scholarly journals Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhao Yang ◽  
C. Mary Schooling ◽  
Man Ki Kwok
Keyword(s):  
Selection Bias ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Potential Effect ◽  
Mr Studies ◽  
Primary Interest ◽  
Data Generating Process ◽  
Systematic Selection ◽  
Causal Structures

Selection bias is increasingly acknowledged as a limitation of Mendelian randomization (MR). However, few methods exist to assess this issue. We focus on two plausible causal structures relevant to MR studies and illustrate the data-generating process underlying selection bias via simulation studies. We conceptualize the use of control exposures to validate MR estimates derived from selected samples by detecting potential selection bias and reproducing the exposure–outcome association of primary interest based on subject matter knowledge. We discuss the criteria for choosing the control exposures. We apply the proposal in an MR study investigating the potential effect of higher transferrin with stroke (including ischemic and cardioembolic stroke) using transferrin saturation and iron status as control exposures. Theoretically, selection bias affects associations of genetic instruments with the outcome in selected samples, violating the exclusion-restriction assumption and distorting MR estimates. Our applied example showing inconsistent effects of genetically predicted higher transferrin and higher transferrin saturation on stroke suggests the potential selection bias. Furthermore, the expected associations of genetically predicted higher iron status on stroke and longevity indicate no systematic selection bias. The routine use of control exposures in MR studies provides a valuable tool to validate estimated causal effects. Like the applied example, an antagonist, decoy, or exposure with similar biological activity as the exposure of primary interest, which has the same potential selection bias sources as the exposure–outcome association, is suggested as the control exposure. An additional or a validated control exposure with a well-established association with the outcome is also recommended to explore possible systematic selection bias.

scholarly journals Iron Status and Cancer Risk in UK Biobank: A Two-Sample Mendelian Randomization Study

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 526 ◽  
Author(s):  
Shuai Yuan ◽  
Paul Carter ◽  
Mathew Vithayathil ◽  
Siddhartha Kar ◽  
Edward Giovannucci ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Brain Cancer ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Odds Ratios ◽  
A Genome

We conducted a two-sample Mendelian randomization study to explore the associations of iron status with overall cancer and 22 site-specific cancers. Single-nucleotide polymorphisms for iron status were obtained from a genome-wide association study of 48,972 European-descent individuals. Summary-level data for breast and other cancers were obtained from the Breast Cancer Association Consortium and UK Biobank. Genetically predicted iron status was positively associated with liver cancer and inversely associated with brain cancer but not associated with overall cancer or the other 20 studied cancer sites at p < 0.05. The odds ratios of liver cancer were 2.45 (95% CI, 0.81, 7.45; p = 0.11), 2.11 (1.16, 3.83; p = 0.02), 10.89 (2.44, 48.59; p = 0.002) and 0.30 (0.17, 0.53; p = 2 × 10−5) for one standard deviation increment of serum iron, transferrin saturation, ferritin and transferrin levels, respectively. For brain cancer, the corresponding odds ratios were 0.69 (0.48, 1.00; p = 0.05), 0.75 (0.59, 0.97; p = 0.03), 0.41 (0.20, 0.88; p = 0.02) and 1.49 (1.04, 2.14; p = 0.03). Genetically high iron status was positively associated with liver cancer and inversely associated with brain cancer.

P6231Iron status and risk of cardio-metabolic diseases in European adults: a Mendelian randomization study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
W Gan ◽  
D Bennett ◽  
A Mahajan ◽  
H Du ◽  
Z Chen ◽  
...  
Keyword(s):  
Serum Iron ◽  
Metabolic Diseases ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Research Centre ◽  
Inverse Association ◽  
Total N

Abstract Background Observational studies have reported conflicting results about the associations of iron status with risk of cardio-metabolic diseases but such studies are constrained by confounding and reverse causality. Purpose To assess the causal relevance of iron status biomarkers (transferrin, serum iron, and ferritin) for risk of coronary artery diseases (CAD), ischaemic stroke (IS), and type 2 diabetes (T2D), using Mendelian randomization (MR). Methods Effect size estimates for genetic variants associated with iron status biomarkers were obtained from the Genetics of Iron Status consortium (transferrin saturation, serum iron, and ferritin: n=48,972). The corresponding effects of these variants on the risk of CAD, IS and T2D were obtained from a meta-analysis of unrelated participants of European ancestry in the UK Biobank (UKB), together with previously recruited participants in CARDIOGRAMplusC4D (total n=90,377 CAD cases), MEGASTROKE (total n=43,381 IS cases) and DIAGRAM (total n=74,124 T2D cases), respectively. The main analysis used a two-sample inverse-variance weighted MR, while the sensitivity analyses used weighted-median, weighted-mode, MR-PRESSO, and MR-Egger approaches. Results MR analysis demonstrated significant inverse association of each of the three genetically-instrumented iron status biomarker with risk of CAD (transferrin saturation OR=0.96 [95% CI: 0.92–0.99], p=0.02; serum iron OR=0.93 [0.89–0.97], p=0.001; and ferritin OR=0.86 (0.79–0.94), p=0.001, per 1 SD higher level). In contrast, these iron status biomarkers showed positive associations with risk of T2D (transferrin saturation OR=1.06 [1.01–1.11], p=0.01; serum iron OR=1.06 [0.99–1.13], p=0.07; and ferritin OR=1.12 [0.99–1.26], p=0.06, per 1 SD higher level). There was positive, but non-significant, association of IS with each of the iron status biomarker analysed. Sensitivity analyses using several different MR approaches yielded concordant results. Conclusions Among European adults, iron status appeared to have causal associations, but in opposite directions, with the risk of CHD and T2D. Our findings highlight the need for caution about strategies for advocating iron supplementation in individuals with normal haemoglobin levels for prevention of CAD. Acknowledgement/Funding British Heart Found, Medical Research Council, Wellcome Trust, NIHR Biomedical Research Centre, Oxford

scholarly journals Iron Status May Not Affect Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahao Cai ◽  
Xiong Chen ◽  
Hongxuan Wang ◽  
Zixin Wei ◽  
Mei Li ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Outcome Data ◽  
Sensitivity Analyses ◽  
A Genome ◽  
Lateral Sclerosis

BackgroundObservational studies have shown an association of increased iron status with a higher risk of amyotrophic lateral sclerosis (ALS). Iron status might be a novel target for ALS prevention if a causal relationship exists. We aimed to reveal the causality between iron status and ALS incidence using a large two-sample Mendelian randomization (MR).MethodsSingle nucleotide polymorphisms (SNPs) for iron status were identified from a genome-wide association study (GWAS) on 48,972 individuals. The outcome data came from the largest ALS GWAS to date (20,806 cases; 59,804 controls). We conducted conservative analyses (using SNPs with concordant change of biomarkers of iron status) and liberal analyses (using SNPs associated with at least one of the biomarkers of iron status), with inverse variance weighted (IVW) method as the main analysis. We then performed sensitivity analyses including weighted median, MR-Egger and MR-pleiotropy residual sum and outlier, as well as leave-one-out analysis to detect pleiotropy.ResultsIn the conservative analyses, we found no evidence of association between four biomarkers of iron status and ALS using IVW method with odds ratio (OR) 1.00 [95% confidence interval (CI): 0.90–1.11] per standard deviation (SD) increase in iron, 0.96 (95% CI: 0.77–1.21) in ferritin, 0.99 (95% CI: 0.92–1.07) in transferrin saturation, and 1.04 (95% CI: 0.93–1.16) in transferrin. Findings from liberal analyses were similar, and sensitivity analyses suggested no pleiotropy detected (all p &gt; 0.05).ConclusionOur findings suggest no causal effect between iron status and risk of ALS. Efforts to change the iron status to decrease ALS incidence might be impractical.

scholarly journals Sex-Specific Genetically Predicted Iron Status in relation to 12 Vascular Diseases: A Mendelian Randomization Study in the UK Biobank

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Fangkun Yang ◽  
Qinyi Bao ◽  
Zhuo Wang ◽  
Menghuai Ma ◽  
Jinlian Shen ◽  
...  
Keyword(s):  
Coronary Atherosclerosis ◽  
Serum Iron ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Vascular Diseases ◽  
Lower Extremities ◽  
Vascular Pathology ◽  
Uk Biobank ◽  
The Uk

Background. Iron overload has been implicated in the pathogenesis of varicose veins (VVs). However, the association of serum iron status with other vascular diseases (VDs) is not well understood, which might be a potential target for VD prevention. This study was aimed at investigating the causal associations between iron status and VDs using the Mendelian randomization (MR) method. Methods. A two-sample MR was designed to investigate whether iron status was associated with VDs, based on iron data from a published genome-wide association study meta-analysis of 48,972 subjects of European descent and VD data obtained from the UK Biobank, including 361,194 British subjects (167,020 males and 194,174 females). We further explored whether there was sex difference in the associations between genetically predicted iron status and VDs. Results. The results demonstrated that iron status had a significant causal effect on VVs of lower extremities ( P < 0.001 ) and a potential effect on coronary atherosclerosis ( P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively), but not on other VDs. Furthermore, higher iron status exerted a detrimental effect on VVs of lower extremities in both genders ( P < 0.05 ) and a protective effect on male patients with coronary atherosclerosis ( P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively). Conclusions. This MR study provides robust evidence that higher iron status increases the risk of VVs of lower extremities, whereas it reduces the incidence of coronary atherosclerosis in the male population, which indicates that iron has divergent effects on vascular pathology.

scholarly journals Causal Effects of Genetically Predicted Iron Status on Sepsis: A Two-Sample Bidirectional Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Yuanlong Hu ◽  
Xiaomeng Cheng ◽  
Huaiyu Mao ◽  
Xianhai Chen ◽  
Yue Cui ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Serum Iron ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Reverse Causality ◽  
Clinical Value ◽  
Causal Direction ◽  
Increased Risk

Background/Aim: Several observational studies showed a significant association between elevated iron status biomarkers levels and sepsis with the unclear direction of causality. A two-sample bidirectional mendelian randomization (MR) study was designed to identify the causal direction between seven iron status traits and sepsis.Methods: Seven iron status traits were studied, including serum iron, ferritin, transferrin saturation, transferrin, hemoglobin, erythrocyte count, and reticulocyte count. MR analysis was first performed to estimate the causal effect of iron status on the risk of sepsis and then performed in the opposite direction. The multiplicative random-effects and fixed-effects inverse-variance weighted, weighted median-based method and MR-Egger were applied. MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran's Q statistic methods were used to assess heterogeneity and pleiotropy.Results: Genetically predicted high levels of serum iron (OR = 1.21, 95%CI = 1.13–1.29, p = 3.16 × 10−4), ferritin (OR = 1.32, 95%CI = 1.07–1.62, p =0.009) and transferrin saturation (OR = 1.14, 95%CI = 1.06–1.23, p = 5.43 × 10−4) were associated with an increased risk of sepsis. No significant causal relationships between sepsis and other four iron status biomarkers were observed.Conclusions: This present bidirectional MR analysis suggested the causal association of the high iron status with sepsis susceptibility, while the reverse causality hypothesis did not hold. The levels of transferrin, hemoglobin, erythrocytes, and reticulocytes were not significantly associated with sepsis. Further studies will be required to confirm the potential clinical value of such a prevention and treatment strategy.

The association between serum iron status and risk of asthma: a 2-sample Mendelian randomization study in descendants of Europeans

2019 ◽  
Vol 110 (4) ◽  
pp. 959-968 ◽  
Author(s):  
Lulu Huang ◽  
Longman Li ◽  
Xiaoyu Luo ◽  
Sifang Huang ◽  
Qingzhi Hou ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Age At Onset ◽  
Transferrin Saturation ◽  
Sensitivity Analyses ◽  
Multidisciplinary Study ◽  
Asthma Risk ◽  
Environmental Causes ◽  
Liberal Approach

ABSTRACT Background Observational studies present conflicting results about a possible association of iron status with asthma risk, pointing to potential modifiable targets for prevention. Objective The aim of this study was to use Mendelian randomization (MR) to estimate associations between iron status and asthma risk. Methods We used the Genetics of Iron Status consortium to identify genetic variants that could be used as instrumental variables for the effect of systemic iron status. The following sets of instruments were used: a conservative set (instruments restricted to variants with concordant relations to 4 iron status biomarkers) and a liberal set (instruments selected using variants associated with at least 1 of 4 iron status biomarkers). Associations of these genetic variants with asthma risk were estimated in data from the Trans-National Asthma Genetics Consortium (TAGC) and the GABRIEL consortium (A Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community). Data on the association of genetic variants with iron status and with asthma were combined to assess the influence of iron status on asthma risk. Results In the conservative approach, the MR OR of asthma was 1.00 (95% CI: 0.91, 1.10) per SD increase in iron, 0.96 (95% CI: 0.78, 1.18) in log-transformed ferritin, 0.99 (95% CI: 0.93, 1.06) in transferrin saturation, and 1.03 (95% CI: 0.93, 1.14) in transferrin in the TAGC dataset (none of the values were statistically significant). An age at onset–stratified analysis in the GABRIEL dataset suggested no effect of iron status in childhood onset, later onset, or unknown age at onset asthma. Findings from the liberal approach were similar, and the results persisted in sensitivity analyses (all P > 0.05). Conclusions This MR study does not provide evidence of an effect of iron status on asthma, suggesting that efforts to change iron concentrations will probably not result in decreased risk of asthma.

scholarly journals Iron Status and Risk of Stroke

Stroke ◽  
2018 ◽  
Vol 49 (12) ◽  
pp. 2815-2821 ◽  
Author(s):  
Dipender Gill ◽  
Grace Monori ◽  
Ioanna Tzoulaki ◽  
Abbas Dehghan
Keyword(s):  
Genetic Variants ◽  
Serum Iron ◽  
Detrimental Effect ◽  
Stroke Risk ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Cardioembolic Stroke ◽  
Sensitivity Analyses ◽  
Ratio Method

Background and Purpose— Both iron deficiency and excess have been associated with stroke risk in observational studies. However, such associations may be attributable to confounding from environmental factors. This study uses the Mendelian randomization technique to overcome these limitations by investigating the association between genetic variants related to iron status and stroke risk. Methods— A study of 48 972 subjects performed by the Genetics of Iron Status consortium identified genetic variants with concordant relations to 4 biomarkers of iron status (serum iron, transferrin saturation, ferritin, and transferrin) that supported their use as instruments for overall iron status. Genetic estimates from the MEGASTROKE consortium were used to investigate the association between the same genetic variants and stroke risk. The 2-sample ratio method Mendelian randomization approach was used for the main analysis, with the MR-Egger and weighted median techniques used in sensitivity analyses. Results— The main results, reported as odds ratio (OR) of stroke per SD unit increase in genetically determined iron status biomarker, showed a detrimental effect of increased iron status on stroke risk (serum iron OR, 1.07; 95% CI, 1.01–1.14; [log-transformed] ferritin OR, 1.18; 95% CI, 1.02–1.36; and transferrin saturation OR, 1.06; 95% CI, 1.01–1.11). A higher transferrin, indicative of lower iron status, was also associated with decreased stroke risk (OR, 0.92; 95% CI, 0.86–0.99). Examining ischemic stroke subtypes, we found the detrimental effect of iron status to be driven by cardioembolic stroke. These results were supported in statistical sensitivity analyses more robust to the inclusion of pleiotropic variants. Conclusions— This study provides Mendelian randomization evidence that higher iron status is associated with increased stroke risk and, in particular, cardioembolic stroke. Further work is required to investigate the underlying mechanism and whether this can be targeted in preventative strategies.

scholarly journals Effects of Genetically Determined Iron Status on Risk of Venous Thromboembolism and Carotid Atherosclerotic Disease: A Mendelian Randomization Study

2019 ◽  
Vol 8 (15) ◽  
Author(s):  
Dipender Gill ◽  
Christopher F. Brewer ◽  
Grace Monori ◽  
David‐Alexandre Trégouët ◽  
Nora Franceschini ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Carotid Plaque ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Media Thickness ◽  
Using Data ◽  
Genetically Determined

Background Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this study was to investigate the effect of genetically determined iron status on carotid intima‐media thickness, carotid plaque, and venous thromboembolism using Mendelian randomization. Methods and Results Genetic instrumental variables for iron status were selected from a genome‐wide meta‐analysis of 48 972 subjects. Genetic association estimates for carotid intima‐media thickness and carotid plaque were obtained using data from 71 128 and 48 434 participants, respectively, and estimates for venous thromboembolism were obtained using data from a study incorporating 7507 cases and 52 632 controls. Conventional 2‐sample summary data Mendelian randomization was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of venous thromboembolism. Odds ratios per SD increase in biomarker levels were 1.37 (95% CI 1.14‐1.66) for serum iron, 1.25 (1.09‐1.43) for transferrin saturation, 1.92 (1.28‐2.88) for ferritin, and 0.76 (0.63‐0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding odds ratios were 0.85 (0.73‐0.99) for serum iron and 0.89 (0.80‐1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no Mendelian randomization evidence of an effect of iron status on carotid intima‐media thickness. Conclusions These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease but increases the risk of thrombosis related to stasis of blood.

scholarly journals Genetic support of a causal relationship between iron status and type 2 diabetes: a Mendelian randomization study

2021 ◽  
Author(s):  
Xinhui Wang ◽  
Xuexian Fang ◽  
Wanru Zheng ◽  
Jiahui Zhou ◽  
Zijun Song ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Iron Overload ◽  
Bayesian Model Averaging ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Meta Analysis ◽  
Transferrin Saturation ◽  
Model Averaging ◽  
Underlying Mechanism

Abstract Context Iron overload is a known risk factor for type 2 diabetes (T2D); however, both iron overload and iron deficiency have been associated with metabolic disorders in observational studies. Objective Using Mendelian randomization (MR), we assessed how genetically predicted systemic iron status affected T2D risk. Design and Methods A two-sample MR analysis was used to obtain a causal estimate. We selected genetic variants strongly associated (P &lt; 5×10 −8) with four biomarkers of systemic iron status from a study involving 48,972 subjects performed by the Genetics of Iron Status consortium and applied these biomarkers to the T2D case-control study (74,124 cases and 824,006 controls) performed by the Diabetes Genetics Replication and Meta-analysis consortium. The simple median, weighted median, MR-Egger, MR analysis using mixture-model, weighted allele scores, and MR based on Bayesian model averaging approaches were used for the sensitivity analysis. Results Genetically instrumented serum iron (OR: 1.07; 95% CI: 1.02–1.12), ferritin (OR: 1.19; 95% CI: 1.08–1.32), and transferrin saturation (OR: 1.06; 95% CI: 1.02–1.09) were positively associated with T2D. In contrast, genetically instrumented transferrin, a marker of reduced iron status, was inversely associated with T2D (OR: 0.91; 95% CI: 0.87–0.96). Conclusions Genetic evidence supports a causal link between increased systemic iron status and increased T2D risk. Further studies involving various ethnic backgrounds based on individual-level data and studies regarding the underlying mechanism are warranted for reducing the risk of T2D.

scholarly journals Genetic support of a causal relationship between Iron status and atrial fibrillation: a Mendelian randomization study

2021 ◽  
Author(s):  
Tianyi Wang ◽  
Jun Cheng ◽  
Yanggan Wang
Keyword(s):  
Atrial Fibrillation ◽  
Causal Relationship ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Nucleotide Polymorphisms ◽  
Positive Effects ◽  
A Genome

Background Atrial fibrillation is the most common arrhythmia disease.Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and the risk of atrial fibrillation may be biased by confounding and reverse causality.The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely appied to estimate the causal effect,to reveal whether systemic iron status was causally related to atrial fibrillation. Methods Single nucleotide polymorphisms (SNPs) strongly associated (P< 5.10-8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium. Summary-level data for the genetic associations with atrial fibrillation were acquired from AFGen (Atrial Fibrillation Genetics) consortium study( including 65,446 atrial fibrillation cases and 522,744 controls) .We used a two-sample MR analysis to obtain a causal estimate, and further verified credibility through sensitivity analysis. Results Genetically instrumented serum iron [OR:1.09;95%; confidence interval (CI)1.02-1.16; p=0.01], ferritin [OR:1.16;95%CI:1.02-1.33; p=0.02], and transferrin saturation [OR:1.05;95%CI:1.01-1.11; p=0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR:0.90;95%CI:0.86-0.97; p=0.006] was an inverse correlation with atrial fibrillation. Conclusion In conclusion,our results strongly elucidated a causal link between genetically determined higher iron status and increased the risk of atrial fibrillation.This provided new ideas for clinical prevention and treatment of atrial fibrillation.

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