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.

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 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 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 Smoking, DNA Methylation, and Breast Cancer: A Mendelian Randomization Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Haibo Tang ◽  
Desong Yang ◽  
Chaofei Han ◽  
Ping Mu
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Cancer Tissue ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Cpg Sites ◽  
Meta Analyses

BackgroundSmoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER− breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.ResultsWe established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91–0.97)], cg0760265 [OR = 1.07, 95% CI (1.03–1.11)], cg0420946 [OR = 0.95, 95% CI (0.93–0.98)], and cg2037583 [OR =1.09, 95% CI (1.04–1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all p &lt; 1.83 × 10−11) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 &gt; 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with IMP3 expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER− breast cancer.ConclusionsThese findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.

Self-Report vs. Computerized Measures of Impulsivity as a Correlate of Suicidal Behavior

Crisis ◽  
2001 ◽  
Vol 22 (1) ◽  
pp. 27-31 ◽  
Author(s):  
Netta Horesh
Keyword(s):  
Suicidal Behavior ◽  
Attention Deficit Disorder ◽  
Impulse Control ◽  
Performance Test ◽  
Adolescent Suicide ◽  
Continuous Performance Test ◽  
Self Report ◽  
Suicide Attempters ◽  
Computerized Measures ◽  
Adolescent Suicide Attempters

Objectives: To compare the use of a self-report form of impulsivity versus a computerized test of impulsivity in the assessment of suicidal adolescent psychiatric inpatients. Methods: Sixty consecutive admissions to an adolescent in patient unit were examined. The severity of suicidal behavior was measured with the Childhood Suicide Potential Scale (CSPS), and impulse control was measured with the self report Plutchik Impulse Control Scale (ICS) and with the Test of Variables of Attention (TOVA), a continuous performance test (CPT). The TOVA is used to diagnose adolescents with attention deficit disorder. Results: There was a significant but low correlation between the two measures of impulsivity. Only the TOVA commission and omission errors differentiated between adolescent suicide attempters and nonattempters. Conclusions: Computerized measures of impulsivity may be a useful way to measure impulsivity in adolescent suicide attempters. Impulsivity appears to play a small role only in nondepressed suicidal adolescents, especially boys.

Validity of Proxy-Based Reports of Impulsivity and Aggression in Chinese Research on Suicidal Behavior

Crisis ◽  
2010 ◽  
Vol 31 (3) ◽  
pp. 137-142 ◽  
Author(s):  
Jing An ◽  
Michael R. Phillips ◽  
Kenneth R. Conner
Keyword(s):  
Risk Factors ◽  
Suicidal Behavior ◽  
Rural China ◽  
Suicide Attempters ◽  
Barratt Impulsiveness Scale ◽  
Single Location ◽  
Aggression Questionnaire ◽  
Community Controls

Background: In studies about the risk factors for suicidal behavior, the assessment of impulsiveness and aggression often depend on information from proxy informants. Aims: To assess the validity of proxy informants’ reports on impulsiveness and aggression in China. Methods: Modified Chinese versions of the Barratt Impulsiveness Scale (BIS-CV) and the Buss-Perry Aggression Questionnaire (AQ-CV) were administered to 131 suicide attempters treated at a hospital in rural China, to coresident relatives about the attempters, to 131 matched community controls, and to coresident relatives about the controls. Results: BIS-CV and AQ-CV total scores and subscale scores were all significantly higher for suicide attempters than for matched controls. Proxy informants considered subjects slightly more impulsive and aggressive than the subjects reported themselves. Subject-proxy concordance for total BIS-CV and AQ-CV scores were excellent for both attempters and controls (ICCs = 0.76–0.83). Concordance for the three BIS-CV subscales was 0.74–0.81 for attempters and 0.74–0.83 for controls. Concordance for the five AQ-CV subscales was 0.66–0.85 for attempters and 0.56–0.82 for controls. Limitations: Results are based on respondents from a single location in rural China. Conclusions: The results support the validity of the BIS-CV and AQ-CV and of research on suicidal behavior in China that uses proxy-based reports of impulsiveness and aggression.

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

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.

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