The next step in Mendelian randomization

Weith, Matthias; Beyer, Andreas

doi:10.7554/elife.86416

Cited by 18 publications

(9 citation statements)

References 11 publications

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“…MR is an increasingly popular and effective causal inference method in recent years ( Weith and Beyer, 2023 ). It employs genetic variation (single-nucleotide polymorphisms, SNPs) as instrumental variables (IVs) to infer causal relationships between exposures and outcomes, effectively circumventing confounding biases present in traditional epidemiological studies ( Birney, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study

Zhang,

Liu,

Pan

et al. 2023

Front. Neurosci.

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BackgroundAging is a significant risk factor for many neurodegenerative diseases and neurological tumors. Previous studies indicate that the frailty index, facial aging, telomere length (TL), and epigenetic aging clock acceleration are commonly used biological aging proxy indicators. This study aims to comprehensively explore potential relationships between biological aging and neurodegenerative diseases and neurological tumors by integrating various biological aging proxy indicators, employing Mendelian randomization (MR) analysis.MethodsTwo-sample bidirectional MR analyses were conducted using genome-wide association study (GWAS) data. Summary statistics for various neurodegenerative diseases and neurological tumors, along with biological aging proxy indicators, were obtained from extensive meta-analyses of GWAS. Genetic single-nucleotide polymorphisms (SNPs) associated with the exposures were used as instrumental variables, assessing causal relationships between three neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis), two benign neurological tumors (vestibular schwannoma and meningioma), one malignant neurological tumor (glioma), and four biological aging indicators (frailty index, facial aging, TL, and epigenetic aging clock acceleration). Sensitivity analyses were also performed.ResultsOur analysis revealed that genetically predicted longer TL reduces the risk of Alzheimer’s disease but increases the risk of vestibular schwannoma and glioma (All Glioma, GBM, non-GBM). In addition, there is a suggestive causal relationship between some diseases (PD and GBM) and DNA methylation GrimAge acceleration. Causal relationships between biological aging proxy indicators and other neurodegenerative diseases and neurological tumors were not observed.ConclusionBuilding upon prior investigations into the causal relationships between telomeres and neurodegenerative diseases and neurological tumors, our study validates these findings using larger GWAS data and demonstrates, for the first time, that Parkinson’s disease and GBM may promote epigenetic age acceleration. Our research provides new insights and evidence into the causal relationships between biological aging and the risk of neurodegenerative diseases and neurological tumors.

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Section: Introductionmentioning

confidence: 99%

Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study

Zhang,

Liu,

Pan

et al. 2023

Front. Neurosci.

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“…The MR-Egger intercept test detects unmeasured horizontal pleiotropy, and when the intercept is significant ( P < 0.05), the result is implausible 31 . MR-PRESSON is more stringent compared to the Weighted median method and evaluates whether causality values have changed by identifying and excluding correcting outlier SNPs 32 . Therefore, diets effect on disease only when two or more statistical methods are in the same direction.…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization study reveals the relationship between dietary factors and respiratory diseases

Lai,

Li,

Peng

et al. 2023

Sci Rep

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The existence of causal relationship between dietary factors and respiratory diseases is uncertain. We comprehensively investigated the association between dietary factors and respiratory diseases by using Mendelian randomization (MR). Genetic variants linked to dietary factors were selected as instrumental variables with genome-wide significance. These instrumental variables were obtained from large GWAS databases. These databases include Biobank, the FinnGen study, and other large consortia. We used multivariate MR analyses to control the effects of smoking and education. Median analysis was conducted to evaluate whether body mass index (BMI) played a role in dietary factors in respiratory diseases. Dried fruit intake was found to be associated with a decreased risk of chronic obstructive pulmonary disease (COPD) (OR: 0.211; 95% CI 0.117–0.378; P < 0.001) and asthma (OR: 0.539; 95% CI 0.357–0.815; P = 0.003). Conversely, pork intake was associated with an increased risk of international pharmaceutical federation (IPF) (OR: 1.051*102, 95% CI 4.354–2.56*103, P = 0.004). However, no significant associations were observed between the 20 dietary factors and obstructive sleep apnea (OSA). In addition, multivariate MR analyses showed that the above results were unchanged in smoking and nonsmoking populations, while the effect of dried fruit intake on asthma was significantly attenuated after corrective education. The results of the mediator variable analysis indicated that BMI could serve as a mediator of the above results. This study found that dried fruits slowed the progression of COPD and asthma, while pork promoted IPF. However, no effect of dietary factors on OSA was found. Meanwhile, we showed that the above results were unchanged in smoking and non-smoking populations. In contrast, education could influence the role of diet on asthma, and BMI could be used as a mediating variable to influence the above results.

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“…MR mediation methods require certain assumptions that can enhance causal inference in mediation analysis 43 . In the future, it may be feasible to extend the MR approach with transcripts and metabolites 44 .…”

Section: Discussionmentioning

confidence: 99%

Negative causal exploration of systemic sclerosis: a Mendelian randomization analysis

Han,

Wang

et al. 2024

Sci Rep

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Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-related connective tissue disease with a complex and unknown pathophysiological mechanism with genes association. Several articles have reported a high prevalence of thyroid disease in SSc patients, while one study suggested a potential contribution of appendicitis to the development of SSc. To investigate this causal association, we conducted Mendelian randomization (MR) analysis using instrumental variables (IVs) to assess exposure and outcome. In the MR study involving two cohorts, all analyses were conducted using the TwoSampleMR package in R (version 4.3.0). Single nucleotide polymorphisms (SNPs) meeting a statistically significant threshold of 5E−08 were included in the analysis. Multiple complementary approaches including MR-IVW, MR-Egger, weighted median, simple mode, and weighted mode were employed to estimated the relationship between the exposure and outcome. Leave-one-out analysis and scatter plots were utilized for further investigation. Based on the locus-wide significance level, all of the MR analysis consequences manifested no causal association between the risk of appendicitis with SSc (IVW OR 0.319, 95% CI 0.063–14.055, P = 0.966). Negative causal effects of autoimmune thyroiditis (AT) on SSc (IVW OR 0.131, 95% CI 0.816–1.362, P = 0.686), Graves’ disease (GD) on SSc (IVW OR 0.097, 95% CI 0.837–1.222, P = 0.908), and hypothyroidism on SSc (IVW OR 1.136, 95% CI 0.977–1.321, P = 0.096) were derived. The reverse MR revealed no significant causal effect of SSc on thyroid disease. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. The consequences indicated no significant association between AT, GD, and hypothyroidism with SSc. Similarly, there was no observed relationship with appendicitis.

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The next step in Mendelian randomization

Abstract: Expanding a statistical approach called Mendelian randomization to include multiple variables may help researchers to identify new molecular causes of specific traits.

Cited by 18 publications

References 11 publications

Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study

Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study

Mendelian randomization study reveals the relationship between dietary factors and respiratory diseases

Negative causal exploration of systemic sclerosis: a Mendelian randomization analysis

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