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

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.

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

10.1101/2021.11.02.21265752 ◽

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

Frontiers in Genetics ◽

10.3389/fgene.2021.617245 ◽

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 > 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.

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EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

International Journal of Stroke ◽

10.1177/17474930211006285 ◽

2021 ◽

pp. 174749302110062

Author(s):

Bin Yan ◽

Jian Yang ◽

Li Qian ◽

Fengjie Gao ◽

Ling Bai ◽

...

Keyword(s):

Sensitivity Analysis ◽

Ischemic Stroke ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Visceral Adiposity ◽

Large Artery ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

A Genome ◽

Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5Ã10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48Ã10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01Ã10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16Ã10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

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Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy225 ◽

2018 ◽

Vol 109 (1) ◽

pp. 90-98 ◽

Cited By ~ 4

Author(s):

Dylan M Williams ◽

Sara Hägg ◽

Nancy L Pedersen

Keyword(s):

Alzheimer Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Disease Risk ◽

Late Onset ◽

Association Studies ◽

Nucleotide Polymorphisms ◽

Primary Methods ◽

A Genome ◽

Β Carotene

ABSTRACT Background Higher circulating antioxidant concentrations are associated with a lower risk of late-onset Alzheimer disease (AD) in observational studies, suggesting that diet-sourced antioxidants may be modifiable targets for reducing disease risk. However, observational evidence is prone to substantial biases that limit causal inference, including residual confounding and reverse causation. Objectives In order to infer whether long-term circulating antioxidant exposure plays a role in AD etiology, we tested the hypothesis that AD risk would be lower in individuals with lifelong, genetically predicted increases in concentrations of 4 circulating antioxidants that are modifiable by diet. Methods Two-sample Mendelian randomization analyses were conducted. First, published genetic association studies were used to identify single-nucleotide polymorphisms (SNPs) that determine variation in circulating ascorbate (vitamin C), β-carotene, retinol (vitamin A), and urate. Second, for each set of SNP data, statistics for genotype associations with AD risk were extracted from data of a genome-wide association study of late-onset AD cases and controls (n = 17,008 and 37,154, respectively). Ratio-of-coefficients and inverse-variance-weighted meta-analyses were the primary methods used to assess the 4 sets of SNP-exposure and SNP-AD associations. Additional analyses assessed the potential impact of bias from pleiotropy on estimates. Results The models suggested that genetically determined differences in circulating ascorbate, retinol, and urate are not associated with differences in AD risk. All estimates were close to the null, with all ORs for AD ≥1 per unit increase in antioxidant exposure (ranging from 1.00 for ascorbate to 1.05 for retinol). There was little evidence to imply that pleiotropy had biased results. Conclusions Our findings suggest that higher exposure to ascorbate, β-carotene, retinol, or urate does not lower the risk of AD. Replication Mendelian randomization studies could assess this further, providing larger AD case-control samples and, ideally, using additional variants to instrument each exposure.

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Prioritization of candidate causal genes in GWAS signals of asthma in UK Biobank

10.21203/rs.3.rs-68257/v1 ◽

2020 ◽

Author(s):

Kim Valette ◽

Zhonglin Li ◽

Valentin Bon-Baret ◽

Arnaud Chignon ◽

Jean-Christophe Bérubé ◽

...

Keyword(s):

Genome Wide Association Study ◽

Mendelian Randomization ◽

Association Studies ◽

Uk Biobank ◽

Gamma Chain ◽

Gene Encoding ◽

Putative Gene ◽

A Genome ◽

Causal Genes ◽

High Affinity Ige Receptor

Abstract To identify susceptibility loci and candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS revealed 72 asthma-associated loci from 116 independent significant variants (PGWAS<5.0E-8). As expected, the yield of exonic variants associated with asthma was low, but nine were identified as potentially deleterious (CADD > 20) including a stop-gain mutation in the filaggrin (FLG) gene. The top lung TWAS gene on 17q12-q21 was GSDMB (PTWAS=1.42E-54). Other TWAS genes of interest include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). A novel risk locus was also revealed by the lung asthma TWAS on 1q23.3 with the putative gene encoding the gamma chain of the high-affinity IgE receptor (FCER1G, PTWAS=2.13E-6), which was also replicated in GTEx lung (PTWAS=3.71E-7). By testing a comprehensive set of cells and tissues, we then demonstrated that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants was in the blood. We mapped 485 eQTL-regulated genes associated with asthma in the blood and 50 of them were shown to be causally associated with asthma by Mendelian randomization. Prioritization of druggable genes revealed known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.

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

BioMed Research International ◽

10.1155/2020/6246041 ◽

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.

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Blood Pressure and Risk of Cardiovascular Disease in UK Biobank

Hypertension ◽

10.1161/hypertensionaha.120.16138 ◽

2021 ◽

Author(s):

Eric Yuk Fai Wan ◽

Wing Tung Fung ◽

C. Mary Schooling ◽

Shiu Lun Au Yeung ◽

Man Ki Kwok ◽

...

Keyword(s):

Blood Pressure ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Randomization Test ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Causal Association ◽

Uk Biobank ◽

Cvd Risk ◽

The Uk

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25–1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15–1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24–1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14–1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24–1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12–1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.

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Abstract P430: Educational Attainment, Adherence to Healthy Lifestyle, and Risk of Cardiovascular Diseases

Circulation ◽

10.1161/circ.141.suppl_1.p430 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Xiang Li ◽

Tao Zhou ◽

Hao Ma ◽

Dianjianyi Sun ◽

Yoriko Heianza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Educational Attainment ◽

Genome Wide Association Study ◽

Healthy Lifestyle ◽

Smoking Status ◽

Significant Proportion ◽

Nucleotide Polymorphisms ◽

Uk Biobank ◽

Mediation Analyses ◽

A Genome

Introduction: Lower educational attainment is one of the major socioeconomic factors contributing to cardiovascular diseases (CVD); higher education tends to be associated with healthier behaviors and lower risk of CVD. However, whether education plays a causal role in adherence to a healthy lifestyle, and if there is causality, how much of the education-CVD association is mediated by the lifestyle factors, has not been established. Methods: A healthy lifestyle score was constructed on body mass index, smoking status, physical activity, and diet. The causal relations between educational attainment and adherence to a healthy lifestyle was assessed by two-sample Mendelian Randomization analyses using summary statistics for single nucleotide polymorphisms (SNPs) identified from a genome-wide association study (GWAS) of educational attainment (N=1,131,881) and the UK Biobank cohort (N=425,770). We further performed mediation analyses to quantify the effect of educational attainment on the risk of CVD through healthy lifestyle among 386,442 participants in UK Biobank. Results: We found a significant positive causal relationship between years of education and adherence to a healthy lifestyle, independent of age, sex, alcohol intake, and person’s socioeconomic status. In addition, we found that adherence to favorable lifestyle mediated a 42.1%, 40.3%, and 33.5% reduction in the incidence of coronary heart disease (CHD), CVD events, and CVD mortality, respectively (all p <0.05). Conclusions: Our results indicate that educational attainment is causally associated with adherence to a healthy lifestyle, which in turn, mediates a significant proportion of the effect of educational attainment on cardiovascular events.

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Periodontitis and pulmonary function: a Mendelian randomization study

Clinical Oral Investigations ◽

10.1007/s00784-021-04000-9 ◽

2021 ◽

Author(s):

Sebastian-Edgar Baumeister ◽

Michael Nolde ◽

Birte Holtfreter ◽

Hansjörg Baurecht ◽

Sven Gläser ◽

...

Keyword(s):

Pulmonary Function ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Forced Expiratory Volume ◽

Sensitivity Analyses ◽

Observational Research ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

A Genome ◽

The Uk

Abstract Objectives Observational research suggests that periodontitis affects pulmonary function; however, observational studies are subject to confounding and reverse causation, making causal inference and the direction of these associations difficult. We used Mendelian randomization (MR) to assess the potential causal association between genetic liability to periodontitis and pulmonary function. Materials and methods We used six single-nucleotide polymorphisms (SNPs) associated with periodontitis (P < 5 × 10−6) from a genome-wide association study (GWAS) of 17,353 European descent periodontitis cases and 28,210 controls from the GeneLifestyle Interactions in Dental Endpoints consortium and the UK Biobank, and related these to SNPs from a lung function GWAS including 79,055 study participants of the SpiroMeta Consortium. Results MR analysis suggested no effect of periodontitis on the ratio of forced expiratory volume in one second to lower forced vital capacity (standard deviation increment in outcome per doubling of the odds of the exposure (95% confidence interval) = − 0.004 (− 0.028; 0.020)). Replication analysis using genetic instruments from two different GWAS and sensitivity analyses to address potential pleiotropy led to no substantial changes in estimates. Conclusions Collectively, these findings do not support a relationship between genetic liability for periodontitis and pulmonary function. Clinical relevance Periodontitis does not seem to be a risk factor for worsening of pulmonary function.

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Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

Communications Biology ◽

10.1038/s42003-021-02227-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Kim Valette ◽

Zhonglin Li ◽

Valentin Bon-Baret ◽

Arnaud Chignon ◽

Jean-Christophe Bérubé ◽

...

Keyword(s):

Genome Wide Association Study ◽

Mendelian Randomization ◽

Association Studies ◽

Uk Biobank ◽

Susceptibility Loci ◽

Functional Annotations ◽

Fold Enrichment ◽

Genome Wide ◽

A Genome ◽

Causal Genes

AbstractTo identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on a broad asthma definition (n = 56,167 asthma cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide association studies (TWAS) and Mendelian randomization in lung (n = 1,038) and blood (n = 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (PGWAS < 5.0E-8). The most significant lung TWAS gene on 17q12-q21 is GSDMB (PTWAS = 1.42E-54). Other TWAS genes include TSLP on 5q22, RERE on 1p36, CLEC16A on 16p13, and IL4R on 16p12, which all replicated in GTEx lung (n = 515). We demonstrate that the largest fold enrichment of regulatory and functional annotations among asthma-associated variants is in the blood. We map 485 blood eQTL-regulated genes associated with asthma and 50 of them are causal by Mendelian randomization. Prioritization of druggable genes reveals known (IL4R, TSLP, IL6, TNFSF4) and potentially new therapeutic targets for asthma.

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