Causal effect of alcohol consumption on hyperuricemia using a Mendelian randomization design

2019 ◽  
Vol 22 (10) ◽  
pp. 1912-1919
Author(s):  
Yon Ho Jee ◽  
Keum Ji Jung ◽  
Yong‐Beom Park ◽  
Wes Spiller ◽  
Sun Ha Jee
Keyword(s):  
Alcohol Consumption ◽  
Mendelian Randomization ◽  
Causal Effect

scholarly journals A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mark Gormley ◽  
Tom Dudding ◽  
Eleanor Sanderson ◽  
Richard M. Martin ◽  
Steven Thomas ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Alcohol Consumption ◽  
Oropharyngeal Cancer ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Strong Association ◽  
Smoking Behaviour ◽  
Standard Deviation Increase ◽  
Independent Effects

AbstractThe independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.

scholarly journals Evidence of causal effect of major depression on alcohol dependence: Findings from the Psychiatric Genomics Consortium

2018 ◽  
Author(s):  
Renato Polimanti ◽  
Roseann E. Peterson ◽  
Jue-Sheng Ong ◽  
Stuart MacGregor ◽  
Alexis C. Edwards ◽  
...  
Keyword(s):  
Major Depression ◽  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Causal Relationships ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Genetic Mechanisms ◽  
Shared Genetic

ABSTRACTBackgroundDespite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood.MethodsThis study was conducted using genome-wide data from the Psychiatric Genomics Consortium (MD: 135,458 cases and 344,901 controls; AD: 10,206 cases and 28,480 controls) and UK Biobank (AC-Frequency: from “daily or almost daily” to “never”, 438,308 individuals; AC-Quantity: total units of alcohol per week, 307,098 individuals). Linkage disequilibrium score regression and Mendelian Randomization (MR) analyses were applied to investigate shared genetic mechanisms (horizontal pleiotropy) and causal relationships (mediated pleiotropy) among these traits.OutcomesPositive genetic correlation was observed between MD and AD (rgMD-AD=+0.47, P=6.6×10-10). AC-Quantity showed positive genetic correlation with both AD (rgAD-AC-Quantity=+0.75, P=1.8×10-14) and MD (rgMD-AC-Quantity=+0.14, P=2.9×10-7), while there was negative correlation of AC-Frequency with MD (rgMD-AC-Frequency=-0.17, P=1.5×10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e., causal relationship) with a causal role of MD on AD (beta=0.28, P=1.29×10-6) that does not appear to be biased by confounding such as horizontal pleiotropy. No evidence of reverse causation was observed as the AD genetic instrument did not show a causal effect on MD.InterpretationResults support a causal role for MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity not only addresses important public health concerns but also has the potential to facilitate prevention and intervention efforts.FundingNational Institute of Mental Health and National Institute on Drug Abuse.Putting data into contextEvidence before this studyWe searched PubMed up to August 24, 2018, for research studies that investigated causality among alcohol-and depression related phenotypes using Mendelian randomization approaches. We used the search terms “alcohol” AND “depression” AND “Mendelian Randomization”. No restrictions were applied to language, date, or article type. Ten articles were retrieved, but only two were focused on alcohol consumption and depression-related traits. The studies were based on genetic variants in alcohol dehydrogenase (ADH) genes only, did not find evidence for a causal effect of alcohol consumption on depression phenotypes, with one study finding a causal effect of alcohol consumption on alcoholism. Both studies noted that future studies are needed with increased sample sizes and clinically derived phenotypes. To our knowledge, no previous study has applied two-sample Mendelian randomization to investigate causal relationships between alcohol dependence and major depression.Twin studies show genetic factors influence susceptibility to MD, AD, and alcohol consumption. Differently from observational approaches where several studies have investigated the relationship between alcohol-and depression-related phenotypes, very limited use of molecular genetic data has been applied to investigate this issue. Additionally, the use of genetic information has been shown to be less biased by confounders and reverse causation than observation data. However, genetic approaches, like Mendelian randomization, require large sample sizes to be informative.Added value of this studyIn this study, we used genome-wide data from the Psychiatric Genomic Consortium and UK Biobank, which include information regarding hundred thousands of individuals, to test the presence of shared genetic mechanisms and causal relationships among major depression, alcohol dependence, and alcohol consumption. The results support a causal influence of MD on AD, while alcohol consumption showed shared genetic mechanisms with respect to both major depression and alcohol dependence.Implications of all the available evidenceGiven the significant morbidity and mortality associated with MD, AD, and the comorbid condition, understanding mechanisms underlying these associations not only address important public health concerns but also has the potential to facilitate prevention and intervention efforts.

scholarly journals Associations between alcohol use and accelerated biological ageing

2020 ◽  
Author(s):  
Sunniva M. K. Bøstrand ◽  
Kadi Vaher ◽  
Laura De Nooij ◽  
Mathew A. Harris ◽  
James H. Cole ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alcohol Consumption ◽  
Alcohol Use ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Positive Association ◽  
Biological Ageing ◽  
Age Related ◽  
Brain Ageing ◽  
Brain Age

AbstractBackgroundHarmful alcohol use is a leading cause of premature death, and is associated with age-related disease. Ageing is highly variable between individuals, and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (based on DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates.MethodsFirst, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (AUDIT scores), and accelerated brain and epigenetic ageing in 20,258 and 8,051 individuals, respectively. Second, we used Mendelian randomization to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing.ResultsAlcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β=0.053, p=3.16×10−13; AUDIT-P: β=0.052, p=1.6×10−13; total AUDIT score: β=0.062, p=5.52×10−16; units/week: β=0.078, p=2.20×10−16), and DNA methylation GrimAge (Units/week: β=0.053, p=1.48×10− 7) and PhenoAge (Units/week: β=0.077, p=2.18×10−10). Mendelian randomization analyses revealed some evidence for a causal effect of AUD on accelerated brain ageing (β=0.272, p=0.044), and no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing.ConclusionsWe provide consistent phenotypic evidence linking alcohol use with accelerated biological ageing. There is possible evidence for a causal effect of AUD on brain age, but not for any other alcohol-related trait on brain or epigenetic age acceleration. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.

scholarly journals Educational attainment causally impacts drinking behaviors and risk for alcohol dependence: results from a two-sample Mendelian randomization study in ~ 780,000 study participants

2019 ◽  
Author(s):  
Daniel B. Rosoff ◽  
Falk W. Lohoff
Keyword(s):  
Alcohol Consumption ◽  
Educational Attainment ◽  
Alcohol Dependence ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Reverse Causality ◽  
Risky Alcohol ◽  
Study Participants

ABSTRACTBackgroundObservational studies suggest that lower educational attainment may be associated with risky alcohol consumption behaviors. However, these findings may be biased by confounding and reverse causality. Using two-sample Mendelian randomization (MR), we can determine whether education is causally related to alcohol consumption behaviors and alcohol dependence (AD).MethodsWe performed two-sample MR using summary statistics from recent genome-wide association studies (GWAS) in 784,726 study participants to assess the causal effects of educational attainment on alcohol consumption behaviors, including intake frequency, total weekly drinks, beverage preferences, whether alcohol is consumed with meals, as well as AD risk. Of 53 independent (linkage disequilibrium R2=0.001, kb distance<10,000) nucleotide polymorphisms (SNPs) that predict educational attainment, and after removal of palindromes with intermediate allele frequency, 51 were present in the alcohol consumption behaviors, and 44 were present in the AD GWAS. Complementary MR techniques accommodating different assumptions about genetic pleiotropy (inverse variance weighted (IVW), Egger, weighted median, and weighted mode MR) tested the sensitivity of our results.ResultsWe found strong evidence of a causal effect between years of education and alcohol consumption behaviors generally. Higher educational attainment decreased alcohol intake frequency (IVW odds ratio (ORIVW), 0.718, 95% CI, 0.673-0.765, PIVW=4.62E-24), as well as weekly distilled spirits intake (ORIVW, 0.874, 95% CI, 0.833-0.917, PIVW=3.91E-08), and weekly beer plus cider intake (ORIVW, 0.837, 95% CI, 0.805-0.869, P=5.58E-20), but increased weekly white wine (ORIVW, 1.220, 95% CI, 1.172-1.269, PIVW=7.96E-23), red wine (ORIVW, 1.227, 95% CI, 1.174-1.282, PIVW=6.67E-20), and fortified wine intake (ORIVW, 1.051, 95% CI, 1.027-1.075, PIVW] =1.87E-07). We also found evidence educational attainment reduced AD risk (ORIVW.508, 95% CI, .315-.819, PIVW=5.51E-03). We found no evidence for total weekly consumption (ORIVW.508, 95% CI,.315-.819, PIVW=5.51E-03). Consistency of results across complementary MR methods strengthens our causal inferences.ConclusionsOur findings show low educational attainment is causally associated with increased alcohol consumption frequency, increased preference for beer, cider, and spirits, and AD risk, indicating a potential mechanism explaining reported associations between educational attainment and adverse health outcomes, including cardiovascular disease. These findings suggest increased educational attainment might be a useful prevention strategy to reduce risky alcohol behaviors and AD.

scholarly journals OP96 The causal effect of BMI on neurodevelopment: a within family mendelian randomization study using MoBa

2020 ◽  
Author(s):  
AM Hughes ◽  
H Ask ◽  
T Tesli ◽  
RB Askeland ◽  
T Reichborn-Kjennerud ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect

A Preliminary Report on Alcohol-Associated DNA Methylation Changes and Suicidal Behavior: Evidence Using Mendelian Randomization

2021 ◽  
pp. 105413732095224
Author(s):  
Charleen D. Adams
Keyword(s):  
Public Health ◽  
Dna Methylation ◽  
Suicidal Behavior ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Economic Stress ◽  
Self Report ◽  
Health Concern ◽  
The Us

Suicide is a major public health concern. In 2015, it was the 10th leading cause of death in the US. The number of suicides increased by 30% in the US from 1999 to 2016, and a greater uptick in suicides is predicted to occur as a result of the COVID-19 crisis, for which the primary public-health strategy is physical distancing and during which alcohol sales have soared. Thus, current strategies for identifying at-risk individuals and preventing suicides, such as relying on self-reported suicidal ideation, are insufficient, especially under conditions of physical distancing, which exacerbate isolation, loneliness, economic stress, and possibly alcohol consumption. New strategies are urgent now and into the future. To that aim, here, a two-sample Mendelian randomization (an instrumental variables technique using public genome-wide association study data as data sources) was performed to determine whether alcohol-associated changes in DNA methylation mediate risk for suicidal behavior. The results suggest that higher alcohol-associated DNA methylation levels at cg18120259 confer a weak causal effect. Replication and triangulation of the results, both experimentally and with designs other than Mendelian randomization, are needed. If the findings replicate, the information might be utilized to raise awareness about the biological links between alcohol and suicide and possibly explored as a biomarker of risk, perhaps especially for early detection of those who may not self-report suicidal intent.

scholarly journals Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

2021 ◽  
Author(s):  
Shuai Yuan ◽  
Maria Bruzelius ◽  
Susanna C. Larsson
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Increased Risk ◽  
Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

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 Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Shuai Yuan ◽  
Edward L. Giovannucci ◽  
Susanna C. Larsson
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Pancreatitis ◽  
Alcohol Consumption ◽  
Mendelian Randomization ◽  
Gallstone Disease ◽  
Smoking Initiation ◽  
Disease Type ◽  
Uk Biobank ◽  
Increased Risk

AbstractWe conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10−8 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.

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