian randomization studies
Open accessAbstract
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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“This pattern is consistent with a directional influence of disease liability on longevity27,64 and is also compatible with vertical pleiotropy65.”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [65]
In the citing paper
“However, confounding of the genetic variants with the outcome in a sample can be induced by population stratification, dynastic effects and assortative mating,60 violating the second IV condition.”
From Mendelian randomization (2022) · cites this paper as [60]
In the citing paper
“If there are many correlated candidate variants in a gene region, then including all variants in a single analysis will typically result in numerical instability, as the analysis can be highly sensitive to small changes in the variant correlation matrix 62 .”
From Guidelines for performing Mendelian randomization investigations (2020) · cites this paper as [62]
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Citations
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“…assortative mating (i.e. individuals with similar characteristics tend to mate with each other), linkage disequilibrium (i.e. genetic variants that are close together in a gene are correlated), and horizontal pleiotropy (i.e. that one genetic variant affects multiple traits) [19–21].”
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“However, if the genetic variants affect ALS susceptibility through other pathways than micronutrients (horizontal pleiotropy), the causal estimate may be biased (Hemani et al., 2018).”
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“According to Mendelian’s third hypothesis, genetic variation must affect the outcome variable only through the pathway of the exposure variable; thereby, horizontal pleiotropy occurs when a pathway other than the pathway of the exposure variable influences the outcome (Hemani et al. 2018).”
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“When at least 50% of the SNPs are effective instrumental variables, the causal effects of exposure and outcome can be determined using this method [23, 24].”
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Kidney Function Measures and Mortality: A Mendelian Randomization Study
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“33 The heterogeneity test for MR was performed using Cochran’s Q test, where P > 0.05 indicating the absence of heterogeneity, while P ≤ 0.05 suggesting the presence of heterogeneity.”
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MethodRen, M., Yu, H., Xiao, B., Zhao, Y., Yan, J., & Liu, J. X. (2024) · Brain and Behavior · doi:10.1002/brb3.3417 · Cited by 3
“The R version 4.2.2 with the “Two-Sample MR” and “MR-PRESSO” packages was used to perform all statistical analyses (Hemani et al., 2018).”
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Patel, A., DiTraglia, F. J., Zuber, V., & Burgess, S. (2024) · The Annals of Applied Statistics · doi:10.1214/23-aoas1856 · Cited by 6
“The data used for our analyses are publicly available through the MR-Base platform (Hemani et al., 2018), and R code to perform our empirical investigation is available on GitHub at github.com/ash-res/focused-MR/.”
Ma, X., Zhang, Y., Wu, F., Liu, X., & Zhang, W. (2024) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-024-01331-x · Cited by 4
“Furthermore, we investigated the diversity among particular independent variables by utilizing Cochrane’s Q-value [23].”
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Jin, Y.-J., Wu, X.-Y., & An, Z. (2024) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2507262 · Cited by 5
“In practical applications, the availability of cis-eQTL (expression– quantification–trait–loci) for most genes in the genome that are used as IVs is limited, and frequently reflects the complex genetic basis of traits and pathways between the traits [73].”
BackgroundShi, F., Li, T., Shi, H., Wei, Y., Wang, J., Liu, C., & Liang, R. (2024) · Skin Research and Technology · doi:10.1111/srt.13916 · Cited by 4
“19 The expression level of a gene may be considered a lifelong exposure, and eQTLs located in druggable gene regions are often regarded as proxy variables.”
BackgroundLiu, H., Zheng, H., Zhou, S., & Lin, Q. (2024) · Journal of Cosmetic Dermatology · doi:10.1111/jocd.16515 · Cited by 3
Li, B., Zhang, L., Li, Q., Zhang, J., Wang, W., & Quan, J. (2024) · PLoS ONE · doi:10.1371/journal.pone.0308815 · Cited by 4
Feng, Y., Li, C., Cheng, B., Chen, Y., Chen, P., Wang, Z., Zheng, X., He, J., Zhu, F., Wang, W., et al. (2024) · Translational Lung Cancer Research · doi:10.21037/tlcr-24-65 · Cited by 5
“These analyses allowed us to explore pleiotropy due to confounders (28,32,50).”
Jiang, Z., Xiao, L. X., Die, X., Hou, J., Wang, Y., Wang, Y., & Feng, W. (2024) · Journal of Asthma · doi:10.1080/02770903.2024.2409418 · Cited by 4
“In addition, sensitivity analyses were performed using the leave-one-out method to explore the extent to which the removal of individual SNPs affected the overall results, and further visualized through funnel plots (25).”
Uncovering Molecular and Genetic Drivers of Dental Caries Via scRNA-seq and Mendelian Randomisation
Wang, J., Zhou, Y., Xu, W., Li, Z., Guo, C., & Bian, Q. (2024) · International Dental Journal · doi:10.1016/j.identj.2024.10.005 · Cited by 6
“21 Mendelian randomisation has been widely used in medical research.”
Navigating Mendelian Randomization in Sleep Medicine: Challenges, Opportunities, and Best Practices
BaHammam, A. S., & Jahrami, H. (2024) · Nature and Science of Sleep · doi:10.2147/nss.s495411 · Cited by 4
“31 Additionally, genetic instruments used should be derived from well-powered GWAS showing a robust association with sleep duration, while accounting for confounders like population stratification to ensure valid conclusions.”
InfluentialSu, C., Liao, Z., Li, H., Pei, Y., Wang, Z., Li, J., & Liu, J. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1428334 · Cited by 4
Baltramonaityte, V., Karhunen, V., Felix, J. F., Penninx, B. W. J. H., Cecil, C. A. M., Fairchild, G. F., Milaneschi, Y., & Walton, E. (2025) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.01.024 · Cited by 4
Ren, Q., Ding, K., Jiang, W., Zhu, W., & Gao, Y. (2025) · Experimental Gerontology · doi:10.1016/j.exger.2025.112729 · Cited by 4
“Finally, using MR Egger regression, the pleiotropy between instrumental variables was tested, and a P -value of 0.05 was considered statistically significant (Hemani et al., 2018).”
InfluentialLi, T.-L., Fu, M. J., Wang, L., Wang, J.-L., Liu, Y.-W., & Huang, L. (2025) · European Cardiology Review · doi:10.15420/ecr.2024.44 · Cited by 4
“20 This phenomenon is categorised into uncorrelated pleiotropy, where distinct mechanisms drive the genetic variant’s effect on exposure and outcome, and correlated pleiotropy, where a genetic variant affects both through a shared pathway.”
Wen, J., Yang, Y., Zhang, H., Wu, W., Dai, Z., Liang, X., & Chen, S. (2025) · Clinical and Experimental Medicine · doi:10.1007/s10238-025-01644-9 · Cited by 4
“Thus, we supplemented the other two methods, which were relatively robust to horizontal pleiotropy, although the statistical power was partially sacrificed [32].”
Insights into modifiable risk factors of retinal vascular occlusion: A Mendelian randomization study
Jiang, B., Wei, X., Cao, X., & Zheng, C. (2025) · Medicine · doi:10.1097/md.0000000000041752 · Cited by 4
“[38] We used two main means to detect horizontal pleiotropy, including the MR–Egger inter-cept and MR-PRESSO methods.”
Air pollution is the risk factor for psychiatric disorders: a two-step Mendelian randomization study
Zhou, J., Lu, Z., Xu, K., Zhao, G., Zhu, Y., Yuan, R., Sun, Y., Zhang, Y., & Yue, W. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.119475 · Cited by 4
Mendelian Randomization Studies of Myopia: Choosing the Right Summary Statistics
Nguyen, T.-N., Terry, L., & Guggenheim, J. A. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.13.57 · Cited by 4
“57 Although these additional issues fall outside the focus of our article, we emphasize that MR, although a powerful tool for causal inference, must be applied with methodological rigor and critical judgment.”
A Mendelian randomization study on the association of bone mineral density with periodontitis
Yu, Y., Chu, T., Dong, J., Deng, H., Pan, Y., & Wang, Y. (2023) · Oral Diseases · doi:10.1111/odi.14582 · Cited by 5
Mendelian randomization: using genetic information in epidemiological studies (review)
Plotnikov, D. (2023) · RESEARCH RESULTS IN BIOMEDICINE · doi:10.18413/2658-6533-2023-9-2-0-1 · Cited by 4
Vasectomy and risk of prostate cancer: A Mendelian randomization study and confounder analysis
Di, H., & Wen, Y. (2023) · The Prostate · doi:10.1002/pros.24646 · Cited by 4
“33 ( 2 ) If there”
Lin, S., Gao, B., Xu, R., Shang, H., Xiong, Y., Zhou, J., Yang, Z., Jiang, C., & Yan, S. (2024) · eJHaem · doi:10.1002/jha2.890 · Cited by 4
“For ARS, AD, PD, SD, NAFL, and MM, we relaxed the p value threshold to a less stringent value of p < 5 × 10 − 6 to extract sufficient SNPs to perform M [36, 37].”
BackgroundMethodDu, R., Zhu, Y., Chen, P., Li, M., Zhang, Y., & Huang, X. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1357070 · Cited by 5
“To evaluate the impact of genetically-predicted OSA on ALS for each SNP, we employed the Wald ratio (Hemani et al., 2018).”
MethodWang, Q., Chen, S., Wang, G., Zhang, T., & Gao, Y. (2024) · BMC Cancer · doi:10.1186/s12885-024-12513-1 · Cited by 4
“In addition, we also applied sensitivity analyses in this study, such as heterogeneity, pleiotropy, and leave-one-out analysis, to assess the stability of our outcomes [25, 26].”
MethodMa, X., Zhuang, H., Xu, M., Hou, F., & Xue, C. (2024) · Skin Research and Technology · doi:10.1111/srt.13905 · Cited by 3
“30,31 The MR-PRESSO outlier test computed a p -value to represent the signifi-canceofpleiotropyforeachSNP.”
RetractedIdentification and Inference with Invalid Instruments
Kang, H., Guo, Z., Liu, Z., & Small, D. S. (2024) · Annual Review of Statistics and Its Application · doi:10.1146/annurev-statistics-112723-034721 · Cited by 5
“We remark that the InSIDE assumption is similar to balanced horizontal pleiotropy (Bowden et al. 2017, Hemani et al. 2018, Zhao et al. 2020), which states that π j ind N 0, τ 2 and π j s are independent of Γ ˆ and γ ˆ”
Wei, J., Xiao, Y., Feng, Q., Liu, H., Zou, K., & Li, L. (2024) · Scientific Reports · doi:10.1038/s41598-024-79650-2 · Cited by 4
Choi, K. W., Stein, M. B., Nishimi, K. M., Ge, T., Coleman, J. R. I., Chen, C., Ratanatharathorn, A. D., Zheutlin, A. B., Dunn, E. C., Breen, G. D., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/759753 · Cited by 4
Causally Associations of Blood Lipids Levels with COVID-19 Risk: Mendelian Randomization StudyPreprint
Zhang, K., Guo, Y., Wang, Z., Ding, J., Yao, S., Chen, H., Zhu, D., Zhang, K., Xue, H., Huang, W., et al. (2020) · Research Square · doi:10.21203/rs.3.rs-86425/v1 · Cited by 5
Clayton, G., Soares, A. G., Goulding, N., Borges, M. C., Holmes, M. V., Smith, G. D., Tilling, K. M., Lawlor, D. A., & Carter, A. R. (2022) · medRxiv · doi:10.1101/2022.03.03.22271836 · Cited by 4
“the outcome through pathways not including the risk factor of interest) and confounding by population 94 stratification are widely discussed (7-9), selection and misclassification bias are less commonly 95 discussed, particularly in applied papers (6, 10, 11).”
BackgroundHAI-VECT(SCD): AI-Humanoid Enabled Virtual Clinical Trial for Sickle Cell DiseasePreprint
Danter, W. R. (2023) · medRxiv · doi:10.1101/2023.10.17.23297152 · Cited by 4
“Challenges of MR include pleiotropy, linkage disequilibrium, and the potential for imprecise estimates of causal effects [24].”
BackgroundCheng, Z., Liu, B., & Liu, X. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1407265 · Cited by 3
“Otherwise, random-effect models are appropriate (23).”
Allantoin Serves as a Novel Risk Factor for the Progression of MASLD
Lv, W., Wang, X., Feng, Z., Sun, C., Wu, H., Zeng, M., Gao, T., Cao, K., Xu, J., Zou, X., et al. (2025) · Antioxidants · doi:10.3390/antiox14050500 · Cited by 3
Evidence supporting the role of hypertension in the onset of migraine
Xiao, G., Huang, Z., Lan, Q., Hu, J., Shi, H., Chen, Y., Zhou, C., Chenghua, L., & Zhou, B. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06187-x · Cited by 5
Wei, F., Zhao, M., Sun, X., Ma, H., Yin, H., & Shen, X. (2025) · Medicine · doi:10.1097/md.0000000000042596 · Cited by 3
“First, the horizontal plei-otropy of IVs was assessed using the MR-PRESSO global test [25] and MR-Egger regression [22] ; Second, Cochran Q test [26] was used to assess heterogeneity among IVs; Third, leave-one-out sensitivity analysis [27] was used to assess the effects of a single SNP.…”
Yu, K., Jiang, R., Zhou, D., & Zhao, Z. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251344572 · Cited by 3
“Confounding factors, such as socioeconomic variables, 10 are often dif fi cult to quantify and control in these studies.”
Shi, X., Zhang, L., Huang, W., Li, M., Chen, Y., Hu, Y., Lu, C., Xu, C., & Liu, Z. (2025) · British Journal of Hospital Medicine · doi:10.12968/hmed.2025.0067 · Cited by 3
Guo, Q., Chen, C., Wang, Y., Guo, L., & Shang, S. (2025) · Brain and Behavior · doi:10.1002/brb3.70722 · Cited by 3
“Sensitivity analyses included Cochrane’s Q test for heterogeneity ( p < 0.05 indicating heterogeneity) and MR-Egger for pleiotropy (intercept p < 0.05 suggesting pleiotropy) (Hemani et al. 2018).”
Influential
Metadata
- 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
- 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
- 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
- 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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