Mendelian Randomization: Approach and Applications

Editorial

28 September 2021

Editorial: Mendelian Randomization: Approach and Applications

Guo-Liang Wu

Yao-Zhong Liu

and

Lei Zhang

4,349 views

2 citations

Editors

Impact

Review

12 August 2021

Mendelian Randomization in Stroke: A Powerful Approach to Causal Inference and Drug Target Validation

Julián N. Acosta

, 1 more and

Guido J. Falcone

9,543 views

12 citations

Bar plot of the type I error rates of all methods under the null hypothesis of H0 : β = 0. Sample size (n = 1,000, 5,000, 10,000, 20,000), the number of genetic variants m = 25, and σα = 0.1. μα = 0, −0.1, 0.1 represents the mean of pleiotropic effect and ρg = 0, 0.3, 0.6 stands for the relative strength of LD between the genetic variants. The red dashed horizontal line indicates the nominal significance of 0.05.

Original Research

12 July 2021

A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data

Yuquan Wang

, 3 more and

Yue-Qing Hu

6,553 views

8 citations

Causal effects between CP and kidney function measures using different MR approaches. SNP: single-nucleotide polymorphism; No.: number; MR: Mendelian randomization; CI: confidence interval; p, p-value; CP: chronic periodontitis; eGFR: estimated glomerular filtration rate; BUN: blood urea nitrogen; IVW: inverse variance weighted; WM: weighted median; MR–Egger: the Mendelian randomization–Egger method.

Original Research

07 June 2021

Causal Inference Between Chronic Periodontitis and Chronic Kidney Disease: A Bidirectional Mendelian Randomization Analysis in a European Population

Jie Yang

, 3 more and

Xingang Li

5,436 views

6 citations

MR estimates for associations between 5 environment factors and asthma. The odds ratio is plotted as dots with the 95% confidence interval. White dots are the IVW method, and black dots are the GSMR method. The P value indicates significance when P < 7.25E-04 (0.05/69) by Bonferroni correction. The Q value by Cochran’s Q statistic indicates residual heterogeneity in the MR estimates.

Original Research

20 May 2021

Association Between Environmental Factors and Asthma Using Mendelian Randomization: Increased Effect of Body Mass Index on Adult-Onset Moderate-to-Severe Asthma Subtypes

Tae-Woong Ha

, 7 more and

Bermseok Oh

7,113 views

9 citations

Methods

17 March 2021

Mendelian Randomization With Refined Instrumental Variables From Genetic Score Improves Accuracy and Reduces Bias

Lijuan Lin

, 10 more and

Feng Chen

6,460 views

19 citations

Original Research

18 February 2021

Assessment of Causal Direction Between Gut Microbiota and Inflammatory Bowel Disease: A Mendelian Randomization Analysis

Zi-Jia Zhang

, 5 more and

Bin Li

9,051 views

39 citations

Original Research

15 January 2021

Use of Multivariable Mendelian Randomization to Address Biases Due to Competing Risk Before Recruitment

C. M. Schooling

, 4 more and

Jian V. Huang

Background: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist.

Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk.

Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80–2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68–0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy.

Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly.

7,730 views

91 citations

Forest plots and scatter plots of CRP-associated SNPs potential effects on intracerebral hemorrhage (ICH). Forest plot (A) shows the odds ratio (OR) with a horizontal line representing 95% CI for the CRP-associated SNP allele for ICH risk. Scatter plot (B) shows the per-allele association with ICH risk plotted against the per-allele association with 1 SD of CRP (vertical and horizontal black lines presenting the 95% CI of OR for each SNP), with the slope of each line corresponding to estimated Mendelian randomization (MR) effect per method.

Original Research

04 February 2021

The Role of C-Reactive Protein and Fibrinogen in the Development of Intracerebral Hemorrhage: A Mendelian Randomization Study in European Population

Biyan Wang

, 12 more and

Youxin Wang

4,084 views

7 citations

Scatter plots of genetic associations with 2-h postprandial glucose against osteoarthritis using different MR methods. (A) 2-h postprandial glucose and hip osteoarthritis results; (B) 2-h postprandial glucose and knee osteoarthritis results. The slopes of each line represent the causal association for each method. The green line represents the inverse variance weighted estimate, the purple line represents the MR–Egger estimate, the red line represents the MR.RAPS estimate, and the blue line represents the weighted median estimate.

Original Research

13 January 2021

Type 2 Diabetes and Glycemic Traits Are Not Causal Factors of Osteoarthritis: A Two-Sample Mendelian Randomization Analysis

Zhiyong Cui

, 4 more and

Yun Tian

5,243 views

16 citations

Assumptions for the Mendelian randomization (MR) and study design. The MR was based on three principal assumptions, including: (1) the genetic variants selected to be instrumental variables should be correlated with the exposure [fibroblast growth factor 23 (FGF23) levels]; (2) the genetic variants should be unrelated to confounding factors; (3) genetic variants must influence the risks of the outcome [ischemic stroke (IS)] only through the exposure (FGF23 levels).

Original Research

23 December 2020

Association of Fibroblast Growth Factor 23 With Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study

Kai Zheng

, 5 more and

Wei Jiang

3,333 views

11 citations

Sensitivity analysis for the causality of sleep traits with the risk of T2DM. T2DM, Type 2 diabetes mellitus; N SNPs, number of SNPs retained and used in the MR analysis after filtered by individual Q outlier test; OR, odds ratio; CI, confidence interval.

Original Research

15 December 2020

Investigating Causal Relations Between Sleep-Related Traits and Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study

Xue Gao

, 4 more and

Tong Wang

5,856 views

27 citations

Scatter plots of the genetic associations with inflammatory bowel disease against ankylosing spondylitis risk using different MR methods. (A) Ulcerative colitis against ankylosing spondylitis risk; (B) Crohn’s disease against ankylosing spondylitis risk; and (C) inflammatory bowel disease against ankylosing spondylitis risk. The slopes of each line represent the causal association for each method. The green line represents the inverse variance weighted estimate, the purple line represents the MR-Egger estimate, the red line represents the MR.RAPS estimate, and the blue line represents the weighted median estimate.

Original Research

19 November 2020

Bidirectional Causal Associations Between Inflammatory Bowel Disease and Ankylosing Spondylitis: A Two-Sample Mendelian Randomization Analysis

Zhiyong Cui

, 4 more and

Yun Tian

Background: Associations between inflammatory bowel disease (IBD) [including ulcerative colitis (UC) and Crohn’s disease (CD)] and ankylosing spondylitis (AS) were discovered in observational studies, but no evidence supported the causal relationship between the two diseases.

Methods: We employed two-sample Mendelian randomization (MR) to estimate the unconfounded bidirectional causal associations between IBD (including UC and CD) and AS. We selected single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) after strictly assessing the quality of the studies in the IEU GWAS database. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.

Results: We found positive causal effects of genetically increased UC, CD, and IBD risk on AS (e.g., UC and AS, IVW OR: 1.0256, 95% CI: 1.0130∼1.0385, p = 6.43E-05). However, we did not find significant causal associations of AS with UC, CD, or IBD (e.g., AS and UC, IVW OR: 1.1858, 95% CI: 0.8639∼1.6278, p = 0.2916). The sensitivity analysis also confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., UC and AS, MR-Egger: intercept p = 0.1326). The leave-one-out analysis also demonstrated that the observed links were not driven by SNP. No evidence of heterogeneity was found between the genetic variants (e.g., UC and AS, MR-Egger: Q statistic = 43.1297, I²<0.0001, p = 0.7434).

Conclusion: Our results provide new evidence indicating there are positive causal effects of IBD on AS in the European population. We suggest that the features of inflammatory bowel disease in particular should be assessed in the diagnosis of ankylosing spondylitis. We also provide some advice for preventing and treating the two diseases.

7,326 views

45 citations

Relationship between the single nucleotide polymorphism (SNP) effect sizes of leukocyte telomere length (LTL) (x-axis) and the corresponding effect sizes of cancer (y-axis). (A) Malignant melanoma. (B) Hodgkin’s lymphoma/Hodgkin’s disease. (C) Chronic lymphocytic leukemia. (D) Multiple myeloma. In the plot, horizontal/vertical lines represent the 95% confidence interval.

Original Research

23 October 2020

Assessing the Relationship Between Leukocyte Telomere Length and Cancer Risk/Mortality in UK Biobank and TCGA Datasets With the Genetic Risk Score and Mendelian Randomization Approaches

Yixin Gao

, 4 more and

Ping Zeng

10,814 views

29 citations

Scatter plot of CESD-10 scores over age by gender, genotypes, and groups of alcohol use (N = 476). CESD-10 scores over age were plotted by different combinations of ALDH2 rs671 (horizontal) and ADH1B rs1229984 (vertical) genotypes (with the number of effect alleles in parenthesis). Each dot represents a single subject. The solid and dashed black horizontal lines denote for cut-off scores of 12 (optimal) and 10 for the depression, respectively. Different genders (female/male) and groups of alcohol use (never drinkers/former drinkers/moderate drinkers/heavy drinkers) were represented by distinct shapes and colors, respectively.

Brief Research Report

19 October 2020

Alcohol Use and Depression: A Mendelian Randomization Study From China

Chen Zhu

, 4 more and

Qiran Zhao

Background: Alcohol use has been linked to a number of physical conditions, but the relationship between alcohol drinking and depression, one of the most common mental disorders that is a significant contributor to the global burden of disease, is still under debate. We aim to help fill the literature gap on the causal effect of alcohol use on depression by using genetic instruments of ALDH2 rs671 and ADH1B rs1229984 in the Mendelian randomization (MR) framework.

Materials and Methods: We collected a sample of 476 middle-aged and older adults from mainland China. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to measure the status of depression. The frequency and intensity of alcohol consumption were measured by (1) a binary indicator of drinking or not, (2) the total number of drinking occasions during the past 30 days, and (3) the weekly ethanol consumption in grams.

Results: MR estimates indicated that alcohol use was causally associated with a lower risk of depression. Parameter estimates of drinking or not (b = −0.127, p = 0.048), number of drinking occasions (b = −0.012, p = 0.040), and weekly ethanol consumption (b = −0.001, p = 0.039) were all negative and statistically significant. The results were robust after adjustments for potential confounders (e.g., income, smoking, and parental drinking behaviors), and the exclusion of heavy or former drinkers.

Conclusions: This is one of the first study to investigate the causal relationship between alcohol use and mental health using an MR design in East Asian populations. Further studies are needed to clarify the mechanisms of this causal link.

8,501 views

36 citations