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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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“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]
In the citing paper
“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]
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InfluentialJiang, Y., Chen, R., Xu, S., Ding, Y., Zhang, M., Bao, M., He, B., & Li, S. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1321576 · Cited by 70
Can Mendelian Randomization Shift into Reverse Gear?
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MethodMendelian randomization as a tool to inform drug development using human genetics
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“The weighted mode estimate may also be used even when the majority of the SNPs are invalid instruments so long as the SNPs that form a cluster of homogenous results are valid [48, 52].”
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“One approach which could be used to address this is Steiger filtering which can be used to exclude SNPs which explain the variance in the outcome over and above the variance in the exposure [10, 23].”
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Self-citationSearch for multiple myeloma risk factors using Mendelian randomization
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“Pleiotropy exists when a single genetic variant influences multiple phenotypes.(33) Horizontal pleiotropy refers to a situation where the genetic instrument influences disease outcome via a different pathway that is not under investigation.”
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“In two-sample MR, the resulting bias is towards the null, making estimates more conservative (see below for how this was dealt with) [61].”
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“The IVW method can give unbiased estimates when horizontal pleiotropy is balanced or in the absence of horizontal pleiotropy.(19) The used GWASs were based on individuals of solely European origin and adjustment was made for population structure through genetic principal components in these GWASs.”
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“In the MR literature a large (and growing) set of sensitivity analyses allow relaxation of some of the assumptions required for identification [38].”
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“This can occur as horizontal pleiotropy where a genetic variant or gene affects two traits through independent pathways, or vertical pleiotropy/causation where one trait is an outcome of the other trait (Hemani et al., 2018).”
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“…the MR-Egger and the weighted median and mode methods (a divergence among them would also suggest horizontal pleiotropy); and generating a scatterplot as a visual check for potentially pleiotropic outliers in the variant-specific causal estimates (Bowden et al. , 2015, 2016; Hemani et al. , 2018).”
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“pathways other than the middle exposure variable [55].”
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“The fact that genotypes are not modifiable by disease onset also limits reverse causation.(8) This makes MR well suited for mediation analysis.”
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“Once pleiotropy is detected, the credibility of the causal relationship between exposure and outcome will be greatly reduced.(33) Finally, a leave-one-out analysis was conducted by sequentially removing each SNP and calculating the meta-effect of the”
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“34 Additionally, we performed sensitivity analyses to evaluate the robustness of our findings.”
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“61 An alternative approach is to assume that only half of SNP instruments are valid and then take the median effect of available SNP instruments to estimate causal effects, including Simple median and Weighted median.”
InfluentialMolecular genetic overlap between posttraumatic stress disorder and sleep phenotypes
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“where an instrument [SNP] has an effect on the outcome variable that is independent [not mediated by] of its effect on the exposure variable), whereas these assumptions are less stringent within the MR Egger method [33, 38].”
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“Causal estimates and findings may be skewed due to the pleiotropy of SNPs in the IVW study (19).”
BackgroundInvestigating Associations of Omega-3 Fatty Acids, Lung Function Decline, and Airway Obstruction
Patchen, B., Balte, P., Bartz, T. M., Barr, R. G., Fornage, M., Graff, M., Jacobs, D. R., Kalhan, R., Lemaître, R. N., O’Connor, G. T., et al. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202301-0074oc · Cited by 49
Circulating immune cells and risk of osteosarcoma: a Mendelian randomization analysis
Li, L., Sun, Y., Luo, J. C., & Liu, M. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1381212 · Cited by 51
“Finally, we also conducted a leave-one-out analysis to test the stability of the causality after excluding SNPs one by one.”
BackgroundMethodInfluentialSeddighi, S., Houck, A. L., Rowe, J. B., & Pharoah, P. D. P. (2019) · Scientific Reports · doi:10.1038/s41598-019-49795-6 · Cited by 48
The Role of Mendelian Randomization Studies in Deciphering the Effect of Obesity on Cancer
Fang, Z., Song, M., Lee, D. H., & Giovannucci, E. L. (2021) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djab102 · Cited by 50
Said, M. A., van de Vegte, Y. J., Verweij, N., & van der Harst, P. (2020) · Journal of the American Heart Association · doi:10.1161/jaha.120.016808 · Cited by 47
“Caffeine from coffee 0 (0-0) 15 (6-60) 120 (85-120) 180 (170-180) 240 (240-240) 300 (255-300) 360 (340-360) 480 (425-595)”
InfluentialCausal inference on neuroimaging data with Mendelian randomisation
Taschler, B., Smith, S. M., & Nichols, T. E. (2022) · NeuroImage · doi:10.1016/j.neuroimage.2022.119385 · Cited by 47
Mendelian Randomization: Principles and its usage in Lp(a) research
Lamina, C. (2022) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2022.04.013 · Cited by 47
Herpes simplex virus and Alzheimer’s disease: a Mendelian randomization study
Kwok, M. K., & Schooling, C. M. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.09.025 · Cited by 55
Zhu, X., Li, X., Xu, R., & Wang, T. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btaa985 · Cited by 41
Meisinger, C., & Freuer, D. (2022) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2022.151992 · Cited by 45
Association Between Human Blood Metabolome and the Risk of Psychiatric Disorders
Jia, Y., Hui, L., Sun, L., Guo, D., Shi, M., Zhang, K., Yang, P., Wang, Y., Liu, F., Shen, O., et al. (2022) · Schizophrenia Bulletin · doi:10.1093/schbul/sbac130 · Cited by 44
Karhunen, V., Bond, T. A., Zuber, V., Hurtig, T. M., Moilanen, I. K., Järvelin, M., Evangelou, M., & Rodriguez, A. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01584-4 · Cited by 44
Zhao, G., Lu, Z., Sun, Y., Kang, Z., Feng, X., Liao, Y., Sun, J., Zhang, Y., Huang, Y., & Yue, W. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02492-5 · Cited by 45
Bond, T. A., Richmond, R. C., Karhunen, V., Cuéllar-Partida, G., Borges, M. C., Zuber, V., Alves, A. C., Mason, D., Yang, T., Gunter, M. J., et al. (2022) · BMC Medicine · doi:10.1186/s12916-021-02216-w · Cited by 42
“Furthermore, most of the SNPs included in the lassosum BMI PRS had small effect sizes, and the consequences of this for the extent of horizontal pleiotropic effects are unclear [72], so we explored how MR estimates varied with varying SNP effect size distributions.”
BackgroundKamiza, A. B., Fatumo, S., Singini, M. G., Yeh, C., & Chikowore, T. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104003 · Cited by 46
“the MR analysis [28] and a different MR method was used to report the results.”
Baurecht, H., Welker, C., Baumeister, S., Weidinger, S., Meisinger, C., Leitzmann, M. F., & Emmert, H. (2021) · British Journal of Dermatology · doi:10.1111/bjd.20092 · Cited by 44
Graves Disease and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization
Xian, W., Wu, D., Liu, B., Hong, S., Huo, Z., Xiao, H., & Li, Y. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac683 · Cited by 44
Cerani, A., Zhou, S., Forgetta, V., Morris, J. A., Trajanoska, K., Rivadeneira, F., Larsson, S. C., Michaëlsson, K., & Richards, J. B. (2019) · BMJ · doi:10.1136/bmj.l4410 · Cited by 44
Harrison, S., Davies, N. M., Howe, L. D., & Hughes, A. (2021) · Science Advances · doi:10.1126/sciadv.abf8257 · Cited by 44
Life Course Adiposity and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study
Zhang, L., Tang, L., Huang, T., & Fan, D. (2020) · Annals of Neurology · doi:10.1002/ana.25671 · Cited by 41
“Therefore, the 6 SNPs are valid instruments.(40) Fourth, there are SNPs that were significantly associated with childhood BMI and BMI, according to the results of the study (see Supplementary Table 5).”
ResultThapar, A., Livingston, L. A., Eyre, O., & Riglin, L. (2022) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.13678 · Cited by 42
“Mendelian randomisation (MR) is an alternative method, utilising genetic data to infer causality (Hemani, Bowden, & Davey Smith, 2018), although it requires many assumptions.”
MethodKnutson, K. A., Deng, Y., & Pan, W. (2020) · NeuroImage · doi:10.1016/j.neuroimage.2020.117347 · Cited by 41
“However, the IVW and Egger estimators (and by extension their multivariate version) suffer from substantial power loss when restricted to a smaller set of independent IVs/SNPs ( Hemani et al., 2018 ), ( Bowden et al., 2016 ).”
Qiu, S., Cao, P., Guo, Y. L., Lu, H., & Hu, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.643582 · Cited by 41
Xu, X., Eales, J., Jiang, X., Sanderson, E. C. M., Drzal, M., Saluja, S., Scannali, D., Williams, B., Morris, A. P., Guzik, T. J., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab357 · Cited by 44
“MRPRESSO were chosen to minimize any potential bias arising from horizontal pleiotropy.(48) To further quantify the magnitude of horizontal pleiotropy, we employed MR-Egger intercept test.”
Satterfield, B. A., Dikilitas, O., Safarova, M. S., Clarke, S. L., Tcheandjieu, C., Zhu, X., Bastarache, L., Larson, E. B., Justice, A. E., Shang, N., et al. (2021) · Circulation: Genomic and Precision Medicine · doi:10.1161/circgen.120.003354 · Cited by 40
Han, X., Laíns, I., Li, J., Li, J., Chen, Y., Yu, B., Qi, Q., Boerwinkle, E., Kaplan, R. C., Thyagarajan, B., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101085 · Cited by 41
“Two types of pleiotropy exist in MR analysis: vertical pleiotropy and horizontal pleiotropy.(39) In vertical pleiotropy, genetic variants associate with multiple traits on the same pathway, not invalidating the MR assumption, while horizontal pleiotropy indicates genetic variants affecting multiple traits through sepa…”
BackgroundMaimaiti, A., Turhon, M., Abulaiti, A., Dilixiati, Y., Zhang, F., Axier, A., Kadeer, K., Zhang, Y., Maimaitili, A., & Yang, X. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04512-w · Cited by 43
“Weighted median, for instance, facilitates grouping SNPs into clusters and deriving an estimate based on the cluster with the most SNPs, under the assumption that at least half of the SNPs are valid [44].”
BackgroundEstimating causality between smoking and abdominal obesity by Mendelian randomization
Carrasquilla, G. D., García‐Ureña, M., Romero-Lado, M. J., & Kilpeläinen, T. O. (2024) · Addiction · doi:10.1111/add.16454 · Cited by 42
Marchi, M., Alkema, A., Xia, C., Thio, C. H. L., Chen, L.-Y., Schalkwijk, W., Galeazzi, G. M., Ferrari, S., Pingani, L., Kweon, H., et al. (2024) · Nature Human Behaviour · doi:10.1038/s41562-024-01919-3 · Cited by 47
“However, to break the assumptions of MR, it is not sufficient for the genetic variants in the instrumental variable to have pleiotropic effects 70 .”
BackgroundHDL cholesterol levels and susceptibility to COVID-19
Chidambaram, V., Kumar, A., Majella, M. G., Seth, B., Sivakumar, R. K., Voruganti, D. C., Bavineni, M., Baghal, A., Gates, K., Kumari, A., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104166 · Cited by 40
“27 Despite contrasting reports, substantial evidence supports the biological plausibility of our findings.”
Russell, A. E., Ford, T., Gunnell, D., Heron, J., Joinson, C., Moran, P., Relton, C., Suderman, M., Hemani, G., & Mars, B. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.05.065 · Cited by 39
“An important limitation in MR analysis is that it is difficult to prove that there is no path from the instrument to the outcome that is not through the exposure (also known as horizontal pleiotropy (49)).”
BackgroundSelf-citationZhang, K., Li, A., Zhou, J., Zhang, C., & Chen, M. (2023) · Respiratory Research · doi:10.1186/s12931-022-02309-x · Cited by 38
“Secondly, Cochran’s Q test was employed to determine heterogeneity among Ivs [30].”
MethodPlotnikov, D., & Guggenheim, J. A. (2019) · Ophthalmic and Physiological Optics · doi:10.1111/opo.12596 · Cited by 37
“See Hemani et al.(34) for an in-depth discussion of these issues.”
Applications of Mendelian randomization in psychiatry: a comprehensive systematic review
Saccaro, L. F., Gasparini, S., & Rutigliano, G. (2022) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000327 · Cited by 35
“Prominent among the limitations of MR studies, is the nondemonstrable assumption that the exposure mediates the apparent pleiotropic associations (thus reflecting vertical pleiotropy), and that the selected SNP does not influence both the exposure and the outcomes through unrelated pathways (thus violating the exclusi…”
BackgroundSu, Y., Xu, S., Ma, Y., Yin, P., Hao, X., Zhou, J., Fung, W. K., Jiang, H., & Wang, P. (2024) · Statistics in Medicine · doi:10.1002/sim.10245 · Cited by 40
“Another concern is the violation of the exclusion restriction assumption owing to widespread horizontal pleiotropy, where the SNP affects the outcome through pathways not mediated by the exposure variable [14, 15].”
Use of Mendelian Randomization to Examine Causal Inference in Osteoporosis
Zheng, J., Frysz, M., Kemp, J. P., Evans, D. M., Smith, G. D., & Tobias, J. H. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00807 · Cited by 36
Vilar‐Ribó, L., Sánchez‐Mora, C., Rovira, P., Vanesa Richarte, B., Montse Corrales, F., Fadeuilhe, C., Arribas, L., Casas, M., Ramos‐Quiroga, J. A., Marta Ribasés, A., et al. (2020) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32827 · Cited by 40
“…variants and additional MR methods were implemented as sensitivity analyses for IVW significant findings: MR-Egger regression (Bowden et al., 2015), weighted median regression (Bowden, Davey Smith, et al., 2016a), MR-PRESSO (Verbanck et al., 2018), and Steiger filtering (Hemani et al., 2018).”
MethodSaid, M. A., Yeung, M. W., van de Vegte, Y. J., Benjamins, J. W., Dullaart, R. P. F., Ruotsalainen, S., Ripatti, S., Natarajan, P., Juarez-Orozco, L. E., Verweij, N., et al. (2021) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.120.315300 · Cited by 39
Zhang, Q., Greenbaum, J., Shen, H., Zhao, L., Zhang, W., Sun, C., & Deng, H.-W. (2020) · Osteoporosis International · doi:10.1007/s00198-020-05640-5 · Cited by 37
Xu, S., Wang, P., Fung, W. K., & Liu, Z. (2022) · Biometrics · doi:10.1111/biom.13732 · Cited by 36
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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