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Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases
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Abstract
Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the 'no horizontal pleiotropy' assumption can cause severe bias in MR. We developed the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that the MR-PRESSO test is best suited when horizontal pleiotropy occurs in <50% of instruments. Next we applied the MR-PRESSO test, along with several other MR tests, to complex traits and diseases and found that horizontal pleiotropy (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from -131% to 201%; (iii) induced false-positive causal relationships in up to 10% of relationships; and (iv) could be corrected in some but not all instances.
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“We further used the MR-PRESSO global test49 to assess for horizontal pleiotropy and found no significant P values in the four studies used in the MR meta-analysis (UKB GWAX P = 0.07, UKB GWAS P = 0.20, FinnGen P = 0.84 and GR@ACE P = 0.91, all P values unadjusted for multiple comparisons).”
From Clonal hematopoiesis is associated with protection from Alzheimer’s disease (2023) · cites this paper as [49]
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“To ensure the robustness of our findings, we employed sensitivity analyses using Cochran’s Q statistic to assess heterogeneity among instrumental variables and the MR–Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) to evaluate potential pleiotropy90.”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [90]
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Cites
A global reference for human genetic variation
The 1000 Genomes Project Consortium, authors, C., Auton, A., Abecasis, G. R., Steering committee, Altshuler, D. M., Durbin, R. M., Abecasis, G. R., Bentley, D. R., Chakravarti, A., et al. (2015) · Nature · doi:10.1038/nature15393 · Cited by 18,247
Self-citationBowden, J., Davey Smith, G., & Burgess, S. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv080 · Cited by 9,816
Bowden, J., Davey Smith, G., Haycock, P. C., & Burgess, S. (2016) · Genetic Epidemiology · doi:10.1002/gepi.21965 · Cited by 8,922
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577
Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data
Burgess, S., Butterworth, A., & Thompson, S. G. (2013) · Genetic Epidemiology · doi:10.1002/gepi.21758 · Cited by 6,050
Davey Smith, G., & Ebrahim, S. (2003) · International Journal of Epidemiology · doi:10.1093/ije/dyg070 · Cited by 5,882
Genetic studies of body mass index yield new insights for obesity biology
Study, T. L. C., Locke, A. E., The ADIPOGen Consortium, The AGEN-BMI Working Group, The CARDIOGRAMplusC4D Consortium, The CKDGen Consortium, The, G. L. G. C., The, I. C. B. P., The MAGIC Investigators, The MuTHER Consortium, et al. (2015) · Nature · doi:10.1038/nature14177 · Cited by 4,534
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336
An atlas of genetic correlations across human diseases and traits
ReproGen Consortium, Bulik-Sullivan, B., Psychiatric Genomics Consortium, Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3, Finucane, H. K., Anttila, V., Gusev, A., Day, F. R., Loh, P.-R., Duncan, L., et al. (2015) · Nature Genetics · doi:10.1038/ng.3406 · Cited by 4,255
Self-citationRobust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption
Hartwig, F. P., Davey Smith, G., & Bowden, J. (2017) · International Journal of Epidemiology · doi:10.1093/ije/dyx102 · Cited by 3,485
Research works printed but not linked: 1
- Fox, J. & Long, J. S. Modern Methods of Data Analysis (Sage Publications, Thousand Oaks, CA, USA, 1990).
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Items 1,001–1,027 of 1,027
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Song, W., Shi, Y., Wang, W., Pan, W., Qian, W., Yu, S., Zhao, M., & Lin, G. N. (2021) · Nature Human Behaviour · doi:10.1038/s41562-021-01231-4 · Cited by 25
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Minică, C. C., Boomsma, D. I., Dolan, C. V., de Geus, E., & Neale, M. C. (2020) · International Journal of Epidemiology · doi:10.1093/ije/dyaa013 · Cited by 23
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Lai, Y., & Xiong, P. (2025) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2025.03.012 · Cited by 20
Diemer, E. W., Labrecque, J., Tiemeier, H., & Swanson, S. A. (2020) · Epidemiology · doi:10.1097/ede.0000000000001126 · Cited by 19
Zheng, S., Liu, L., Liang, K., Yan, J., Meng, D., Liu, Z., Tian, S., & Shan, Y. (2024) · Communications Biology · doi:10.1038/s42003-024-06680-x · Cited by 15
Brown, B. C., & Knowles, D. A. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.10.006 · Cited by 15
Polimanti, R., Peterson, R. E., Ong, J.-S., MacGregor, S., Edwards, A. C., Clarke, T.-K., Frank, J., Gerring, Z., Gillespie, N. A., Lind, P. A., et al. (2018) · doi:10.1101/412098 · Cited by 108
“The MR-PRESSO global test38 also supported the absence of horizontal pleiotropy (RSSobs=285.6, P=0.143).”
MethodInfluentialHe, Y., Chen, C.-L., He, J., & Liu, S.-D. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i44.5872 · Cited by 10
Self-citationShen, J.-Y., Xu, L., Ding, Y., & Wu, X.-Y. (2023) · World Journal of Clinical Cases · doi:10.12998/wjcc.v11.i23.5468 · Cited by 7
Xiao, J., Zhou, X., Xia, T., Zhang, W., Xing, X., Zhang, Y., & Xiong, L. (2025) · European Spine Journal · doi:10.1007/s00586-025-08794-0 · Cited by 6
Brigos-Barril, E., Vasallo, C., Farré, X., Morcillo-Suárez, C., Polo-Alonso, S., Rodríguez-Fernández, B., Valenzuela, A., Sarabia, C., Bosch, E., Laayouni, H., et al. (2026) · Nature Ecology & Evolution · doi:10.1038/s41559-026-03140-z · Cited by 6
Yang, L., Xu, M., Gao, X., Liu, J., Zhang, D., Zhang, Z., Ye, Z., Wen, J., & Liu, P. (2024) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2508292 · Cited by 6
“MR-PRESSO, meanwhile, was utilized to automatically detect potential outliers and remove SNPs exhibiting potential pleiotropy [35].”
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Wang, Z., Zhu, H., Chen, L., Gan, C., Min, W., Xiao, J., Zou, Z., & He, Y. (2024) · Journal of Attention Disorders · doi:10.1177/10870547241264660 · Cited by 4
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Gao, Y., Xu, C., & Yan, Q. (2025) · Scientific Reports · doi:10.1038/s41598-025-91240-4 · Cited by 4
“Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) is method to detect and correct for pleiotropic outliers 28 .”
The hidden genetic and microbial networks connecting neuropsychiatric and digestive disorders
Xiong, J., Xu, T., Wang, Z., Huang, Y., Zhang, S., Yang, G., Yang, J., Gao, S., Wang, T., Jian, X., et al. (2025) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2025.07.029 · Cited by 4
Liu, Z., Zhang, Y., Graham, S., Pique-Regi, R., Dong, X. C., Chen, Y. E., Willer, C., & Liu, W. (2019) · doi:10.1101/657734 · Cited by 250
Gao, J., & Liu, J. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1389453 · Cited by 3
Hou, Y., Zhao, J., Xu, W., Chen, L., Yang, J., Wang, Z., & Si, K. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e34089 · Cited by 2
Xiang, N., Hu, Y., Peng, W., Luo, M., Chen, H., & Zhang, Q. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1400491 · Cited by 1
Yan, T., Liu, J., Liu, Y., Gu, W., Liu, J., Li, Y., Lv, R., Zhang, C., Ding, J., Zha, C., et al. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00542-0
“Sensitivity analyses included Cochran’s Q test for heterogeneity, MR-Egger intercept test for directional pleiotropy, and MR-PRESSO global test with outlier removal [46].”
MR-MAS: an end-to-end multi-agent system for autonomous Mendelian randomization analysis
Wei, W., Fan, Y., Li, L., Le, T. D., Li, X., Cheng, D., & Feng, Z. (2026) · Bioinformatics · doi:10.1093/bioinformatics/btag722
“For each pair, we applied five core MR methods: IVW, MR-Egger regression, weighted median, weighted mode, and MR-PRESSO, and recorded the corresponding P -values and effect directions.”
Wang, Z., Wang, Z., Ji, X., Zhao, L., Zheng, K., Yu, W., Zhang, H., Chang, H., & Liu, F. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08301-z
“Horizontal pleiotropy was evaluated using the MR-Egger intercept test and the MR-PRESSO (Mendelian Randomization Pleiot-ropy RESidual Sum and Outlier) global test [40].”
Metadata
- Authors
- Verbanck, M., Chen, C.-Y., Neale, B., & Do, R.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Broad Institute (US)
- Corresponding author
- Neale, Benjamin
- Do, Ron
- Venue
- Nature Genetics
- Published
- 2018-04-23
- Volume
- 50
- Issue
- 5
- Pages
- 693-698
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6083837
- OpenAlex
- W2803072880
- Cited by
- 8,591
- References
- 77
- Citations by year
- 2026: 837 · 2025: 1873 · 2024: 2845 · 2023: 1422 · 2022: 743 · 2021: 441 · 2020: 252 · 2019: 136 · 2018: 35
- FWCI
- 134.78
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-07-02)
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (15CVGPSD27130014)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL139865)
- National Institute of Mental Health (R01MH107649, R01MH094469)
- National Human Genome Research Institute (U01HG009088)
- National Institute of General Medical Sciences (R35GM124836)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Keywords
- horizontal pleiotropy, Mendelian randomization, MR-PRESSO, causal inference, complex traits, disease, summary-level data
- MeSH terms
- Disease, Humans, Genetic Variation, Genetic Predisposition to Disease, Genetic Pleiotropy
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