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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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Cites
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Borges, M. C., Haycock, P., Zheng, J., Hemani, G., Howe, L. J., Schmidt, A. F., Staley, J. R., Lumbers, R. T., Henry, A., Lemaître, R. N., et al. (2022) · Human Molecular Genetics · doi:10.1093/hmg/ddac153 · Cited by 19
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Genetically Determined Birthweight Associates With Atrial Fibrillation
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“We considered the outcome of the IVW method as the primary results due to its higher statistical power compared to the others (Hemani et al., 2018a).”
ResultThe Interface of Therapeutics and Genomics in Cardiovascular Medicine
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Circulating phosphorus concentration and risk of prostate cancer: a Mendelian randomization study
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“MR uses genetic variants as instruments to mimic a random allocation procedure in randomized controlled trials [12], thereby avoiding issues of confounding and reverse causation [13].”
MethodYang, H., Song, J., Li, A., Lv, L., Sun, X., Mao, Y., & Ye, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1139799 · Cited by 20
“05) was observed; otherwise, the random-effects model was utilized (19).”
MethodLi, H., Chen, K., Yang, L., Wang, Q.-L., Zhang, J., & He, J. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1107780 · Cited by 20
“Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) regression analyses identified potentially pleiotropic outliers and estimated values after eliminating the outlier SNPs (51).”
BackgroundLiu, M., Lan, Y., Zhang, H., Wu, M., Zhang, X., Leng, L., Zheng, H., & Li, J. (2023) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.19484 · Cited by 20
“All statistical analyses regarding MR were conducted using R packages MendelianRandomization 16 and MR-PRESSO 17 on R version 4.2.0.”
MethodInfluentialChen, C., Zhang, H., Lan, Y., Yan, W., Liu, S., Chen, Y., Xie, T., Ning, J., Yan, X., Shang, L., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05097-8 · Cited by 20
“The fixed-effects IVW method was applied in scenarios devoid of heterogeneity [36].”
MethodObstructive sleep apnea and mental disorders: a bidirectional mendelian randomization study
Liu, H., Wang, X., Hu, F., Zhou, S., Pan, J., Ouyang, C., & Hu, X. (2024) · BMC Psychiatry · doi:10.1186/s12888-024-05754-8 · Cited by 21
“Therefore, we use two different MR methods that are relatively robust to horizontal pleiot-ropy, although at the cost of reduced statistical power [32].”
MethodCirculating Proteins and IgA Nephropathy
Tang, C., Chen, P., Xu, L.-L., Lv, J., Shi, S., Zhou, S., Liu, L., & Zhang, H. (2024) · Journal of the American Society of Nephrology · doi:10.1681/asn.0000000000000379 · Cited by 20
“35 The presence of horizontal pleiotropy was tested using MR-Egger regression when three or more instrumental variables were included, and cis-pQTLs with a signi fi cant MR-Egger regression intercept ( P , 0.05) would be removed.”
InfluentialRobinson, J. W., Martin, R. M., Tsavachidis, S., Howell, A., Relton, C. L., Armstrong, G., Bondy, M. L., Zheng, J., & Kurian, K. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-82169-5 · Cited by 20
Bowden, J., Pilling, L. C., Türkmen, D., Kuo, C., & Melzer, D. R. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009783 · Cited by 18
Self-citationUsing Genetic Instruments to Estimate Interactions in Mendelian Randomization Studies
North, T.-L., Davies, N. M., Harrison, S., Carter, A. R., Hemani, G., Sanderson, E., Tilling, K., & Howe, L. D. (2019) · Epidemiology · doi:10.1097/ede.0000000000001096 · Cited by 19
Self-citationLiao, L., Li, W., Liu, Y., Li, J.-P., Zhuang, X., & Liao, X. (2019) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2019.09.013 · Cited by 19
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Palmos, A., Hübel, C., Lim, K. X., Hunjan, A. K., Coleman, J. R. I., & Breen, G. D. (2022) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2022.01.003 · Cited by 18
Strengthening Causal Inference in Exposomics Research: Application of Genetic Data and Methods
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“The random-effects model assumes that all SNPs are valid instrumental variables (35) or the horizontal pleiotropy is balanced (36).”
BackgroundBidirectional Mendelian randomization study of psychiatric disorders and Parkinson’s disease
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“The horizontal pleiotropy, which occurs when an IV affects the outcome outside of its effect on the exposure, is the main factor that violates the assumptions (Hemani et al., 2018).”
BackgroundChen, C., Lan, Y., Wang, Z., Yan, W., Yan, X., & Han, J. (2023) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02176-3 · Cited by 19
“When there was no evidence of heterogeneity, the fixed effects IVW model was used [38].”
Zhang, Z., Duan, Y., & Huo, J. (2023) · Calcified Tissue International · doi:10.1007/s00223-023-01160-6 · Cited by 19
“In contrast, in studies of molecular traits represented by molecular modifications or gene expression, there is usually only a very small number of strongly correlated genetic variants [30, 31].”
Jiang, Y., Chen, R., Xu, S., Ding, Y., Zhang, M., Bao, M., He, B., & Li, S. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1295040 · Cited by 19
“This approach used inverse-variance based weighting, and constrained the regression line intercept to cross zero (25).”
MethodCYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility
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Yang, Y., Chen, B., Zheng, C., Zeng, H., Zhou, J., Chen, Y., Su, Q., Wang, J., Wang, J., Wang, Y., et al. (2024) · Cell & Bioscience · doi:10.1186/s13578-024-01214-8 · Cited by 19
“To assess the heterogeneity of IVs and detect any pleiotropic effects, we conducted the Cochran’s Q test, with a significance threshold set at a P-value for heterogeneity 0.05 [50].”
MethodInfluentialAmmous, F., Zhao, W., Ratliff, S. M., Kho, M., Shang, L., Jones, A. C., Chaudhary, N. S., Tiwari, H. K., Irvin, M. R., Arnett, D. K., et al. (2020) · Epigenetics · doi:10.1080/15592294.2020.1827717 · Cited by 19
“Additionally, we applied the MR Egger test to examine pleiotropy because IVW MR is invalid in the presence of horizontal pleiotropic effects of IVs [56].”
MethodHughes, A., Torvik, F. A., van Bergen, E., Hannigan, L. J., Corfield, E. C., Andreassen, O. A., Ystrøm, E., Ask, H., Smith, G. D., Davies, N. M., et al. (2024) · npj Science of Learning · doi:10.1038/s41539-024-00260-8 · Cited by 22
“In additional analyses, we therefore apply ‘ two-sample ’ Mendelian randomization methods, designed to assess horizontal pleiotropy by comparing associations of individual genetic variants with exposures and outcomes 24 .”
InfluentialAdams, B., Jacocks, L., & Guo, H. (2020) · BMC Cardiovascular Disorders · doi:10.1186/s12872-020-01542-w · Cited by 18
“RAPS enhances the IVW estimation by replacing each weight with a function form of the causal effect and the variation of the instrument strength [23].”
BackgroundChen, J., Zhang, J., So, H., Ai, S., Wang, N., Tan, X. W., & Wing, Y. K. (2021) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4406 · Cited by 18
Stroke Genetics: Turning Discoveries into Clinical Applications
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Gormley, M., Dudding, T., Kachuri, L., Burrows, K., Chong, A., Martin, R. M., Thomas, S. J., Tyrrell, J., Ness, A., Brennan, P., et al. (2022) · BMC Medicine · doi:10.1186/s12916-022-02233-3 · Cited by 18
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Considering strategies for SNP selection in genetic and polygenic risk scores
St.-Pierre, J., Zhang, X., Lu, T., Jiang, L., Loffree, X., Wang, L., Bhatnagar, S., Greenwood, C. M. T., & CANSSI team on Improving Robust High-Dimensional Causal Inference and Prediction Modelling (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.900595 · Cited by 18
“One challenge is that the SNPs used to construct the GRS may violate assumption 3) due to pleiotropy, a phenomenon where a genetic variant may influence a disease or trait through independent pathways (Hemani et al., 2018).”
BackgroundWang, Y., Kong, L., Ye, C., Dou, C., Zheng, J., Xu, M., Xu, Y., Li, M., Zhao, Z., Lu, J., et al. (2023) · Liver International · doi:10.1111/liv.15669 · Cited by 18
“19 The UVMR and MVMR results for each liver disease from FinnGen and UK Biobank were pooled using fixed-effects meta-analysis.”
MethodLiu, C., Ran, J., Hou, B., Li, Y., Morelli, J. N., & Li, X. (2023) · Journal of Orthopaedic Research® · doi:10.1002/jor.25656 · Cited by 17
“31 All MR analyses were performed using the R software (version 4.1.2, http://www.r-project.org) and the packages “ TwoSampleMR, ” “ MRPRES-SO ” and “ RadialMR.”
MethodInfluentialBalit, J., Erlangsen, A., Docherty, A. R., Turecki, G., & Orri, M. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02465-0 · Cited by 20
“Pleiotropy does not bias the analysis, unless it is unbalanced [35].”
Dai, X.-C., Yu, Y., Zhou, S.-Y., Yu, S., Xiang, M., & Ma, H. (2024) · BioData Mining · doi:10.1186/s13040-024-00356-2 · Cited by 20
“Therefore, we compared IVW results with other established MR methods whose estimates are known to be relatively robust to horizontal pleiotropy, albeit at the expense of reduced statistical power [22].”
ResultAdams, C. D., & Boutwell, B. B. (2020) · Scientific Reports · doi:10.1038/s41598-020-69114-8 · Cited by 18
Drake, I., Fryk, E., Strindberg, L., Lundqvist, A., Rosengren, A. H., Groop, L., Ahlqvist, E., Borén, J., Orho‐Melander, M., & Jansson, P. (2021) · Diabetologia · doi:10.1007/s00125-021-05594-1 · Cited by 18
“MR analyses were performed using the ‘TwoSample MR’ package [28].”
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Saunders, C. N., Cornish, A. J., Kinnersley, B., Law, P., Houlston, R. S., Collaborators, Claus, E. B., Il’yasova, D., Schildkraut, J. M., Barnholtz‐Sloan, J. S., et al. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01083-1 · Cited by 17
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“Leave-one-out analysis was performed to identify potential bias from individual SNPs [31].”
Higbee, D., Granell, R., Walton, E., Korologou‐Linden, R., Smith, G. D., & Dodd, J. W. (2021) · BMJ Open Respiratory Research · doi:10.1136/bmjresp-2020-000759 · Cited by 17
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“Because the MR results might be confounded when the genetic instruments show horizontal pleiotropy, we compared the IVW results with the weighed median (29) and the MREgger (24) tests, whose estimates are known to be relatively robust to horizontal pleiotropy (30).”
ResultHu, Y., Cheng, X., Mao, H., Chen, X., Cui, Y., & Qiu, Z. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.747547 · Cited by 16
“The random-effects IVW model was used if the substantial heterogeneity was significant (24).”
MethodInfluentialMbutiwi, F. I. N., Dessy, T., & Sylvestre, M. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.803238 · Cited by 17
“Two-sample data were defined as the use of summary statistics on SNPexposure and SNP-outcome associations both from two distinct samples (Hemani et al., 2018a).”
BackgroundMethodInfluentialJia, Y., Wang, R., Guo, D., Sun, L., Shi, M., Zhang, K., Yang, P., Zang, Y., Wang, Y., Liu, F., et al. (2022) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2022.04.019 · Cited by 18
Lv, L., Sun, X., Liu, B., Song, J., Wu, D., Gao, Y. L., Li, A., Hu, X., Mao, Y., & Ding, Y. (2022) · Clinical Epidemiology · doi:10.2147/clep.s367547 · Cited by 17
“Otherwise the random-effect model was used.(23) The maximum likelihood–based method provides estimated causal association by assuming that there is a linear relationship between exposure and outcome and normal bivariate distribution for the genetic association estimates.”
MethodCabrera‐Mendoza, B., Wendt, F. R., Pathak, G. A., Angelis, F. D., Lillo, A. D., Koller, D., & Polimanti, R. A. (2022) · International Journal of Epidemiology · doi:10.1093/ije/dyac129 · Cited by 19
“Thus, we re-estimated the effects using the MR–RAPS approach with using squared error loss method (I(2)) to account for overdispersion (systematic pleiotropy) within the genetic instrument.(37) The result observed was consistent with the IVW estimates (b1⁄40.”
MethodResultBody shape and risk of glaucoma: A Mendelian randomization
Yuan, R., Liu, K., Cai, Y., He, F., Xiao, X., & Zou, J. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.999974 · Cited by 18
Jiang, W., Lu, K., Zhuang, Z., Wang, X., Tang, X., Huang, T., Gao, P., Wang, Y., & Du, J. (2023) · Metabolites · doi:10.3390/metabo13030403 · Cited by 17
Wang, W., Zhang, L., Xia, K., Huang, T., & Fan, D. (2023) · Biomedicines · doi:10.3390/biomedicines11051359 · Cited by 17
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Ye, L., Wang, F., Wu, H., Yuan, Y., & Zhang, Q. (2024) · Scientific Reports · doi:10.1038/s41598-024-74883-7 · Cited by 17
“IVW method, which is the most commonly used method of causality estimation in MR analysis 35 , was the main method for estimating the causal relationship between asthma and lung cancer in the present study.”
MethodInfluentialPhysical Activity Does Not Lower the Risk of Lung Cancer
Baumeister, S., Leitzmann, M. F., Bahls, M., Meisinger, C., Amos, C. I., Hung, R. J., Teumer, A., & Baurecht, H. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-1127 · Cited by 18
“The MR-Pleiotropy RESidual Sum and Outlier (MRPRESSO) method (22, 29) was used to detect and correct for outliers in the IVW linear regression.”
MethodIlboudo, Y., Garrett, M. E., Bartolucci, P., Brugnara, C., Clish, C. B., Hirschhorn, J. N., Galactéros, F., Ashley‐Koch, A. E., Telen, M. J., & Lettre, G. (2020) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2020.102504 · Cited by 18
“MR analyses using the sensitivity tests MR-Egger and weighted-median did not yield significant associations for Model 2, suggesting insufficient statistical power for these tests [12] or potential residual horizontal pleiotropy (Supplementary Table 6).”
MethodAi, S., Wang, X., Wang, S., Zhao, Y., Guo, S., Li, G., Chen, Z., Lin, F., Guo, S. J., Li, Y., et al. (2022) · Cardiovascular Diabetology · doi:10.1186/s12933-022-01540-6 · Cited by 17
“By removing each SNP in turn, the leave-one-out analysis could evaluate whether the MR estimate is driven or biased by potentially pleiotropic SNPs [35].”
MethodPolimanti, R. A., Wendt, F. R., Pathak, G. A., Tylee, D. S., Tcheandjieu, C., Hilliard, A. T., Levey, D. F., Adhikari, K., Gaziano, J. M., O’Donnell, C. J., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01735-z · Cited by 17
“the variants included in the genetic instrument have an effect on disease outside their effects on the exposure in MR [49]) under different scenarios in the MR estimates.”
BackgroundSeviiri, M., Law, M. H., Ong, J., Gharahkhani, P., Nyholt, D. R., Olsen, C. M., Whiteman, D. C., & MacGregor, S. (2021) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-20-1765 · Cited by 19
“In addition, due to the limited number of PUFA SNPs, a multivariable MR approach (47) was not appropriate to assess highly polygenic potential confounders including; BMI, vitamin D, and educational attainment in the same model as this would introduce the regression dilution bias toward the null for the PUFA estimates…”
BackgroundMethodGenetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk
Wang, Z., Yin, Z., Sun, G., Zhang, D., & Zhang, J. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02455-3 · Cited by 16
“This approach allowed us to overcome some limitations of observational studies and provided more robust evidence for causal associations [18, 19].”
Adams, C. D., & Boutwell, B. B. (2021) · Scientific Reports · doi:10.1038/s41598-021-97410-4 · Cited by 16
“It uses insights from Mendel’s laws of inheritance and genotype assignment at conception 14–16 to improve causal inference in epidemiologic studies.”
Bosman, A., Campos‐Obando, N., Medina‐Gómez, C., Voortman, T., Uitterlinden, A. G., & Zillikens, M. C. (2021) · Journal of Nutrition · doi:10.1093/jn/nxab351 · Cited by 17
“Horizontal pleiotropy would violate the exclusion-restriction condition in MR (18).”
BackgroundInfluentialDamoah, C. E., Snir, O., Hindberg, K., Garred, P., Ludviksen, J. K., Brækkan, S. K., Morelli, V. M., Mollnes, T. E., & Hansen, J. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.317746 · Cited by 16
Zou, Y., Wang, Q., & Cheng, X. (2023) · Neurology and Therapy · doi:10.1007/s40120-023-00458-9 · Cited by 16
“The IVW method only provides unbiased estimates when horizontal pleiotropy is balanced or absent [25].”
MethodCortisol and periodontitis: Prospective observational and Mendelian randomization studies
Baumeister, S., Reckelkamm, S. L., Grabe, H. J., Nauck, M. A., Klinger-König, J., Völzke, H., Kocher, T., Friedrich, N., & Holtfreter, B. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1100985 · Cited by 19
“To ensure that results from primary and secondary IVW analysis were not biased by horizontal pleiotropy, we used Cochran’s Q and I2 to test heterogeneity of estimates, performed MR Egger’s intercept test for directional pleiotropy, and leave-one-out analysis to assess whether the IVW estimate was driven by a single SN…”
MethodVitamin D and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study
Lin, T., Zhou, F., Mao, H., Xie, Z., & Jin, Y. (2023) · BMC Pulmonary Medicine · doi:10.1186/s12890-023-02589-z · Cited by 16
“We also assessed heterogeneity among selected IVs using Cochrane’s Q-value [24].”
MethodXu, Q., Cai, M., Ji, Y., Ma, J., Liu, J., Zhao, Q., Chen, Y., Zhao, Y., Zhang, Y., Wang, H., et al. (2023) · Schizophrenia · doi:10.1038/s41537-023-00389-2 · Cited by 17
“The IVW method could provide an unbiased estimation in the absence of horizontal pleiotropy or under the assumption of balanced pleiotropy 44 .”
MethodGu, P., Pu, B., Ma, Y., Yue, D., Qiao, X., Li, H., Liu, T., Zheng, X., & Ou-Yang, C.-Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1238757 · Cited by 16
“If heterogeneity persisted, we reported the results from the IVW random-effects model as the primary effect estimate; otherwise, we used the fi xed-effects model (26).”
MethodLan, G., Xie, M., Lan, J., Huang, Z., Xie, X., Liang, M., Chen, Z., Jiang, X., Lu, X., Ye, X., et al. (2024) · Respiratory Research · doi:10.1186/s12931-024-02722-4 · Cited by 16
“…method was developed: (1) The genetic variation must be closely related to the exposure in the MR analysis; (2) Genetic variation cannot be associated with confounding factors between exposure and outcome; (3) Exposure must be the mechanism through which genetic variables influence outcomes [21].”
MethodCausal association of immune cells and endometriosis: a Mendelian randomization study
Fang, X., Deng, Q., Yang, H., Yan, Z., Peng, Z., Zhao, Y., Liao, T., Tu, Z., Liu, J., Liu, L., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1397670 · Cited by 16
“MR uses single nucleotide polymorphisms (SNPs) identi fi ed through genome-wide association studies (GWAS) as instrumental variables, effectively simulating randomized controlled trials (RCTs) and mitigating biases associated with confounding and reverse causation (38).”
MethodMendelian randomization analyses support causal relationships between gut microbiome and longevity
Chen, S., Chen, W., Wang, X., & Liu, S. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05823-2 · Cited by 17
“If significant heterogeneity was observed ( P < 0.05), we adopted the random-effects model; otherwise, the fixed-effects model was utilized [34].”
InfluentialEducation, intelligence, and amyotrophic lateral sclerosis: A Mendelian randomization study
Zhang, L., Tang, L., Xia, K., Huang, T., & Fan, D. (2020) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51156 · Cited by 16
Wang, K., Ding, L., Yang, C., Hao, X., & Wang, C. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.608630 · Cited by 17
Butler‐Laporte, G., Nakanishi, T., Mooser, V., Renieri, A., Amitrano, S., Zhou, S., Chen, Y., Forgetta, V., & Richards, J. B. (2020) · International Journal of Epidemiology · doi:10.1093/ije/dyaa229 · Cited by 16
“Lastly, the variants must only be associated with the outcome of interest through their effect on the exposure (also known as an absence of horizontal pleiotropy).(16) ACE inhibitors act by decreasing ACE activity.”
BackgroundOsteoarthritis: Insights Offered by the Study of Bone Mass Genetics
Hartley, A. E., Gregson, C. L., Paternoster, L., & Tobias, J. H. (2021) · Current Osteoporosis Reports · doi:10.1007/s11914-021-00655-1 · Cited by 17
Zhang, Q., Zhang, X., Zhang, J., Wang, B., Meng, X., Tian, Q., Zhang, J., Jiang, M., Zhang, Y., Zheng, D., et al. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.769198 · Cited by 16
“Multivariable MR (mvMR) integrates a series of pleiotropic SNPs (22) associated with at least one risk factors as IVs to evaluate the causal influence of each risk factor on the outcome.”
BackgroundWhy are education, socioeconomic position and intelligence genetically correlated?Preprint
Morris, T., Davies, N. M., Hemani, G., & Smith, G. D. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/630426 · Cited by 16
Self-citationSpiller, W., Hartwig, F. P., Sanderson, E., Smith, G. D., & Bowden, J. (2020) · doi:10.1101/2020.07.27.20162909 · Cited by 15
Self-citationAlcohol consumption and frailty risk: a dose–response meta-analysis of cohort studies
Soltani, S., Jayedi, A., Ghoreishy, S. M., Mousavirad, M., Movahed, S., Jabbari, M., & Asoudeh, F. (2024) · Age and Ageing · doi:10.1093/ageing/afae199 · Cited by 15
Coneys, R., Storm, C. S., Kia, D. A., Almramhi, M. M., & Wood, N. W. (2021) · Movement Disorders · doi:10.1002/mds.28662 · Cited by 15
Park, S., Lee, S., Kim, Y., Cho, S., Kim, K., Kim, Y. C., Han, S. S., Lee, H., Lee, J. P., Joo, K. W., et al. (2021) · Liver International · doi:10.1111/liv.15118 · Cited by 15
Liao, Z., Vosberg, D. E., Pausová, Z., & Paus, T. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac484 · Cited by 15
Gong, Z., Liu, Y., Ding, F., Ba, L., & Zhang, M. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.981371 · Cited by 15
“The presence of pleiotropy was detected when the intercept significantly deviated from the origin in the MR-Egger regression method (Hemani et al., 2018).”
MethodDeep mendelian randomization: Investigating the causal knowledge of genomic deep learning models
Malina, S., Cizin, D. M., & Knowles, D. A. (2022) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009880 · Cited by 15
“MR-Egger seeks robustness to violations of Exclusion Restriction, otherwise known as horizontal pleiotropy in statistical genetics [36].”
BackgroundTen interleukins and risk of prostate cancer
Li, B.-H., Yan, S., Luo, L.-S., Zeng, X., Wang, Y., & Wang, X. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1108633 · Cited by 16
“method with multiplicative random effects was used (13, 20).”
MethodDementia prevention: the Mendelian randomisation perspective
Anderson, E. L., Davies, N. M., Korologou‐Linden, R., & Mika Kivimaki, B. (2023) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2023-332293 · Cited by 18
“26 MR studies can seek to interrogate whether pleiotropy is a likely source of bias by reporting Cochran’s Q heterogeneity statistics, the MR-Egger intercept and any pleiotropy-adjusted causal effect estimates.”
BackgroundXu, Q., Li, H., & Zhu, D. (2024) · Schizophrenia · doi:10.1038/s41537-024-00471-3 · Cited by 20
“We performed an MR-Egger intercept test method 37 to evaluate the mean value of the Egger intercept was non-zero, in which case the pleiotropy could be directed 38 .”
Causal roles of skin microbiota in skin cancers suggested by genetic study
Zhu, Y., Liu, W., Wang, M., Wang, X., & Wang, S. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1426807 · Cited by 15
“We applied five MR methods for features with multiple IVs: inverse-variance weighted (IVW) (Burgess et al., 2013), weighted median (Bowden et al., 2016), MR-Egger regression (Bowden et al., 2015), simple mode (Hemani et al., 2018a), and weighted mode (Hartwig et al., 2017).”
MethodCXCL12 drives natural variation in coronary artery anatomy across diverse populations
Coronado, P. E. R., Zhou, J., Fan, X., Zanetti, D., Naftaly, J. A., Prabala, P., Jaimes, A. M. M., Farah, E. N., Kundu, S., Deshpande, S., et al. (2025) · Cell · doi:10.1016/j.cell.2025.02.005 · Cited by 17
“56,68 In summary, our findings provide solid evidence that CXCL12 patterns human coronary artery growth and branching.”
Korologou‐Linden, R., Anderson, E. L., Jones, H. J., Smith, G. D., Howe, L. D., & Stergiakouli, E. (2019) · International Journal of Epidemiology · doi:10.1093/ije/dyz080 · Cited by 16
“The second possibility is the presence of horizontal pleiotropy.(34,35) SNPs associated with Alzheimer’s disease could be associated with lower academic achievement and lower cognitive ability through biological pathways that are completely unrelated to the disease (Figure 1b).”
BackgroundHu, X., Zhuang, X., Mei, W., Liu, G., Du, Z., Liao, X., & Li, Y. (2019) · Therapeutic Advances in Chronic Disease · doi:10.1177/2040622320909040 · Cited by 16
Relationship between smoking and ALS: Mendelian randomisation interrogation of causality
Opie-Martin, S., Wootton, R. E., Budu‐Aggrey, A., Shatunov, A., Jones, A. R., Iacoangeli, A., Khleifat, A. A., Smith, G. D., & Al‐Chalabi, A. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323316 · Cited by 15
Ma, W., Gu, Z., Lin, Q., Cao, M., Li, X., Li, X., Li, H., Lin, Y., Zhong, J., Xu, M., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1659251 · Cited by 17
“Cis-SNPs were characterized as single nucleotide polymorphisms (SNPs) located within 1 megabase of the gene that encodes the corresponding Schematic representation of the research design.”
InfluentialJones, D., Richardson, T. G., Smith, G. D., Gunnell, D., Munafo, M. R., & Wootton, R. E. (2020) · Crohn s & Colitis 360 · doi:10.1093/crocol/otaa018 · Cited by 16
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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