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 A preliminary report on alcohol-associated DNA methylation and suicidal behavior: evidence using Mendelian randomization

2019 ◽  
Author(s):  
Charleen D. Adams
Keyword(s):  
Dna Methylation ◽  
Suicidal Behavior ◽  
Preliminary Report ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Higher Alcohol ◽  
Suicide Attempters ◽  
Replication Studies ◽  
Null Effect ◽  
Trait Locus

AbstractAlcohol consumption, a risk factor for suicide, is associated with changes in DNA methylation, which may play a role in the pathophysiology of suicidality. Here, Mendelian randomization probes 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. cg18120259 is instrumented by a cis-methylation quantitative trait locus (rs9472155) that is upstream of VEGFA and associated with circulating VEFG levels. To ascertain whether the cg18120259 finding is confounded by VEGF levels, a Mendelian randomization of VEGF levels on suicidality was performed, revealing a null effect. This implies circulating VEGF levels (observed among suicide attempters) may mark but not cause suicide. Both mechanisms should be re-examined in large replication studies, as the information might be harnessed for early detection of at-risk individuals and possibly save lives.

Clinical Research on Antioxidant-Based Modalities in 2021

2021 ◽  
Vol 11 ◽  
Author(s):  
Editorial Office ROS
Keyword(s):  
Vitamin C ◽  
Mediterranean Diet ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Biological Activities ◽  
Controlled Trial ◽  
Positive Finding ◽  
Randomized Controlled ◽  
The Us ◽  
Anti Inflammatory

Being updated biweekly till the end of the year, this Education & Resources web page lists major clinical studies on antioxidant-based modalities or related entities in disease intervention and health promotion, which have been published in highly influential journals during 2021. It should be noted that this is not intended to be a complete list, but is rather to focus on rigorously designed and well conducted high-profile randomized controlled trials (RCTs) whose findings were reported in medical or bioscience journals of the highest impact. For more comprehensive information on antioxidant-based clinical trials, the reader may refer to the ClinicalTrials.gov (https://clinicaltrials.gov), the largest clinical trials database, run by the US National Library of Medicine, that holds registrations from over 368,000 trials from 219 countries. 2021 LIST IN REVERSE CHRONOLOGICAL ORDER Xu et al. Edaravone dexborneol versus edaravone alone for the treatment of acute ischemic stroke: a phase III, randomized, double-blind, comparative trial. Stroke 2021 Mar; 52(3):772-780. doi: https://dx.doi.org/10.1161/STROKEAHA.120.031197. Key finding: Edaravone dexborneol (a combination of edaravone and borneol) was superior to edaravone alone in improving the clinical outcomes of the acute ischemic stroke patients. Note: Edaravone, a synthetic free radical scavenger, was approved by the US FDA in 2017 for treating amyotrophic lateral sclerosis (ALS). Borneol is a phytochemical with diverse biological activities including antioxidative and anti-inflammatory effects. Kim et al. Reactive oxygen species scavenger in acute intracerebral hemorrhage patients: a multicenter, randomized controlled trial. Stroke 2021 Feb 25; doi: https://doi.org/10.1161/STROKEAHA.120.032266. Key finding: Giving N-acetylcysteine 2000 mg/day and selenium 1600 µg/day, intravenously, for 14 days significantly improved the clinical outcomes in the acute intracerebral hemorrhage patients. Note: N-Acetylcysteine is a precursor of glutathione (GSH). Selenium acts as an antioxidant element due, at least partly, to its essentialness for the function of various selenoproteins, including selenium-dependent glutathione peroxidases (GPx). Kalstad et al. Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 2021 Feb 9; 143(6):528-539. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.120.052209. Key finding: Null Note: n-3 Fatty acids, also known as omega-3 fatty acids, possess potent antioxidative and anti-inflammatory activities. Lynch et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol 2021 Feb; 89(2):212-225. doi: https://dx.doi.org/10.1002/ana.25934. Key finding: Omaveloxolone significantly improved neurological function compared to placebo and is well tolerated. Note: Omaveloxolone, a synthetic oleanane triterpenoid, is an activator of Nrf2, the chief regulator of cellular antioxidant and other cytoprotective genes. Meir et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut 2021 Jan 18; gutjnl-2020-323106. doi: https://dx.doi.org/10.1136/gutjnl-2020-323106. Key finding: Green-Mediterranean diet enriched with green plants and polyphenols improved non-alcoholic fatty liver disease (NAFLD). Note: Mediterranean diet and green plants (green tea) and nuts are rich in antioxidants and anti-inflammatory compounds and possess many health benefits, especially cardiovascular protection. However, the exact contribution of antioxidant components to the health benefits of Mediterranean diet remains to be established. Rinott et al. Effects of diet-modulated autologous fecal microbiota transplantation on weight regain. Gastroenterology 2021 Jan; 160(1):158-173.e10. doi: https://dx.doi.org/10.1053/j.gastro.2020.08.041. Key finding: Polyphenol-enriched diet-modulated autologous fecal microbiota transplantation attenuated weight regain and preserved glycemic control. Note: Dietary polyphenols possess antioxidative, anti-inflammatory, and many other biological activities. Zheng et al. Plasma vitamin C and type 2 diabetes: genome-wide association study and Mendelian randomization analysis in European populations. Diabetes Care 2021 Jan; 44(1):98-106. doi: https://dx.doi.org/10.2337/dc20-1328. Key finding: Null; no evidence to support an efficacy of vitamin C supplement in type 2 diabetes prevention. Note: Vitamin C is a multitasking compound; it is an antioxidant, but also possesses many other biological functions. According to Dr Davey Smith,  Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship. Luo et al. Diet-derived circulating antioxidants and risk of coronary heart disease: a Mendelian randomization study. J Am Coll Cardiol 2021 Jan 5; 77(1):45-54. doi: https://dx.doi.org/10.1016/j.jacc.2020.10.048. Key finding: Null Note: According to Dr Davey Smith,  Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies (from the US CDC website: https://cdc.gov). A positive finding in a Mendelian randomization study provides strong evidence for a causal relationship.

scholarly journals Cognitive networks identify dimensions of distress in suicide notes: Anxiety, emotional profiles, and "words not said"

2021 ◽  
Author(s):  
Trevor Swanson ◽  
Andreia Sofia Teixeira ◽  
Brianne N. Richson ◽  
Ying Li ◽  
Thomas Hills ◽  
...  
Keyword(s):  
Public Health ◽  
Suicidal Behavior ◽  
Real World ◽  
Network Science ◽  
Cognitive Networks ◽  
Health Concern ◽  
Public Health Concern ◽  
High Anxiety ◽  
Emotion Words ◽  
Suicide Notes

Suicide remains a serious public-health concern that is difficult to accurately predict in real-world settings. To identify potential predictors of suicide, we examined the emotional content of suicide notes using methods from cognitive network science. Specifically, we compared the co-occurrence networks of suicide notes with those constructed out of emotion words written by individuals scoring low or high on measures of depression, anxiety, and stress. Our objective was to identify which networks were most similar to the suicide notes network, in particular with regard to the connectivity between words and their emotional contents. We also investigated what types of words remained in the high/low emotion networks after controlling for the words present in the suicide notes, which we conceptualize as the “words not said” in the suicide notes. We found that patterns of connectivity among emotion words in suicide notes were most similar to those in texts written by low-anxiety individuals. However, upon analyzing the “words not said” in suicide notes, we observed that the remaining collection of emotions in suicide notes was most similar to those expressed by high-anxiety individuals. We discuss how these findings relate with existing clinical psychological literature as well as their potential implications for predicting suicidal behavior.

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 The effect of body mass index on smoking behaviour and nicotine metabolism: a Mendelian randomization study

2018 ◽  
Author(s):  
Amy E. Taylor ◽  
Rebecca C. Richmond ◽  
Teemu Palviainen ◽  
Anu Loukola ◽  
Jaakko Kaprio ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Dna Methylation ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Smoking Initiation ◽  
Smoking Behaviour ◽  
Bidirectional Association ◽  
Metabolite Ratio ◽  
Nicotine Metabolite Ratio

AbstractBackgroundGiven clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight.Methods and FindingsWe undertook Mendelian randomization analyses using 97 genetic variants associated with BMI. We performed two sample Mendelian randomization analyses of the effects of BMI on smoking behaviour in UK Biobank (N=335,921) and the Tobacco and Genetics consortium genomewide association study (GWAS) (N≤74,035) respectively, and two sample Mendelian randomization analyses of the effects of BMI on cotinine levels (N≤4,548) and nicotine metabolite ratio (N≤1,518) in published GWAS, and smoking-related DNA methylation in the Avon Longitudinal Study of Parents and Children (N≤846).In inverse variance weighted Mendelian randomization analysis, there was evidence that higher BMI was causally associated with smoking initiation (OR for ever vs never smoking per one SD increase in BMI: 1.19, 95% CI: 1.11 to 1.27) and smoking heaviness (1.45 additional cigarettes smoked per day per SD increase in BMI, 95% CI: 1.03 to 1.86), but little evidence for a causal effect with smoking cessation. Results were broadly similar using pleiotropy robust methods (MR-Egger, median and weighted mode regression). These results were supported by evidence for a causal effect of BMI on DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus. There was no strong evidence that BMI was causally associated with cotinine, but suggestive evidence for a causal negative association with the nicotine metabolite ratio.ConclusionsThere is a causal bidirectional association between BMI and smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism. It may be useful to consider BMI and smoking together when designing prevention strategies to minimise the effects of these risk factors on health outcomes.

scholarly journals Smoking, DNA methylation and lung function: a Mendelian randomization analysis to investigate causal relationships

2019 ◽  
Author(s):  
Emily Jamieson ◽  
Roxanna Korologou-Linden ◽  
Robyn E. Wootton ◽  
Anna L. Guyatt ◽  
Thomas Battram ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lung Function ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Forced Expiratory Volume ◽  
Multiple Trait ◽  
Genome Wide ◽  
Causal Variants ◽  
Association Data ◽  
Randomization Analysis

AbstractWhether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in one second (FEV1) in two-sample Mendelian randomization (MR) using methylation quantitative trait loci and genome-wide association data for FEV1. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p<1.2×10−4). Replication analysis supported a causal effect at three CpGs (cg21201401 (ZGPAT), cg19758448 (PGAP3) and cg12616487 (AHNAK) (p<0.0028). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites may influence lung function via effects on smoking. Using multiple-trait colocalization, we found evidence of shared causal variants between lung function, gene expression and DNA methylation. Findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although large, tissue-specific datasets are required to confirm these results.

scholarly journals Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes

2019 ◽  
Vol 4 ◽  
pp. 113 ◽  
Author(s):  
Venexia M Walker ◽  
Neil M Davies ◽  
Gibran Hemani ◽  
Jie Zheng ◽  
Philip C Haycock ◽  
...  
Keyword(s):  
Risk Factors ◽  
Web Application ◽  
Drug Targets ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
R Package ◽  
Sensitivity Analyses ◽  
Link Type ◽  
Study Results

Mendelian randomization (MR) estimates the causal effect of exposures on outcomes by exploiting genetic variation to address confounding and reverse causation. This method has a broad range of applications, including investigating risk factors and appraising potential targets for intervention. MR-Base has become established as a freely accessible, online platform, which combines a database of complete genome-wide association study results with an interface for performing Mendelian randomization and sensitivity analyses. This allows the user to explore millions of potentially causal associations. MR-Base is available as a web application or as an R package. The technical aspects of the tool have previously been documented in the literature. The present article is complementary to this as it focuses on the applied aspects. Specifically, we describe how MR-Base can be used in several ways, including to perform novel causal analyses, replicate results and enable transparency, amongst others. We also present three use cases, which demonstrate important applications of Mendelian randomization and highlight the benefits of using MR-Base for these types of analyses.

Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study

2021 ◽  
Author(s):  
Christa Meisinger ◽  
Dennis Freuer
Keyword(s):  
Inflammatory Bowel Disease ◽  
Atopic Dermatitis ◽  
Bowel Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
The Other ◽  
Uk Biobank ◽  
Inflammatory Bowel ◽  
The Uk

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

Long-Acting Reversible Contraception (LARC) and Teen Pregnancy

2021 ◽  
pp. 159-163
Author(s):  
Jaclyn Grentzer
Keyword(s):  
Public Health ◽  
Teen Pregnancy ◽  
Induced Abortion ◽  
Health Concern ◽  
Intrauterine Devices ◽  
The Us ◽  
Economic Barriers ◽  
Contraceptive Choice ◽  
Contraceptive Implants ◽  
Long Acting

Long-acting, reversible contraception (LARC), including intrauterine devices (IUDs) and contraceptive implants, are associated with higher contraceptive efficacy and continuation rates. Teen pregnancy rates have declined over the past 2 decades but continue to be a public health concern. Only 10% of teen girls elect to use LARC, likely due to educational, logistical, and economic barriers. The Contraceptive CHOICE Project enrolled 1404 girls aged 14 to 19. Of these teens, more than 70% chose LARC when given standardized contraceptive counseling and barriers to receiving LARC were removed. Pregnancy, live birth, and induced abortion rates in this cohort were lower than rates for the US population of sexually active teen girls. Failure rates were lower for LARC users, as compared to users of other reversible contraceptive methods.

scholarly journals The Establishment of the Household Air Pollution Consortium (HAPCO)

Atmosphere ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 422
Author(s):  
H. Dean Hosgood ◽  
Madelyn Klugman ◽  
Keitaro Matsuo ◽  
Alexandra J. White ◽  
Atsuko Sadakane ◽  
...  
Keyword(s):  
Public Health ◽  
Air Pollution ◽  
Smoking Status ◽  
Household Air Pollution ◽  
Health Concern ◽  
Lung Cancer Death ◽  
Specific Effects ◽  
Carcinogenic Potential ◽  
The Us ◽  
Disease Specific Mortality

Household air pollution (HAP) is of public health concern, with ~3 billion people worldwide (including >15 million in the US) exposed. HAP from coal use is a human lung carcinogen, yet the epidemiological evidence on carcinogenicity of HAP from biomass use, primarily wood, is not conclusive. To robustly assess biomass’s carcinogenic potential, prospective studies of individuals experiencing a variety of HAP exposures are needed. We have built a global consortium of 13 prospective cohorts (HAPCO: Household Air Pollution Consortium) that have site- and disease-specific mortality and solid fuel use data, for a combined sample size of 587,257 participants and 57,483 deaths. HAPCO provides a novel opportunity to assess the association of HAP with lung cancer death while controlling for important confounders such as tobacco and outdoor air pollution exposures. HAPCO is also uniquely positioned to determine the risks associated with cancers other than lung as well as nonmalignant respiratory and cardiometabolic outcomes, for which prospective epidemiologic research is limited. HAPCO will facilitate research to address public health concerns associated with HAP-attributed exposures by enabling investigators to evaluate sex-specific and smoking status-specific effects under various exposure scenarios.

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