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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“The leave-oneout sensitivity test was used to appraise whether the MR results were sensitized to single SNP changes (35).”
Method
Blood Cells and Venous Thromboembolism Risk: A Two-Sample Mendelian Randomization Study
He, J., Jiang, Q., Yao, Y., Shen, Y., Li, J., Yang, J., Ma, R., Zhang, N., & Liu, C. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.919640 · Cited by 12
“Genetic variants associated with cell indices are used as instrumental variables (IVs) to assess causal associations with VTE risk.”
Method
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Lin, L., Lin, J., Qiu, J., Feng, W., Bai, X., Ma, W., Zeng, J., & Lin, D. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.994170 · Cited by 12
“Reverse causation is defined as the observed variance of the outcome outweighing the observed variance of the exposure (Hemani et al., 2018a).”
Background
Assessment of bidirectional relationships between depression and rheumatoid arthritis among adults: a two-sample Mendelian randomization study
Fang, S., Huang, S., Tian, F., Han, Y., Yang, K., & Zhang, Q. (2022) · Clinical Rheumatology · doi:10.1007/s10067-022-06455-x · Cited by 12
“Otherwise, other established MR methods relatively robust to horizontal pleiotropy (including simple median approach, weighted median approach, and MREgger regression) should be more appropriate, although at the cost of reduced statistical power [15].”
Mendelian randomisation studies of Attention Deficit Hyperactivity Disorder
Riglin, L., & Stergiakouli, E. (2022) · JCPP Advances · doi:10.1002/jcv2.12117 · Cited by 12
“Indeed, the main source of bias for MR studies is horizontal pleiotropy (Lawlor et al., 2016); although different methods have been developed to address this, these also have limitations (Hemani et al., 2018).”
Sleep behaviors and Parkinson's disease: A bidirectional Mendelian randomization analysis
Ling, Y., Zhu, J., Yan, F., Tse, L. A., Kinra, S., & Jiang, M. (2023) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.114281 · Cited by 12
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Associations between depressive symptom profiles and immunometabolic characteristics in individuals with depression and their siblings
de Kluiver, H., Milaneschi, Y., Jansen, R., van Sprang, E. D., Giltay, E. J., Hartman, C. A., & Penninx, B. W. J. H. (2020) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2020.1761562 · Cited by 12
“In the second, genetic variants impact on one trait that, in turn, influences the development of the second trait (‘vertical pleiotropy’) (Hemani et al. 2018).”
BackgroundInfluential
Circulating chemerin levels are determined through circulating platelet counts in nondiabetic Taiwanese people: A bidirectional Mendelian randomization study
Hsu, L., Chou, H., Teng, M., Wu, S., & Ko, Y. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.01.014 · Cited by 12
The relationship between body mass index and income: Using genetic variants from HUNT as instrumental variables
Edwards, C. H., Bjø‌rngaard, J. H., & Kinge, J. M. (2021) · Health Economics · doi:10.1002/hec.4285 · Cited by 13
“Detailed information about The HUNT Studies is available from Holmen et al. (2003) and Krokstad et al. (2013).”
Background
Valid Causal Inference with (Some) Invalid InstrumentsPreprint
Hartford, J., Veitch, V., Sridhar, D., & Leyton‐Brown, K. (2020) · RePEc: Research Papers in Economics · doi:10.48550/arxiv.2006.11386 · Cited by 12
“The possibility of such “direct effects”—referred to as “horizontal pleiotropy" in the genetic epidemiology literature—is regarded as a key challenge for Mendelian randomization [Hemani et al., 2018].”
Commentary: Mendelian randomization and education–Challenges remain
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Mendelian Randomization Methods for Causal Inference: Estimands, Identification and Inference
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“The violation of Assumption A3 may occur due to the widespread horizontal pleiotropy, where the genetic variant influences the outcome through other biological pathways that do not involve the exposure in view [23, 68–70].”
Birth weight, adult weight, and cardiovascular biomarkers: Evidence from the Cardiovascular Young Finns Study
Pehkonen, J., Viinikainen, J., Kari, J. T., Böckerman, P., Lehtimäki, T. J., Viikari, J. S. A., & Raitakari, O. T. (2021) · Preventive Medicine · doi:10.1016/j.ypmed.2021.106894 · Cited by 11
“(von Hinke et al., 2016; Hemani et al., 2018) Our research design, based on PGSs instead of individual SNPs, the use of MVMR modeling, and anthropometric measures (birth weight and BMI) obtained by health care professionals mitigates the potential problems of MR in two ways.”
BackgroundMethod
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Common genetic and environmental effects on cognitive ability, conscientiousness, self-perceived abilities, and school performance
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“If the results vary significantly after the removal of a specific SNP, this indicates that the SNP may be a potentially influential variant, and we should draw a conclusion with caution [38].”
Background
Assessing causality between inflammatory bowel diseases with frailty index and sarcopenia: a bidirectional Mendelian randomization study
Wang, P., Tao, W., Zhang, Z., Xu, C., Qiu, Y., & Xiao, W. (2024) · European journal of medical research · doi:10.1186/s40001-023-01614-5 · Cited by 12
“In the context of the inverse variance weighted (IVW) study, it is crucial to consider the potential impact of pleiotropy on causal estimates and findings [27].”
BackgroundInfluential
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Possible Causal Association between Type 2 Diabetes and Glycaemic Traits in Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomisation Study
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“In addition, the SNP-exposure and SNP-outcome relationships are not correctly specified—i.e., in the two-sample setting, the causal relationship between the exposure and the outcome is different in each of the samples [65].”
Background
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“The MR– Egger intercept and MR-PRESSO methods were undertaken to examine the presence of horizontal pleiotropy [28].”
Method
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“Finally, a modified Cochran Q statistic and leave-one-out analysis were conducted to detect heterogeneity in the results [26].”
BackgroundMethod
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“46 When SNPs are signiﬁcantly associated with both the exposure and the outcome, colocalisation analysis is veri-ﬁed as a valid research method to investigate whether the exposure and outcome share the same causal SNP. 32 Evidence indicates that proteins subjected to both MR and colocalisa-tion…”
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“We performed MR-Egger regression, which tests directional pleiotropy through its intercept, where a non-zero intercept suggests that pleiotropic effects are biasing the causal estimate [30,31].”
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“Technical details of these alternative models have been previously described(35, 37, 38).”
Method
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“Potential heterogeneity, measured by Cochran’s Q statistic, was evaluated via multiplicative random effects IVW (Hemani et al., 2018).”
Method
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“Second, if IVs can directly affect the results without exposure factors, then they violate the idea of MR; that is, the level of pleiotropy in the test results will lead to serious deviations in MR (Hemani et al., 2018; Ong andMacGregor, 2019).”
Background
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“Further details of these methods are summarised in a recent review [14].”
Method
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“Pleiotropy tests were carried out to investigate the influence of serum 25-Hydroxyvitamin D levels on melanoma risk within the context of MR analysis (65).”
Background
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Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder
Johnson, E. C., Kapoor, M., Hatoum, A. S., Zhou, H., Polimanti, R. A., Wendt, F. R., Walters, R. K., Lai, D., Kember, R. L., Hartz, S. M., et al. (2021) · Psychological Medicine · doi:10.1017/s003329172100266x · Cited by 11
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Evidence of causal effect of major depression on alcohol dependence: Findings from the Psychiatric Genomics Consortium
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“05), the random-effect IVW method was applied to pool the Wald ratio estimates; otherwise, the fixed-effect IVWmodel was used (22).”
Method
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Long, C., Lin, D., Zhang, L., Lin, Y., Yao, Q., Zhang, G., Li, L., Liu, H., Ying, J., Wang, X., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1332712 · Cited by 10
“Notably, alleles undergo random assignment during gamete formation, rendering MR akin to a “ natural ” randomized controlled trial that effectively mitigates the impact of confounding and reverse causality biases (17).”
Background
Association of sleep traits with male fertility: a two-sample Mendelian randomization study
Lu, S., Ma, Z., Zhou, W., Zeng, H., Ma, J., Deng, H., & Zhang, P. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1353438 · Cited by 11
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“The MR-PRESSO outlier test was used to correct for horizontal pleiotropy by removing or down-weighting the outliers when the horizontal pleiotropy was significant ( p 0.05) (Hemani et al., 2018).”
MethodInfluential
Psychological distress and uterine fibroids: a bidirectional two-sample mendelian randomization study
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“Furthermore, the MR-Egger intercept can identify and correct for pleiotropy [25, 27].”
Background
Depression increases the risk of gallstone: A cross-sectional study and Mendelian randomization analysis
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Revealing the link between gut microbiota and brain tumor risk: a new perspective from Mendelian randomization
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“When the result is displayed as TRUE, it means that the direction of the causal relationship is consistent with the hypothesis (Hemani et al., 2018).”
Child maltreatment as a transdiagnostic risk factor for the externalizing dimension: a Mendelian randomization study
Konzok, J., Gorski, M., Winkler, T. W., Baumeister, S. E., Warrier, V., Leitzmann, M. F., & Baurecht, H. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02700-8 · Cited by 11
MR-SPLIT: A novel method to address selection and weak instrument bias in one-sample Mendelian randomization studies
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Exploring the causal effects of serum lipids and lipidomes on lewy body dementia: a Mendelian randomization study
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Autoimmune Diseases and Risk of Non‐Hodgkin Lymphoma: A Mendelian Randomisation Study
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“However, the IVW analysis may be biased if any of the included instruments are invalid (e.g., if the genetic instruments affect multiple traits, which is known as horizontal pleiotropy) [28].”
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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