scholarly journals Impact of Liability to Periodontitis on Glycemic Control and Type II Diabetes Risk: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Parth D. Shah ◽  
C. M. Schooling ◽  
Luisa N. Borrell
Keyword(s):  
Type Ii Diabetes ◽  
Mendelian Randomization ◽  
Fasting Glucose ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Type Ii ◽  
Nucleotide Polymorphisms ◽  
Causal Association ◽  
East Asians

While the association of periodontitis with Type II diabetes (T2DM) is well-established, the causal relationship remains uncertain. We examined the causal association of periodontitis with glycemic traits (HbA1c, fasting glucose, and fasting insulin) and T2DM using Mendelian randomization (MR) taking advantage of large genome-wide association studies of European and East Asian adults, i.e., the UK Biobank (n ≈ 350,000) (HbA1c), trans-ancestral MAGIC (HbA1c, fasting glucose, and insulin), and DIAMANTE (74,124 cases/824,006 controls), and AGEN for T2DM in Europeans and East Asians, respectively. Periodontitis was instrumented using single-nucleotide polymorphisms (SNPs), strongly and independently predicting liability to periodontitis in each ancestry group. SNP-specific Wald estimates were combined using inverse variance weighting. Sensitivity analyses were performed using the weighted median and MR-Egger with meta-analysis of MR estimates for Europeans and East Asians. Genetically instrumented liability to periodontitis was not associated with glycemic traits or T2DM in either ancestry or when ancestry specific estimates were meta-analyzed. Our findings do not support a causal association of liability to periodontitis with glycemic traits or T2DM. However, further research is required confirming these findings among other racial/ethnic groups, especially groups who carry a heavy burden of both periodontitis and T2DM.

scholarly journals Evaluation of glycemic traits in susceptibility to COVID-19 risk: a Mendelian randomization study

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shiu Lun Au Yeung ◽  
Jie V Zhao ◽  
C Mary Schooling
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Predisposition ◽  
Mendelian Randomization ◽  
Fasting Glucose ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Wide Confidence Interval

Abstract Background Observational studies suggest poorer glycemic traits and type 2 diabetes associated with coronavirus disease 2019 (COVID-19) risk although these findings could be confounded by socioeconomic position. We conducted a two-sample Mendelian randomization to clarify their role in COVID-19 risk and specific COVID-19 phenotypes (hospitalized and severe cases). Method We identified genetic instruments for fasting glucose (n = 133,010), 2 h glucose (n = 42,854), glycated hemoglobin (n = 123,665), and type 2 diabetes (74,124 cases and 824,006 controls) from genome wide association studies and applied them to COVID-19 Host Genetics Initiative summary statistics (17,965 COVID-19 cases and 1,370,547 population controls). We used inverse variance weighting to obtain the causal estimates of glycemic traits and genetic predisposition to type 2 diabetes in COVID-19 risk. Sensitivity analyses included MR-Egger and weighted median method. Results We found genetic predisposition to type 2 diabetes was not associated with any COVID-19 phenotype (OR: 1.00 per unit increase in log odds of having diabetes, 95%CI 0.97 to 1.04 for overall COVID-19; OR: 1.02, 95%CI 0.95 to 1.09 for hospitalized COVID-19; and OR: 1.00, 95%CI 0.93 to 1.08 for severe COVID-19). There were no strong evidence for an association of glycemic traits in COVID-19 phenotypes, apart from a potential inverse association for fasting glucose albeit with wide confidence interval. Conclusion We provide some genetic evidence that poorer glycemic traits and predisposition to type 2 diabetes unlikely increase the risk of COVID-19. Although our study did not indicate glycemic traits increase severity of COVID-19, additional studies are needed to verify our findings.

scholarly journals Univariable and Multivariable Two-Sample Mendelian Randomization Investigating the Effects of Leisure Sedentary Behaviors on the Risk of Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Haoxin Peng ◽  
Xiangrong Wu ◽  
Yaokai Wen ◽  
Yiyuan Ao ◽  
Yutian Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Computer Use ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Sedentary Behaviors ◽  
Watching Tv

Background:Leisure sedentary behaviors (LSB) are widespread, and observational studies have provided emerging evidence that LSB play a role in the development of lung cancer (LC). However, the causal inference between LSB and LC remains unknown.Methods: We utilized univariable (UVMR) and multivariable two-sample Mendelian randomization (MVMR) analysis to disentangle the effects of LSB on the risk of LC. MR analysis was conducted with genetic variants from genome-wide association studies of LSB (408,815 persons from UK Biobank), containing 152 single-nucleotide polymorphisms (SNPs) for television (TV) watching, 37 SNPs for computer use, and four SNPs for driving, and LC from the International Lung Cancer Consortium (11,348 cases and 15,861 controls). Multiple sensitivity analyses were further performed to verify the causality.Results: UVMR demonstrated that genetically predisposed 1.5-h increase in LSB spent on watching TV increased the odds of LC by 90% [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.44–2.50; p < 0.001]. Similar trends were observed for squamous cell lung cancer (OR, 1.97; 95%CI, 1.31–2.94; p = 0.0010) and lung adenocarcinoma (OR, 1.64; 95%CI 1.12–2.39; p = 0.0110). The causal effects remained significant after adjusting for education (OR, 1.97; 95%CI, 1.44–2.68; p < 0.001) and body mass index (OR, 1.86; 95%CI, 1.36–2.54; p < 0.001) through MVMR approach. No association was found between prolonged LSB spent on computer use and driving and LC risk. Genetically predisposed prolonged LSB was additionally correlated with smoking (OR, 1.557; 95%CI, 1.287–1.884; p < 0.001) and alcohol consumption (OR, 1.010; 95%CI, 1.004–1.016; p = 0.0016). Consistency of results across complementary sensitivity MR methods further strengthened the causality.Conclusion: Robust evidence was demonstrated for an independent, causal effect of LSB spent on watching TV in increasing the risk of LC. Further work is necessary to investigate the potential mechanisms.

scholarly journals Association of 25 hydroxyvitamin D concentration with risk of COVID-19: a Mendelian randomization study

2020 ◽  
Author(s):  
Di Liu ◽  
Qiuyue Tian ◽  
Jie Zhang ◽  
Haifeng Hou ◽  
Wei Wang ◽  
...  
Keyword(s):  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
25Ohd Concentration ◽  
25 Hydroxyvitamin D

Background In observational studies, 25 hydroxyvitamin D (25OHD) concentration has been associated with an increased risk of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether this association is causal. Methods We performed a two-sample Mendelian randomization (MR) to explore the causal relationship between 25OHD concentration and COVID-19, using summary data from the genome-wide association studies (GWASs) and using 25OHD concentration-related SNPs as instrumental variables (IVs). Results MR analysis did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity (odds ratio [OR]=1.136, 95% confidence interval [CI] 0.988-1.306, P=0.074; OR=0.889, 95% CI 0.549-1.439, P=0.632). Sensitivity analyses using different instruments and statistical models yielded similar findings, suggesting the robustness of the causal association. No obvious pleiotropy bias and heterogeneity were observed. Conclusion The MR analysis showed that there might be no linear causal relationship of 25OHD concentration with COVID-19 susceptibility and severity.

scholarly journals Association of Thyroid Function with Blood Pressure and Cardiovascular Disease: A Mendelian Randomization

2021 ◽  
Vol 11 (12) ◽  
pp. 1306
Author(s):  
Alice Giontella ◽  
Luca A. Lotta ◽  
John D. Overton ◽  
Aris Baras ◽  
Andrea Sartorio ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Thyroid Function ◽  
Lower Risk ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Thyroid Peroxidase ◽  
Genome Wide Association Studies ◽  
Causal Association

Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper- and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs–outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.

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

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiyong Cui ◽  
Hui Feng ◽  
Baichuan He ◽  
Yong Xing ◽  
Zhaorui Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Knee Oa ◽  
Increased Risk

BackgroundIt remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA).MethodsHere, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identified single-nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG), and 2-h postprandial glucose (2hGlu) from genome-wide association studies (GWAS). We used the MR inverse variance weighted (IVW), the MR–Egger method, the weighted median (WM), and the Robust Adjusted Profile Score (MR.RAPS) to reveal the associations of T2D, FG, and 2hGlu with hip and knee OA risks. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.ResultsWe did not find statistically significant causal effects of genetically increased T2D risk, FG, and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR–Egger OR = 1.1708, 95% CI 0.9469–1.4476, p = 0.1547). It was confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR–Egger, intercept = −0.0105, p = 0.1367). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR–Egger Q = 30.1362, I2 < 0.0001, p = 0.6104).ConclusionOur MR study did not support causal effects of a genetically increased T2D risk, FG, and 2hGlu on hip and knee OA risk.

scholarly journals Association of 25 Hydroxyvitamin D Concentration with Risk of COVID-19: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Di Liu ◽  
Qiuyue Tian ◽  
Jie Zhang ◽  
Haifeng Hou ◽  
Wei Wang ◽  
...  
Keyword(s):  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Hydroxyvitamin D ◽  
Increased Risk ◽  
25Ohd Concentration ◽  
25 Hydroxyvitamin D

Abstract Background: Coronavirus disease 2019 (COVID-19) has caused a large global pandemic. In observational studies, 25 hydroxyvitamin D (25OHD) concentration has been associated with an increased risk of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether this association is causal.Methods: We performed a two-sample Mendelian randomization (MR) to explore the causal relationship between 25OHD concentration and COVID-19, using summary data from the genome-wide association studies (GWASs) and using 25OHD concentration-related SNPs as instrumental variables (IVs). Results: MR analysis did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity (odds ratio [OR]=1.136, 95% confidence interval [CI] 0.988-1.306, P=0.074; OR=0.889, 95% CI 0.549-1.439, P=0.632). Sensitivity analyses using different instruments and statistical models yielded similar findings, suggesting the robustness of the causal association. No obvious pleiotropy bias and heterogeneity were observed.Conclusions: The MR analysis showed that there might be no linear causal relationship of 25OHD concentration with COVID-19 susceptibility and severity.

scholarly journals Type 2 diabetes and glycemic traits are not causal factors of osteoarthritis: A two-sample Mendelian randomization analysis

2020 ◽  
Author(s):  
Zhiyong Cui ◽  
Hui Feng ◽  
Baichuan He ◽  
Yong Xing ◽  
Zhaorui Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Knee Oa ◽  
Increased Risk

Abstract Background: It remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA). Methods: Here, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identified single nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG) and 2-hour postprandial glucose (2hGlu) from genome-wide association studies (GWAS) . We used MR inverse variance weighted (IVW), the MR-Egger method, the weighted median (WM) and Robust Adjusted Profile Score (MR.RAPS) to reveal the associations of T2D, FG and 2hGlu with hip and knee OA risk. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.Results: We did not find statistically significant causal effects of genetically increased T2D risk, FG and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR-Egger OR=0.9536, 95% CI 0.5585 to 1.6283, p=0.8629). It was confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR-Egger, intercept=-0.0032, p=0.8518). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR-Egger Q=40.5481, I2=0.1368, p=0.2389). Conclusions: Our MR study did not support causal effects of a genetically increased T2D risk, FG and 2hGlu on hip and knee OA risk.

scholarly journals Gluten-free Diet Reduces the Risk of Irritable Bowel Syndrome: A Mendelian Randomization Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuhao Sun ◽  
Xuejie Chen ◽  
Shuyang Wang ◽  
Minzi Deng ◽  
Ying Xie ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Protective Factor ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Gluten Free Diet ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Gluten Free ◽  
Nucleotide Polymorphisms ◽  
Irritable Bowel

Background: Whether a gluten-free diet (GFD) is a cause of irritable bowel syndrome (IBS) remains controversial. We aim at exploring the causal relationship between gluten intake and IBS within Mendelian randomization (MR) design.Methods: We conducted a two-sample MR and selected single-nucleotide polymorphisms (SNPs) associated with GFD as instrumental variables (IVs). SNPs and genetic associations with GFD and IBS were obtained from the latest genome-wide association studies (GWAS) in Europeans (GFD: cases: 1,376; controls: 63,573; IBS: cases:1,121; controls: 360,073). We performed inverse variance weighting (IVW) as the primary method with several sensitivity analyses like MR-Egger and MR-PRESSO for quality control. The above analyses were re-run using another large dataset of IBS, as well as changing the p-value threshold when screening IVs, to verify the stability of the results.Results: The final estimate indicated significant causal association [per one copy of effect allele predicted log odds ratio (OR) change in GFD intake: OR = 0.97, 95% confidence interval (CI) 0.96 to 0.99, p < 0.01] without heterogeneity statistically (Q = 2.48, p = 0.78) nor horizontal pleiotropy biasing the causality (p = 0.92). Consistent results were found in validation analyses. Results of MR Steiger directionality test indicated the accuracy of our estimate of the causal direction (Steiger p < 0.001).Conclusion: GFD might be a protective factor of IBS. Therefore, we suggest taking a diet of lower gluten intake into account in IBS prevention and clinical practice.

scholarly journals Causal Effect of Visceral Adipose Tissue Accumulation on the Human Longevity: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Binbin Zhao ◽  
Yanhua Wu ◽  
Ling Bai ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Genetic Determinants ◽  
Visceral Adipose ◽  
Mr Study

ObjectiveObservational studies have demonstrated a close relationship between obesity and longevity. The aim of this Mendelian randomization (MR) study is to investigate whether genetic determinants of visceral adipose tissue (VAT) accumulation are causally associated with longevity.MethodsIn this two-sample MR study, we used summary data of genetic determinants (single-nucleotide polymorphisms; p < 5 × 10−8) of VAT accumulation based on genome-wide association studies (GWASs). Longevity was defined as an age beyond the 90th or 99th survival percentile. The causal association of VAT accumulation with longevity was estimated with the inverse variance-weighted (IVW) method. Sensitivity analyses, including weighted median, MR-Egger, and MR–pleiotropy residual sum and outlier (PRESSO), were also employed to assess the stability of the IVW results.ResultsOur MR analysis used 221 genetic variants as instrumental variables to explore the causal association between VAT accumulation and longevity. In the standard IVW methods, VAT accumulation (per 1-kg increase) was found to be significantly associated with lower odds of surviving to the 90th (odds ratio [OR] = 0.69; 95% confidence interval [CI] 0.55 to 0.86, p = 8.32 × 10−4) and 99th (OR = 0.67; 95% CI 0.49 to 0.91, p = 0.011) percentile ages. These findings remained stable in sensitivity analysis.ConclusionThis MR analysis identified a causal relationship between genetically determined VAT accumulation and longevity, suggesting that visceral adiposity may have a negative effect on longevity.

scholarly journals Joint Analysis of Genetic Correlation, Mendelian Randomization and Colocalization Highlights the Bi-Directional Causal Association Between Hypothyroidism and Primary Biliary Cirrhosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanjun Wang ◽  
Ping Guo ◽  
Yanan Zhang ◽  
Lu Liu ◽  
Ran Yan ◽  
...  
Keyword(s):  
Primary Biliary Cirrhosis ◽  
Genetic Correlation ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Joint Analysis ◽  
Biliary Cirrhosis ◽  
Genome Wide Association Studies ◽  
Causal Association

Background: Hypothyroidism and primary biliary cirrhosis (PBC) are often co-existed in observational epidemiological studies. However, the causal relationship between them remains unclear.Methods: Genetic correlation, Mendelian randomization (MR) and colocalization analysis were combined to assess the potential causal association between hypothyroidism and PBC by using summary statistics from large-scale genome-wide association studies. Various sensitivity analyses had been conducted to assess the robustness and the consistency of the findings.Results: The linkage disequilibrium score regression demonstrated significant evidence of shared genetic architecture between hypothyroidism and PBC, with the genetic correlation estimated to be 0.117 (p = 0.006). The OR of hypothyroidism on PBC was 1.223 (95% CI, 1.072–1.396; p = 2.76 × 10−3) in MR analysis with inverse variance weighted (IVW) method. More importantly, the results from other 7MR methods with different model assumptions, were almost identical with that of IVW, suggesting the findings were robust and convincing. On the other hand, PBC was also causally associated with hypothyroidism (OR, 1.049; 95% CI, 1.010–1.089; p = 0.012), and, again, similar results can also be obtained from other MR methods. Various sensitivity analyses regarding the outlier detection and leave-one-out analysis were also performed. Besides, colocalization analysis suggested that there existed shared causal variants between hypothyroidism and PBC, further highlighting the robustness of the results.Conclusion: Our results suggest evidence for the bi-directional causal association between hypothyroidism and PBC, which may provide insights into the etiology of hypothyroidism and PBC as well as inform prevention and intervention strategies directed toward both diseases.

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