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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Method
Mental Health as a Mediator of the Association Between Educational Inequality and Cardiovascular Disease: A Mendelian Randomization Study
Jones, D., Wootton, R. E., Gill, D., Carter, A. R., Gunnell, D., Munafo, M. R., & Sallis, H. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.120.019340 · Cited by 24
“52 We conducted numerous sensitivity analyses, including multiple MR meth-ods and measurement of MR-Egger intercepts to assess for these.”
Causal Associations Between Blood Lipids and COVID-19 Risk: A Two-Sample Mendelian Randomization Study
Zhang, K., Dong, S., Guo, Y., Tang, S.-H., Wu, H., Yao, S., Wang, P., Zhang, K., Xue, H., Huang, W., et al. (2021) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.121.316324 · Cited by 27
Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling
van Vliet, N. A., Bos, M. M., Thesing, C. S., Chaker, L., Pietzner, M., Houtman, E., Neville, M. J., Li‐Gao, R., Trompet, S., Mustafa, R., et al. (2021) · BMC Medicine · doi:10.1186/s12916-021-02130-1 · Cited by 31
Mendelian randomization highlights the causal association of obesity with periodontal diseases
Dong, J., Gong, Y., Chu, T., Wu, L., Li, S., Deng, H., Hu, R., & Wang, Y. (2022) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.13640 · Cited by 27
An Overview of Metabolic Phenotyping in Blood Pressure Research
Tzoulaki, I., Iliou, A., Mikros, E., & Elliott, P. (2018) · Current Hypertension Reports · doi:10.1007/s11906-018-0877-8 · Cited by 28
Indoleamine 2,3-dioxygenase and ischemic heart disease: a Mendelian Randomization study
Li, M., Kwok, M. K., Fong, S. S. M., & Schooling, C. M. (2019) · Scientific Reports · doi:10.1038/s41598-019-44819-7 · Cited by 29
Education plays a crucial role in the pathway from poverty to smoking: a Mendelian randomization study
Shi, X., Yuan, W., Cao, Q., & Cui, W. (2022) · Addiction · doi:10.1111/add.16019 · Cited by 27
Hypertension linked to Alzheimer’s disease via stroke: Mendelian randomization
Tang, C. K., Ma, Y., Lei, X., Ding, Y., Yang, S., & He, D. (2023) · Scientific Reports · doi:10.1038/s41598-023-49087-0 · Cited by 29
“However, since the IVW model assumes that all SNPs are valid instruments and may have directional pleiotropy, the estimates could be biased 33 .”
Background
Serum Uric Acid Level and Multiple Sclerosis: A Mendelian Randomization Study
Niu, P., Song, B., Wang, X., & Xu, Y. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00254 · Cited by 26
The Role of Gallstones in Gallbladder Cancer in India: A Mendelian Randomization Study
Mhatre, S., Richmond, R. C., Chatterjee, N., Rajaraman, P., Wang, Z., Zhang, H., Badwe, R. A., Goel, M., Patkar, S., Shrikhande, S. V., et al. (2020) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-20-0919 · Cited by 27
“As each of these methods make different assumptions regarding horizontal pleiotropy, a consistent effect across multiple MR methods strengthens causal evidence (19).”
Background
Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study
Hernáez, Á., Wootton, R. E., Page, C. M., Skåra, K. H., Fraser, A., Rogne, T., Magnus, P. M., Njølstad, P. R., Andreassen, O. A., Burgess, S., et al. (2022) · Fertility and Sterility · doi:10.1016/j.fertnstert.2022.04.001 · Cited by 29
“In 2-sample MR we explored unbalanced horizontal pleiotropy comparing the main estimates to those obtained from MR-Egger, the weighted median and weighted mode methods (36).”
BackgroundMethodInfluential
Genetic Evidence for a Causal Role of Serum Phosphate in Coronary Artery Calcification: The Rotterdam Study
Campos‐Obando, N., Bosman, A., Kavousi, M., Medina‐Gómez, C., van der Eerden, B. C. J., Bos, D., Franco, O. H., Uitterlinden, A. G., & Zillikens, M. C. (2022) · Journal of the American Heart Association · doi:10.1161/jaha.121.023024 · Cited by 26
Mendelian Randomization Indicates a Causal Role for Omega-3 Fatty Acids in Inflammatory Bowel Disease
Astore, C., Nagpal, S., & Gibson, G. C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214380 · Cited by 28
Causal associations of sleep apnea, snoring with cardiovascular diseases, and the role of body mass index: a two-sample Mendelian randomization study
Wang, J., Campos, A. I., Rentería, M. E., & Xu, L. (2023) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwad005 · Cited by 24
Mendelian Randomization Using the Druggable Genome Reveals Genetically Supported Drug Targets for Psychiatric Disorders
Li, X., Shen, A., Zhao, Y., & Xia, J. (2023) · Schizophrenia Bulletin · doi:10.1093/schbul/sbad100 · Cited by 26
Single nucleus RNA-sequencing integrated into risk variant colocalization discovers 17 cell-type-specific abdominal obesity genes for metabolic dysfunction-associated steatotic liver disease
Lee, S. H., Garske, K. M., Arasu, U. T., Kar, A., Miao, Z., Alvarez, M., Koka, A., Darci-Maher, N., Benhammou, J. N., Pan, D. Z., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105232 · Cited by 31
“77,78 These factors hamper selection of well-de ﬁ ned IVs in MR by increasing horizontal pleiotropy and heterogeneity, 79,80 which may cause a severe bias in MR. 79,80 Signi ﬁ cant heterogeneity in MR also points to pleiotropy and other possible violations of the necessary IV assumptions.”
Associations between Serum Levels of Cholesterol and Survival to Age 90 in Postmenopausal Women
Maihofer, A. X., Shadyab, A. H., Wild, R. A., & LaCroix, A. Z. (2020) · Journal of the American Geriatrics Society · doi:10.1111/jgs.16306 · Cited by 25
“This study was relatively small, however, and it was based on genetic risk scores that can provide confounded results if assumptions are not met.(42) We suggest performing an MR analysis in a resource such as the UK BioBank(43) using parents’ ages at death as proxy measures of longevity for a larger, better powered an…”
Alcohol use and cognitive functioning in young adults: improving causal inference
Mahedy, L., Suddell, S. F., Skirrow, C., Fernandes, G., Field, M., Heron, J., Hickman, M., Wootton, R. E., & Munafo, M. R. (2020) · Addiction · doi:10.1111/add.15100 · Cited by 27
Plasma lipid levels and risk of primary open angle glaucoma: a genetic study using Mendelian randomization
Xu, M., Li, S., Zhu, J., Luo, D., Song, W., & Zhou, M. (2020) · BMC Ophthalmology · doi:10.1186/s12886-020-01661-0 · Cited by 25
MRCIP: a robust Mendelian randomization method accounting for correlated and idiosyncratic pleiotropy
Xu, S., Fung, W. K., & Liu, Z. (2021) · Briefings in Bioinformatics · doi:10.1093/bib/bbab019 · Cited by 24
Evaluating and implementing block jackknife resampling Mendelian randomization to mitigate bias induced by overlapping samples
Fang, S., Hemani, G., Richardson, T. G., Gaunt, T. R., & Smith, G. D. (2022) · Human Molecular Genetics · doi:10.1093/hmg/ddac186 · Cited by 24
“Horizontal 516 pleiotropy could be detected through detailed examination of individual SNPs used for 517 PRS construction in each block separately, through evaluating the between-SNP 518 heterogeneity in the ratio of associations between genotype and the outcome and the 519 exposure (41, 42).”
MethodSelf-citation
Diet-Derived Circulating Antioxidants and Risk of Digestive System Tumors: A Mendelian Randomization Study
Yin, L., Yan, H., Chen, K., Ji, Z., Zhang, X., Ji, G., & Zhang, B. (2022) · Nutrients · doi:10.3390/nu14163274 · Cited by 25
Clarifying the effect of gut microbiota on allergic conjunctivitis risk is instrumental for predictive, preventive, and personalized medicine: a Mendelian randomization analysis
Liu, K., Cai, Y., Song, K., Yuan, R., & Zou, J. (2023) · The EPMA Journal · doi:10.1007/s13167-023-00321-9 · Cited by 26
“To determine heterogeneity, however, we employed Cochran’s Q test [25].”
Method
Associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease: a Mendelian randomization study
Huang, L., Ou, Y., Yang, Y., Wang, Z.-T., Tan, L., & Yu, J. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02553-9 · Cited by 28
“Mendelian randomization (MR) is a novel method that can estimate the causal effects of risk factors in observational studies by using genetic variants to provide evidence of robust associations and incorporating summary statistics from largecohort genome-wide association studies (GWASs) [10].”
Method
Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease
Ward-Caviness, C. K., de Vries, P. S., Wiggins, K. L., Huffman, J. E., Huffman, J. E., Yanek, L. R., Bielak, L. F., Giulianini, F., Guo, X., Kleber, M. E., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0216222 · Cited by 25
“We performed sensitivity analyses using four pleiotropy robust methods each of which uses a different approach to partially relax the no horizontal pleiotropy assumption of MR analyses: [63] MR-Egger [58], MR mode based estimate (MBE),[64] MR PRESSO [65], and Weighted median [66].”
MethodSelf-citation
Korea4K: whole genome sequences of 4,157 Koreans with 107 phenotypes derived from extensive health check-ups
Jeon, S., Choi, H., Jeon, Y., Choi, W.-H., Choi, H., An, K., Ryu, H., Bhak, J., Lee, H., Kwon, Y., et al. (2024) · GigaScience · doi:10.1093/gigascience/giae014 · Cited by 23
“In addition to the investigation on the general pleiotropic relationship, we emplo y ed MR to detect v ertical pleiotr opy that can assert the direction of the phenotypic relationships [ 19 ].”
Association of leukocyte telomere length with chronic kidney disease in East Asians with type 2 diabetes: a Mendelian randomization study
Gurung, R. L., Dorajoo, R., Yiamunaa, M., Wang, L., Liu, S., Liu, J., Shao, Y. M., Chen, Y., Sim, X., Ang, K., et al. (2021) · Clinical Kidney Journal · doi:10.1093/ckj/sfab067 · Cited by 25
“This approach yields a consistent estimate of a true causal effect as long as more than 50% of SNPs are valid (29).”
Background
Causal associations of intelligence with schizophrenia and bipolar disorder: A Mendelian randomization analysis
Ohi, K., Takai, K., Kuramitsu, A., Sugiyama, S., Soda, M., Kitaichi, K., & Shioiri, T. (2021) · European Psychiatry · doi:10.1192/j.eurpsy.2021.2237 · Cited by 19
Investigating the causal association between branched-chain amino acids and Alzheimer's disease: A bidirectional Mendelian randomized study
Qian, X., Liu, X., Zhang, B., Lin, Y., Xu, J., Ding, G.-Y., & Tang, H. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1103303 · Cited by 24
“Cochran’s Q statistic was applied to assess the heterogeneity of IVW andMR-Egger (27).”
Method
Identifying potential drug targets for idiopathic pulmonary fibrosis: a mendelian randomization study based on the druggable genes
Liu, Z., Peng, Z., Lin, H., Zhou, K., Liang, L., Cao, J., Huang, Z., & Mei, J. (2024) · Respiratory Research · doi:10.1186/s12931-024-02848-5 · Cited by 23
“And MR-Egger regression was used to detect potential pleiotropy in the association between the exposures and outcomes [17].”
Method
Unhealthy lifestyle factors and the risk of colorectal cancer: a Mendelian randomization study
Li, X., Chang, Z., Wang, J., Ding, K., Pan, S., Hu, H., & Tang, Q. (2024) · Scientific Reports · doi:10.1038/s41598-024-64813-y · Cited by 23
“When heterogeneity was absent, we used the fixed effects model as the primary method; when heterogeneity was present, we used the random effects model as the primary method 16 .”
Method
Introduction to Mendelian randomization
Yeung, S. L. A., Luo, S., Iwagami, M., & Goto, A. (2024) · Annals of Clinical Epidemiology · doi:10.37737/ace.25004 · Cited by 26
“If instruments weakly associated with exposure are used (i.e. weak instrument bias, often defined as F statistics 10), the MR estimate will be biased towards the confounded observational associa‐ tion 40) .”
A practical guide for nephrologist peer reviewers: understanding and appraising Mendelian randomization studies
Qing, J., Li, Y., Soliman, K., & Cheungpasitporn, W. (2025) · Renal Failure · doi:10.1080/0886022x.2024.2445763 · Cited by 23
“• Cross-Validation: By combining the weighted median approach with MR-Egger and MR-PRESSO, researchers can cross-validate their findings, mitigating biases inherent in any single method [35,51].”
Epigenetic loci for blood pressure are associated with hypertensive target organ damage in older African Americans from the genetic epidemiology network of Arteriopathy (GENOA) study
Kho, M., Zhao, W., Ratliff, S. M., Ammous, F., Mosley, T. H., Shang, L., Kardia, S. L. R., Zhou, X., & Smith, J. A. (2020) · BMC Medical Genomics · doi:10.1186/s12920-020-00791-0 · Cited by 21
Mendelian randomization study on atrial fibrillation and cardiovascular disease subtypes
Kwok, M. K., & Schooling, C. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-98058-w · Cited by 23
Five Major Psychiatric Disorders and Alzheimer’s Disease: A Bidirectional Mendelian Randomization Study
Wei, T., Guo, Z., Wang, Z., Li, C., Zhu, W., Zheng, Y., Yin, Y., Mi, Y., Xia, X., Hou, H., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220010 · Cited by 24
“Cochran’s Q statistic evaluatedheterogeneityacrossgeneticvariantswhere p 0.05 was considered statistical signiﬁcance [32].”
Influential
The genetic etiology of periodic limb movement in sleep
Edelson, J. L., Schneider, L. D., Amar, D., Brink-Kjær, A., Cederberg, K. L. J., Kutalik, Z., Hagen, E. W., Peppard, P. E., Tempaku, P. F., Tufik, S., et al. (2022) · SLEEP · doi:10.1093/sleep/zsac121 · Cited by 23
A framework for assessing selection and misclassification bias in mendelian randomisation studies: an illustrative example between body mass index and covid-19
Clayton, G., Gonçalves, A., Soares, Goulding, N., Borges, M. C., Holmes, M. V., Smith, G. D., Smith, Tilling, K. M., Lawlor, D. A., et al. (2023) · BMJ · doi:10.1136/bmj-2022-072148 · Cited by 26
Identifying underlying patterns in Alzheimer's disease trajectory: a deep learning approach and Mendelian randomization analysis
Fan, Y., Zhang, Y., Yuan, J., Liu, Z., Zhai, F., Hao, A., Wu, F. Q., Somekh, J., Mor Peleg, B., Zhu, Y., et al. (2023) · EClinicalMedicine · doi:10.1016/j.eclinm.2023.102247 · Cited by 27
Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma
(GICC), T. G. I. C.-C. S., Zhang, C., Ostrom, Q. T., Semmes, E. C., Ramaswamy, V., Hansen, H. M., Morimoto, L. M., de Smith, A. J., Pekmezci, M., Vaksman, Z., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01038-w · Cited by 23
“However, a formal application of the MR method, along with various sensitivity analyses, are necessary as prior studies show that risk score association analyses can suffer from higher false positive rates due to horizontal pleiotropy, a violation of the MR assumptions [28, 45].”
Method
Impact of serum calcium levels on total body bone mineral density: A mendelian randomization study in five age strata
Sun, J., Zhang, H., Zhang, Y., Wang, L., Sun, B., Gao, F., & Liu, G. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.03.012 · Cited by 24
A multivariable Mendelian randomization to appraise the pleiotropy between intelligence, education, and bipolar disorder in relation to schizophrenia
Adams, C. D. (2020) · Scientific Reports · doi:10.1038/s41598-020-63104-6 · Cited by 20
Understanding the consequences of educational inequalities on periodontitis: A Mendelian randomization study
Baumeister, S., Freuer, D., Baurecht, H., Reckelkamm, S. L., Ehmke, B., Holtfreter, B., & Nolde, M. (2021) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.13581 · Cited by 25
Multisite chronic pain as a causal risk factor for coronary artery disease: findings from Mendelian randomization
Zhu, J., Wang, N., Liu, H., Jiang, H., Cai, B., Chen, D., & Li, Y. (2022) · Pain · doi:10.1097/j.pain.0000000000002732 · Cited by 23
Plasma lipid levels and risk of retinal vascular occlusion: A genetic study using Mendelian randomization
Zheng, C., Lin, Y., Jiang, B., Zhu, X., Lin, Q., Luo, W., Tang, M., & Xie, L. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.954453 · Cited by 21
“The greatest concern in MR studies is the horizontal pleiotropy, which occurs when the genetic variants influence the outcome of more than one pathway (25).”
Background
Intelligence, education level, and risk of Parkinson’s disease in European populations: A Mendelian randomization study
Shi, J., Tian, J., Fan, Y., Hao, X., Li, M., Li, J., Ma, D., Guo, M., Li, S., Xu, Y., et al. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.963163 · Cited by 23
The causal effect of obesity on diabetic retinopathy: A two-sample Mendelian randomization study
Zheng, C., Wei, X., & Cao, X. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1108731 · Cited by 23
“05 of Cochrane’s Q (30) and I(2) > 25% (31) were considered to indicate significant heterogeneity.”
Background
Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with ‘cigarette smoking initiation’ really capturing?
Reed, Z. E., Wootton, R. E., Khouja, J. N., Richardson, T. G., Sanderson, E. C. M., Smith, G. D., & Munafo, M. R. (2024) · Genetic Epidemiology · doi:10.1002/gepi.22583 · Cited by 23
“Horizontal pleiotropy, however, undermines a key assumption of MR [6].”
Graphical analysis for phenome-wide causal discovery in genotyped population-scale biobanks
Amar, D., Sinnott-Armstrong, N., Ashley, E. A., & Rivas, M. A. (2021) · Nature Communications · doi:10.1038/s41467-020-20516-2 · Cited by 23

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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