scholarly journals Body mass index and height and risk of cutaneous melanoma: Mendelian randomization analyses

2020 ◽  
Vol 49 (4) ◽  
pp. 1236-1245 ◽  
Author(s):  
Jean Claude Dusingize ◽  
Catherine M Olsen ◽  
Jiyuan An ◽  
Nirmala Pandeya ◽  
Matthew H Law ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Positive Association ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Melanoma Risk ◽  
Lifestyle Risk Factors

Abstract Background Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach. Methods We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height. Results Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91–1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02–1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results. Conclusions These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status.

scholarly journals Cannabis Use and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Jianqiang Zhao ◽  
Heng Chen ◽  
Chengui Zhuo ◽  
Shudong Xia
Keyword(s):  
Body Mass Index ◽  
Cardiovascular Diseases ◽  
Body Mass ◽  
Tobacco Use ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Cannabis Use ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genetically Determined

Several observational studies have shown that cannabis use has negative effects on the cardiovascular system, but the causality of this relationship has not been confirmed. The aim of the current study was to estimate the effects of genetically determined cannabis use on risk of cardiovascular diseases. Ten single-nucleotide polymorphisms related to cannabis use were employed as instruments to estimate the association between genetically determined cannabis use and risk of cardiovascular diseases using a two-sample Mendelian randomization (MR) method. Summary statistics data on exposure and outcomes were obtained from different genome-wide association meta-analysis studies. The results of this MR analysis showed no causal effects of cannabis use on the risk of several common cardiovascular diseases, including coronary artery disease, myocardial infarction, stroke and ischemic stroke subtypes, atrial fibrillation (AF), and heart failure. Various sensitivity analyses yielded similar results, and no heterogeneity and directional pleiotropy were observed. After adjusting for tobacco use and body mass index, multivariable MR analysis suggested a causal effect of cannabis use on small vessel stroke (SVS) [odds ratio (OR) 1.17; 95% CI 1.02–1.35; p = 0.03] and AF (OR 1.06; 95% CI 1.01–1.10; p = 0.01), respectively. This two-sample MR study did not demonstrate a causal effect of genetic predisposition to cannabis use on several common cardiovascular outcomes. After adjusting for tobacco use and body mass index, the multivariable MR analysis suggested a detrimental effect of cannabis use on the risk of SVS and AF, respectively.

scholarly journals Using a Two-Sample Mendelian Randomization Method in Assessing the Causal Relationships Between Human Blood Metabolites and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Zixian Wang ◽  
Shiyu Chen ◽  
Qian Zhu ◽  
Yonglin Wu ◽  
Guifeng Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Blood ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Blood Metabolites ◽  
Causal Relationships

Background: Heart failure (HF) is the main cause of morbidity and mortality worldwide, and metabolic dysfunction is an important factor related to HF pathogenesis and development. However, the causal effect of blood metabolites on HF remains unclear.Objectives: Our chief aim is to investigate the causal relationships between human blood metabolites and HF risk.Methods: We used an unbiased two-sample Mendelian randomization (MR) approach to assess the causal relationships between 486 human blood metabolites and HF risk. Exposure information was obtained from Sample 1, which is the largest metabolome-based genome-wide association study (mGWAS) data containing 7,824 Europeans. Outcome information was obtained from Sample 2, which is based on the results of a large-scale GWAS meta-analysis of HF and contains 47,309 cases and 930,014 controls of Europeans. The inverse variance weighted (IVW) model was used as the primary two-sample MR analysis method and followed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis.Results: We observed that 11 known metabolites were potentially related to the risk of HF after using the IVW method (P < 0.05). After adding another four MR models and performing sensitivity analyses, we found a 1-SD increase in the xenobiotics 4-vinylphenol sulfate was associated with ~22% higher risk of HF (OR [95%CI], 1.22 [1.07–1.38]).Conclusions: We revealed that the 4-vinylphenol sulfate may nominally increase the risk of HF by 22% after using a two-sample MR approach. Our findings may provide novel insights into the pathogenesis underlying HF and novel strategies for HF prevention.

scholarly journals Body Mass Index and the Risk of Rheumatoid Arthritis: An Updated Dose-Response Meta-Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Xia Feng ◽  
Xizhu Xu ◽  
Yanjun Shi ◽  
Xuezhen Liu ◽  
Huamin Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Body Mass Index ◽  
Body Mass ◽  
Dose Response ◽  
Meta Analysis ◽  
Prevention Strategy ◽  
Sensitivity Analyses ◽  
Significant Heterogeneity ◽  
Nonlinear Relationship ◽  
Increased Risk

Background. Extensive studies have been carried out to investigate the association between obesity and the risk of rheumatoid arthritis (RA); however, the results of the current reported original studies remain inconsistent. This study aimed to clarify the relationship between body mass index and rheumatoid arthritis by conducting an updated overall and dose-response meta-analysis. Methods. The relevant literature was searched using the PubMed and Embase databases (through 20 September 2018) to identify all eligible published studies. Random-effect models and dose-response meta-analyses were used to estimate the pooled risk ratio (RR) with a 95% confidence interval (CI). Subgroup analyses were also conducted based on the characteristics of the participants. Sensitivity analyses and publication bias tests were also performed to explore potential heterogeneity and bias in the meta-analysis. Results. Sixteen studies that included a total of 406,584 participants were included in the meta-analysis. Compared to participants with normal weight, the pooled RRs of rheumatoid arthritis were 1.12 (95% CI, 1.04-1.20) in overweight and 1.23 (95% CI, 1.09-1.39) in obese participants. There was evidence of a nonlinear relationship between body mass index (BMI) and RA (P  for nonlinearity less than 0.001 in the overall meta-analysis, P for nonlinearity=0.025 in the case-control studies, P for nonlinearity=0.0029 in the cohort studies). No significant heterogeneity was found among studies (I2=10.9% for overweight and I2=45.5% for obesity). Conclusion. The overall and dose-response meta-analysis showed that increased BMI was associated with an increased risk for rheumatoid arthritis, which might present a prevention strategy for the prevention or control of rheumatoid arthritis. The nonlinear relationship between BMI and RA might present a personal prevention strategy for RA.

scholarly journals Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Li Qian ◽  
Yajuan Fan ◽  
Fengjie Gao ◽  
Binbin Zhao ◽  
Bin Yan ◽  
...  
Keyword(s):  
Uric Acid ◽  
Lower Risk ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Strong Predictor ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Inverse Variance

Abstract Background Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches. Methods Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses. Results Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62–0.95; PIVW = 0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01–1.12; PIVW = .0145). Discussion Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism.

scholarly journals Body mass index and the risk of disability retirement: a systematic review and meta-analysis

2019 ◽  
Vol 77 (1) ◽  
pp. 48-55 ◽  
Author(s):  
Rahman Shiri ◽  
Kobra Falah-Hassani ◽  
Tea Lallukka
Keyword(s):  
Body Mass Index ◽  
Cardiovascular Diseases ◽  
Mental Disorders ◽  
Musculoskeletal Disorders ◽  
Publication Bias ◽  
Body Mass ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Case Control Studies ◽  
Disability Retirement

The aim of this study was to determine the associations of body mass index (BMI) with all-cause and cause-specific disability retirement. Literature searches were conducted in PubMed, Embase and Web of Science from their inception to May 2019. A total of 27 (25 prospective cohort and 2 nested case-control) studies consisting of 2 199 632 individuals qualified for a meta-analysis. Two reviewers independently assessed the methodological quality of the included studies. We used a random effects meta-analysis, assessed heterogeneity and publication bias, and performed sensitivity analyses. There were a large number of participants and the majority of studies were rated at low or moderate risk of bias. There was a J-shaped relationship between BMI and disability retirement. Underweight (hazard ratio (HR)/risk ratio (RR)=1.20, 95% CI 1.02 to 1.41), overweight (HR/RR=1.13, 95% CI 1.07 to 1.19) and obese individuals (HR/RR=1.52, 95% CI 1.36 to 1.71) were more commonly granted all-cause disability retirement than normal-weight individuals. Moreover, overweight increased the risk of disability retirement due to musculoskeletal disorders (HR/RR=1.26, 95% CI 1.15 to 1.39) and cardiovascular diseases (HR=1.73, 95% CI 1.24 to 2.41), and obesity increased the risk of disability retirement due to musculoskeletal disorders (HR/RR=1.66, 95% CI 1.42 to 1.94), mental disorders (HR=1.29, 95% CI 1.04 to 1.61) and cardiovascular diseases (HR=2.80, 95% CI 1.85 to 4.24). The association between excess body mass and all-cause disability retirement did not differ between men and women and was independent of selection bias, performance bias, confounding and adjustment for publication bias. Obesity markedly increases the risk of disability retirement due to musculoskeletal disorders, cardiovascular diseases and mental disorders. Since the prevalence of obesity is increasing globally, disease burden associated with excess body mass and disability retirement consequently are projected to increase. Reviewregistrationnumber: CRD42018103110.

scholarly journals Large differences in adiponectin levels have no clear effect on multiple sclerosis risk: A Mendelian randomization study

2016 ◽  
Vol 23 (11) ◽  
pp. 1461-1468 ◽  
Author(s):  
Julia Devorak ◽  
Lauren E Mokry ◽  
John A Morris ◽  
Vincenzo Forgetta ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Strong Support ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Standard Deviation Increase ◽  
Clear Effect ◽  
Genome Wide ◽  
Unit Increase

Background: Mendelian randomization (MR) studies have demonstrated strong support for an association between genetically increased body mass index and risk of multiple sclerosis (MS). The adipokine adiponectin may be a potential mechanism linking body mass to risk of MS. Objective: To evaluate whether genetically increased adiponectin levels influence risk of MS. Methods: Using genome-wide significant single nucleotide polymorphisms (SNPs) for adiponectin, we undertook an MR study to estimate the effect of adiponectin on MS. This method prevents bias due to reverse causation and minimizes bias due to confounding. Sensitivity analyses were performed to evaluate the assumptions of MR. Results: MR analyses did not support a role for genetically elevated adiponectin in risk of MS (odds ratio (OR) = 0.93 per unit increase in natural-log-transformed adiponectin, equivalent to a two-standard deviation increase in adiponectin on the absolute scale; 95% confidence interval (CI) = 0.66–1.33; p = 0.61). Further MR analysis suggested that genetic variation at the adiponectin gene, which influences adiponectin level, does not impact MS risk. Sensitivity analyses, including MR-Egger regression, suggested no bias due to pleiotropy. Conclusion: Lifelong genetically increased adiponectin levels in humans have no clear effect on risk of MS. Other biological factors driving the association between body mass and MS should be investigated.

scholarly journals Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Yalan Li ◽  
Jun Lu ◽  
Jie Wang ◽  
Peizhi Deng ◽  
Changjiang Meng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Cytokines ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Outcome Data ◽  
Sensitivity Analyses ◽  
A Genome

Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear.Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results.Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89–0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88–0.99, unadjusted p < 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke.Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.

scholarly journals Carnitine and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Chunyu Li ◽  
Ruwei Ou ◽  
Qianqian Wei ◽  
Huifang Shang
Keyword(s):  
Causal Relationship ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Carnitine Level ◽  
Standard Deviation Increase ◽  
Inverse Variance ◽  
Weighted Median ◽  
Genetically Determined

Background: Carnitine, a potential substitute or supplementation for dexamethasone, might protect against COVID-19 based on its molecular functions. However, the correlation between carnitine and COVID-19 has not been explored yet, and whether there exists causation is unknown.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between carnitine level and COVID-19. Significant single nucleotide polymorphisms from genome-wide association study on carnitine (N = 7,824) were utilized as exposure instruments, and summary statistics of the susceptibility (N = 1,467,264), severity (N = 714,592) and hospitalization (N = 1,887,658) of COVID-19 were utilized as the outcome. The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method, and further verified by another three MR methods including MR Egger, weighted median, and weighted mode, as well as extensive sensitivity analyses.Results: Genetically determined one standard deviation increase in carnitine amount was associated with lower susceptibility (OR: 0.38, 95% CI: 0.19–0.74, P: 4.77E−03) of COVID-19. Carnitine amount was also associated with lower severity and hospitalization of COVID-19 using another three MR methods, though the association was not significant using the IVW method but showed the same direction of effect. The results were robust under all sensitivity analyses.Conclusions: A genetic predisposition to high carnitine levels might reduce the susceptibility and severity of COVID-19. These results provide better understandings on the role of carnitine in the COVID-19 pathogenesis, and facilitate novel therapeutic targets for COVID-19 in future clinical trials.

scholarly journals Periodontal disease increases the host susceptibility to COVID-19 and its severity: a Mendelian randomization study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi Wang ◽  
Hui Deng ◽  
Yihuai Pan ◽  
Lijian Jin ◽  
Rongdang Hu ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Host Susceptibility ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Inverse Variance ◽  
Weighted Median ◽  
First Time

Abstract Background Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity. Methods Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations. Results The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004–1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003–1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001–1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003–1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19. Conclusions We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.

scholarly journals Cardiometabolic, Lifestyle, and Nutritional Factors in Relation to Varicose Veins: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Shuai Yuan ◽  
Maria Bruzelius ◽  
Scott M. Damrauer ◽  
Susanna C. Larsson
Keyword(s):  
Blood Pressure ◽  
Body Mass Index ◽  
Systolic Blood Pressure ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Varicose Veins ◽  
Nucleotide Polymorphisms ◽  
Nutritional Factors ◽  
Significance Level ◽  
Increased Risk

Background We conducted a 2‐sample Mendelian randomization study to assess the associations of cardiometabolic, lifestyle, and nutritional factors with varicose veins. Methods and Results Independent single‐nucleotide polymorphisms associated with height (positive control), body mass index, type 2 diabetes, diastolic and systolic blood pressure, smoking, alcohol and coffee consumption, 7 circulating vitamins (A, B6, B9, B12, C, 25‐hydroxyvitamin D, and E), and 5 circulating minerals (calcium, iron, magnesium, selenium, and zinc) at the genome‐wide significance level were used as instrumental variables. Summary‐level data for the genetic associations with varicose veins were obtained from the UK Biobank (8763 cases and 352 431 noncases) and the FinnGen consortium (13 928 cases and 153 951 noncases). Genetically predicted higher height, body mass index, smoking, and circulating iron levels were associated with an increased risk of varicose veins. The odds ratios (ORs) per 1‐SD increase in the exposure were 1.34 (95% CI, 1.25–1.43) for height, 1.39 (95% CI, 1.27–1.52) for body mass index, 1.12 (95% CI, 1.04–1.22) for the prevalence of smoking initiation, and 1.24 (95% CI, 1.16–1.33) for iron. Higher genetically predicted systolic blood pressure and circulating calcium and zinc levels were associated with a reduced risk of varicose veins, whereas the association for systolic blood pressure did not persist after adjustment for genetically predicted height. The OR was 0.75 (95% CI, 0.62–0.92) per 1‐SD increase in calcium levels and 0.97 (95% CI, 0.95–0.98) for zinc. Conclusions This study identified several modifiable risk factors for varicose veins.

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