Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases

Verbanck, Marie; Chen, Chia Yen; Neale, Benjamin M.; Do, Ron

doi:10.1038/s41588-018-0099-7

Cited by 5,674 publications

(5,108 citation statements)

References 42 publications

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“…25 We then used the MR-PRESSO global test to identify the potential horizontal pleiotropic effects of the SNPs (p < 1 × 10 −6 ). 26 Specifically, based on the null hypothesis of no horizontal pleiotropy, the overall horizontal pleiotropy among SNPs can be evaluated by comparing the observed residual sum of squares to the expected residual sum of squares. 26 We further performed a series of sensitivity analyses to improve the reliability of the association between the genetic instruments and the exposure.…”

Section: Resultsmentioning

confidence: 99%

“…26 Specifically, based on the null hypothesis of no horizontal pleiotropy, the overall horizontal pleiotropy among SNPs can be evaluated by comparing the observed residual sum of squares to the expected residual sum of squares. 26 We further performed a series of sensitivity analyses to improve the reliability of the association between the genetic instruments and the exposure. We applied leave-one-out analyses to identify SNPs that could potentially bias the causal association.…”

Section: Resultsmentioning

confidence: 99%

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Coffee Consumption and Risk of Stroke: A Mendelian Randomization Study

Huang

et al. 2020

Annals of Neurology

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Objective Observational epidemiological studies have reported a relationship between coffee intake and risk of stroke. However, evidence for this association is inconsistent, and it remains uncertain whether the association is causal or due to confounding or reverse causality. To clarify this relationship, we adopted a Mendelian randomization (MR) approach to evaluate the effects of coffee consumption on the risk of stroke and its subtypes. Methods A meta‐analysis of genome‐wide association studies (GWASs) including 91,462 coffee consumers was used to identify instruments for coffee consumption. Summary‐level data for stroke, intracerebral hemorrhage, ischemic stroke (IS), and IS subtypes were obtained from GWAS meta‐analyses conducted by the MEGASTROKE consortium. MR analyses were performed using the inverse‐variance‐weighted, weighted‐median, MR‐PRESSO (Pleiotropy RESidual Sum and Outlier) test and MR‐Egger regression. Sensitivity analyses were further performed using alternative instruments to test the robustness of our findings. Results Genetically predicted coffee consumption (high vs infrequent/no) was not associated with risk of stroke. Similarly, among coffee consumers, MR analysis did not indicate causal associations between coffee consumption (cups/day) and risk of stroke. However, in the subgroup analysis, we found weak suggestive evidence for a potential protective effect of coffee consumption on risk of small vessel (SV)‐IS, although the association did not reach statistical significance after correction for multiple comparisons. Interpretation This study suggests that coffee consumption is not causally associated with risk of stroke or its subtypes. Further studies are warranted to elucidate the possible association between coffee intake and risk of SV‐IS, as well as its potential underlying mechanisms. ANN NEUROL 2020;87:525–532

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Coffee Consumption and Risk of Stroke: A Mendelian Randomization Study

Huang

et al. 2020

Annals of Neurology

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“…Analysis was performed using R version 3.4.3 software (R Foundation for Statistical Computing) together with the R packages gtx and MR‐PRESSO . The list of genetic variants used appear in Supplementary Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…Analysis was performed using R version 3.4.3 software (R Foundation for Statistical Computing) together with the R packages gtx and MR-PRESSO. 30 The list of genetic variants used appear in Supplementary Table 1. This study used publicly available deidentified data from participating studies that had already obtained relevant authorization from local ethics and/or institutional review boards.…”

Section: Mediation Analysismentioning

confidence: 99%

Mendelian Randomization Study of Obesity and Cerebrovascular Disease

Marini

Merino

Montgomery

et al. 2020

Annals of Neurology

102

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Objective To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease. Methods We used summary statistics from genome‐wide association studies for body mass index (BMI), waist‐to‐hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2‐sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively. Results Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44–113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29–91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59–457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01–0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one‐tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4–20%), but no evidence of mediation was found for average blood glucose. Interpretation Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516–524

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“…24 This test identifies possible bias from horizontal pleiotropy. 24 This test identifies possible bias from horizontal pleiotropy.…”

Section: Mr-presso Analysismentioning

confidence: 99%

Mendelian randomization analysis revealed potential causal factors for systemic lupus erythematosus

Guo

Qian

et al. 2019

Immunology

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Genome-wide association studies (GWAS) have identified many loci for systemic lupus erythematosus (SLE). However, identification of functionally relevant genes remains a challenge. The aim of this study was to highlight potential causal genes for SLE in the GWAS loci. By applying Mendelian randomization (MR) methods, such as summary data-based MR (SMR), generalized SMR and MR pleiotropy residual sum and outlier, we identified DNA methylations in 15 loci and mRNA expression of 21 genes that were causally associated with SLE. The identified genes enriched in 14 specific KEGG pathways (e.g. SLE, viral carcinogenesis) and two GO terms (interferon-c-mediated signaling pathway and innate immune response). Among the identified genes, UBE2L3 and BLK variants were significantly associated with UBE2L3 and BLK methylations and gene expressions, respectively. UBE2L3 was up-regulated in SLE patients in several types of immune cells. Methylations (e.g. cg06850285) and mRNA expression of UBE2L3 were causally associated with SLE. Methylation site cg09528494 and mRNA expression of BLK were causally associated with SLE. BLK single nucleotide polymorphisms that were significantly associated with SLE were strongly associated with plasma cathepsin B level. Deep analysis identified that plasma cathepsin B level was causally associated with SLE. In summary, this study identified hundreds of DNA methylations and genes as potential risk factors for SLE. Genetic variants in UBE2L3 gene might affect SLE by influencing gene expression. Genetic variants in BLK gene might affect SLE by influencing BLK gene expression and plasma cathepsin B protein level.

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Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases

Cited by 5,674 publications

References 42 publications

Coffee Consumption and Risk of Stroke: A Mendelian Randomization Study

Coffee Consumption and Risk of Stroke: A Mendelian Randomization Study

Mendelian Randomization Study of Obesity and Cerebrovascular Disease

Mendelian randomization analysis revealed potential causal factors for systemic lupus erythematosus

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