scholarly journals Plasma Phospholipid Fatty Acids and Risk of Atrial Fibrillation: A Mendelian Randomization Study

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1651 ◽  
Author(s):  
Shuai Yuan ◽  
Susanna C. Larsson
Keyword(s):  
Atrial Fibrillation ◽  
Fatty Acids ◽  
Mendelian Randomization ◽  
Phospholipid Fatty Acid ◽  
Association Studies ◽  
Plasma Phospholipid ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Plasma Fatty Acids ◽  
Inverse Variance

Available evidence on the associations of dietary and circulating levels of long-chain n-3 fatty acids, which have potential antiarrhythmic properties, and other fatty acids with atrial fibrillation is conflicting and limited. We conducted a Mendelian randomization study to assess the associations between plasma phospholipid fatty acid levels and atrial fibrillation. Summary-level data of atrial fibrillation were available from 65,446 cases and 522,744 non-cases included in the Atrial Fibrillation Consortium. Sixteen single-nucleotide polymorphisms associated with ten fatty acids at significance level of p < 5 × 10−8 were identified as instrumental variables from the hitherto largest genome-wide association studies for plasma fatty acids. The fixed-effects inverse-variance weighted method was used to assess the association of individual plasma fatty acids and atrial fibrillation risk. The random-effects inverse-variance weighted method, weighted median method, and Mendelian randomization (MR)-Egger method were employed as the sensitivity analyses. Genetic predisposition to higher levels of any of the ten individual fatty acids was not associated with atrial fibrillation risk.

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 Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Lu Tang ◽  
Tao Huang ◽  
Dongsheng Fan
Keyword(s):  
Blood Pressure ◽  
Amyotrophic Lateral Sclerosis ◽  
Protective Factor ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inverse Variance ◽  
High Level ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate whether there is a causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertension drugs (AHDs), ALS, and their corresponding genome-wide association studies (GWAS) summary datasets were obtained from the updated largest studies. Inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods for sensitivity analyses. To exclude the interference between SBP and DBP, multivariable MR was used. Results We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960–0.996, P = 0.017), and increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003–1.025, P = 0.015). The high level of targeted protein of Calcium channel blocker (CCB) showed a causative relationship with ALS (OR = 0.985, 95% CI 0.971-1.000, P = 0.049). No evidence was revealed that ALS caused results change of BP measurements. Conclusions This study demonstrated that an increase in DBP is a protective factor for ALS, and increased SBP is independently risk for ALS, which may be related to sympathetic excitability. Blood pressure management is important in ALS, in which CCB may be a promising candidate.

scholarly journals Using Genetic Variants to Evaluate the Causal Effect of Plasma Phospholipid Fatty Acids on Breast Cancer and Prostate Cancer: A Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Ze Yang ◽  
Jingjia Li ◽  
Yandi Sun ◽  
Zihao Qu ◽  
Yindan Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Fatty Acids ◽  
Cancer Risk ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Plasma Phospholipid ◽  
Phospholipid Fatty Acids ◽  
Genome Wide Association Studies ◽  
Causal Association

BackgroundObservational studies indicate that phospholipid fatty acids (FAs) have an impact on the etiology in cancers, but the results are conflicting. We aimed to investigate the causal association of phospholipid FAs with breast cancer and prostate cancer.MethodsFourteen single nucleotide polymorphisms (SNPs) were selected as instrumental variables to predict the level of 10 phospholipid FAs from Genome-wide association studies (GWAS). We obtained the summary statistics for the latest and largest GWAS datasets for breast cancer (113,789 controls and 133,384 cases) and prostate cancer (61,106 controls and 79,148 cases) from the Breast Cancer Association Consortium (BCAC) and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Two-sample Mendelian randomization analysis was applied.ResultsThe results demonstrate that the 10 individual plasma phospholipid FAs are not significantly associated with breast cancer risk and prostate cancer risk.ConclusionThe evidence is insufficient to support the causal association of the 10 individual plasma phospholipid FAs with breast cancer and prostate cancer.

scholarly journals Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengyu Li ◽  
Chris Ho Ching Yeung ◽  
C. Mary Schooling
Keyword(s):  
Immune System ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Multiple Comparisons ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Inflammatory Protein ◽  
Inverse Variance ◽  
System Functioning

BackgroundImmune system functioning is relevant to vulnerability to coronavirus disease (COVID-19). Cytokines are important to immunity. To further elucidate the role of the immune system in COVID-19, we used Mendelian randomization (MR) to assess comprehensively and bi-directionally the role of cytokines in COVID-19.MethodsWe assessed primarily whether genetically different levels of 41 cytokines affected risk of any COVID-19 (laboratory confirmed, physician confirmed or self-reported, 36,590 cases, 1,668,938 controls), and conversely if genetic risk of liability to any COVID-19 affected these cytokines (n ≤ 8293) using the most recent genome-wide association studies. We obtained inverse variance weighting (IVW) estimates, conducted sensitivity analyses and used a Benjamini-Hochberg correction to account for multiple comparisons. We also assessed whether any findings were evident for hospitalized COVID-19 (hospitalized laboratory confirmed, 12,888 cases, 1,295,966 controls).ResultsMacrophage inflammatory protein-1β (MIP1b; more commonly known as Chemokine (C-C motif) ligands 4 (CCL4) was inversely associated with COVID-19 [odds ratio (OR) 0.97 per SD, 95% confidence interval (CI) 0.96–0.99] but not after adjustment for multiple comparisons. This finding replicated for hospitalized COVID-19 (OR 0.93, 95% CI 0.89–0.98). Liability to any COVID-19 was nominally associated with several cytokines, such as granulocyte colony-stimulating factor (GCSF) and hepatocyte growth factor (HGF) but not after correction.ConclusionA crucial element of immune response to infection (CCL4) was related to COVID-19, whether it is a target of intervention to prevent COVID-19 warrants further investigation.

scholarly journals Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

2021 ◽  
Author(s):  
Fernando Pires Hartwig ◽  
Kate Tilling ◽  
George Davey Smith ◽  
Deborah A Lawlor ◽  
Maria Carolina Borges
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Real Data ◽  
Sensitivity Analyses ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

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 Association of Physical Activity with Body Composition: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Ferris Alaa Ramadan ◽  
Katherine Ellingson ◽  
Yann Klimentidis
Keyword(s):  
Physical Activity ◽  
Body Composition ◽  
Sedentary Behavior ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Protective Effects ◽  
Dietary Interventions ◽  
The Uk

Background. Studies suggest that body composition can be improved through physical activity (PA) independently of dietary interventions. A separate line of evidence suggests that PA may reduce high-risk visceral adipose tissue (VAT), without clinically meaningful weight change. Genome-wide association studies have previously identified genetic markers associated with PA behaviors and may provide an opportunity to evaluate hypothesized causal relationships with body composition. Methods. We performed a Mendelian randomization (MR) study to test the incremental benefits of various PA exposures on body composition outcomes as assessed by anthropometric indices, lean body mass (LBM) (kg), body fat (%), and VAT (kg). Genetic instruments were identified for both self-reported and accelerometer-measured PA, including sedentary behavior. Outcomes included anthropometric and dual-energy X-ray absorptiometry measures of adiposity, extracted from the UK Biobank and the largest publicly available consortia. Multivariable MR (MVMR) included educational attainment as a covariate to address potential confounding. Sensitivity analyses were evaluated for weak instrument bias and pleiotropic effects.Results. We did not identify associations between genetically-predicted sedentary behavior (self-reported or accelerometer) and body composition outcomes in MVMR analyses. All analyses for self-reported moderate PA were null for body composition outcomes, including BMI, LBM and VAT. Genetically-predicted PA at higher intensities was protective against VAT in MR and MVMR analyses of both accelerometer-measured vigorous PA (MVMR β = -0.15, 95% Confidence Interval (CI): -0.24, -0.07, p&lt;0.001) and self-reported participation in strenuous sports or other exercises (MVMR β = -0.27, 95%CI: -0.52, -0.01, p=0.034), and was robust across several sensitivity analyses. Conclusions. We did not identify evidence of a causal relationship between genetically-predicted PA and body composition, with the exception of a putatively protective effect of higher-intensity PA on VAT. Protective effects of PA against VAT may support prior evidence of biological pathways through which PA decreases risk of downstream cardiometabolic diseases.

scholarly journals Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Gan Zhang ◽  
Yajun Wang ◽  
Tao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Telomere Length ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Leukocyte Telomere Length ◽  
Weighted Median ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. We employed a two-sample Mendelian randomization (MR) approach to explore the causal relationship between leukocyte telomere length (LTL) and ALS based on the most cited and most recent and largest LTL genome-wide association studies (GWASs) that measured LTL with the Southern blot method (n = 9190) and ALS GWAS summary data (n = 80,610). We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR PRESSO method to perform sensitivity analyses. Results We found that genetically determined longer LTL was inversely associated with the risk of ALS (OR = 0.846, 95% CI: 0.744–0.962, P = 0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. In sensitivity analyses, that was confirmed in MR Egger method (OR = 0.647,95% CI = 0.447–0.936, P = 0.050), and a similar trend was shown with the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935 P = 0.535). The MR Egger analyses did not suggest directional pleiotropy, showing an intercept of 0.025 (P = 0.168). Neither the influence of instrumental outliers nor heterogeneity was found. Conclusions Our results suggest that genetically predicted longer LTL has a causal relationship with a lower risk of ALS and underscore the importance of protecting against telomere loss in ALS.

Timing of pubertal development and midlife blood pressure in men and women: A Mendelian randomization study

2021 ◽  
Author(s):  
Io Ieong Chan ◽  
Man Ki Kwok ◽  
C Mary Schooling
Keyword(s):  
Blood Pressure ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Pubertal Development ◽  
Sensitivity Analyses ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Pubertal Maturation ◽  
Pubertal Growth

Abstract Introduction Observational studies suggest earlier puberty is associated with higher adulthood blood pressure (BP), but these findings have not been replicated using Mendelian randomization (MR). We examined this question sex-specifically using larger genome-wide association studies (GWAS) with more extensive measures of pubertal timing. Methods We obtained genetic instruments proxying pubertal maturation (age at menarche (AAM) or voice breaking (AVB)) from the largest published GWAS. We applied them to summary sex-specific genetic associations with systolic and diastolic BP z-scores, and self-reported hypertension in women (n=194174) and men (n=167020) from the UK Biobank, using inverse-variance weighting meta-analysis. We conducted sensitivity analyses using other MR methods, including multivariable MR adjusted for childhood obesity proxied by body mass index (BMI). We used late pubertal growth as a validation outcome. Results AAM (beta per one-year later = -0.030 [95% confidence interval (CI) -0.055, -0.005] and AVB (beta -0.058 [95% CI -0.100, -0.015]) were inversely associated with systolic BP independent of childhood BMI, as were diastolic BP (-0.035 [95% CI -0.060, -0.009] for AAM and -0.046 [95% CI -0.089, -0.004] for AVB) and self-reported hypertension (odds ratios 0.89 [95% CI 0.84, 0.95] for AAM and 0.87 [95% CI 0.79, 0.96] for AVB). AAM and AVB were positively associated with late pubertal growth, as expected. The results were robust to sensitivity analysis using other MR methods. Conclusion Timing of pubertal maturation was associated with adulthood BP independent of childhood BMI, highlighting the role of pubertal maturation timing in midlife BP.

Daytime sleepiness, night sleep changes and ALS: a Mendelian randomization study

2020 ◽  
Author(s):  
Gan Zhang ◽  
Linjing Zhang ◽  
Tao Huang ◽  
Dongsheng Fan
Keyword(s):  
Sleep Duration ◽  
Daytime Sleepiness ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sleep Efficiency ◽  
Genome Wide Association Studies ◽  
Night Sleep ◽  
Inverse Variance ◽  
Point Increase ◽  
Increased Risk

Abstract Background Observational studies have indicated that there is a high prevalence of daytime sleepiness and night sleep changes in amyotrophic lateral sclerosis (ALS). However, the actual relation between these symptoms and ALS remains unclear. We aimed to determine whether daytime sleepiness and night sleep changes have an effect on ALS. Methods We used 2-sample mendelian randomization to estimate the effects of daytime sleepiness, sleep efficiency, number of sleep episodes and sleep duration on ALS. Summary statistics we used was from resent and large genome-wide association studies on the traits we chosen (n = 85,670–452,071) and ALS (cases n = 20,806, controls n = 59,804). Inverse variance weighted method was used as the main method for assessing causality. Results A genetically predicted 1-point increase in the assessment of daytime sleepiness was significantly associated with an increased risk of ALS (inverse-variance-weighted (IVW) odds ratio = 2.70, 95% confidence interval (CI): 1.27–5.76; P = 0.010). ALS was not associated with a genetically predicted 1-SD increase in sleep efficiency (IVW 1.01, 0.64–1.58; P = 0.973), Number of sleep episodes (IVW 1.02, 0.80–1.30; P = 0.859) or sleep duration (IVW 1.00, 1.00–1.01; P = 0.250). Conclusions Our results provide novel evidence that daytime sleepiness causes an increase in the risk of ALS and indicate that daytime sleepiness may be inherent in preclinical and clinical ALS patients, rather than simply affected by potential influencing factors.

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