scholarly journals Smoking and the risk for bipolar disorder: causal evidence from a bidirectional Mendelian randomization study

2019 ◽  
Author(s):  
Jentien Vermeulen ◽  
Robyn Wootton ◽  
Jorien Treur ◽  
Hannah Sallis ◽  
Hannah Jones ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Risk Factor ◽  
Mental Health Problems ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Smoking Initiation ◽  
Smoking Prevention ◽  
Genome Wide Association Studies ◽  
Causal Nature

There is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder. We aimed to investigate the direction and causal nature of the relationship between smoking and bipolar disorder we conducted a bidirectional Mendelian randomization (MR) study. Publicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e., a compound measure of heaviness, duration and cessation). We applied multiple analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger or Egger SIMEX, weighted median, weighted mode, and Steiger filtered analyses. Across different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW=1.46, 95% CI=1.28-1.66, P=1.44x10-8, lifetime smoking ORIVW=1.72, 95% CI=1.29-2.28, P=1.8x10-4). The MR analyses of the liability of bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking heaviness betaIVW=0.028, 95% CI= 0.003-0.053, P=2.9x10-2). These findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to bipolar disorder increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.

scholarly journals Smoking and the risk for bipolar disorder: evidence from a bidirectional Mendelian randomisation study

2019 ◽  
pp. 1-7 ◽  
Author(s):  
Jentien M. Vermeulen ◽  
Robyn E. Wootton ◽  
Jorien L. Treur ◽  
Hannah M. Sallis ◽  
Hannah J. Jones ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Risk Factor ◽  
Mental Health Problems ◽  
Causal Effect ◽  
Association Studies ◽  
Smoking Initiation ◽  
Smoking Prevention ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
The Past

BackgroundThere is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder.AimsWe conducted a bidirectional Mendelian randomisation (MR) study to investigate the direction and evidence for a causal nature of the relationship between smoking and bipolar disorder.MethodWe used publicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e. a compound measure of heaviness, duration and cessation). We applied analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger, MR-Egger SIMEX, weighted-median, weighted-mode and Steiger-filtered analyses.ResultsAcross different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW = 1.46, 95% CI 1.28–1.66, P = 1.44 × 10−8, lifetime smoking ORIVW = 1.72, 95% CI 1.29–2.28, P = 1.8 × 10−4). The MR analyses of the effect of liability to bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking heaviness betaIVW = 0.028, 95% CI 0.003–0.053, P = 2.9 × 10−2).ConclusionsThese findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to bipolar disorder increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.Declaration of interestW.v.d.B received fees in the past 3 years from Indivior, C&A Pharma, Opiant and Angelini. G.M.G. is a National Institute for Health Research (NIHR) Emeritus Senior Investigator, holds shares in P1vital and has served as consultant, advisor or CME speaker in the past 3 years for Allergan, Angelini, Compass Pathways, MSD, Lundbeck (/Otsuka and /Takeda), Medscape, Minervra, P1Vital, Pfizer, Sage, Servier, Shire and Sun Pharma.

scholarly journals Cigarette smoking and personality: Investigating causality using Mendelian randomization

2018 ◽  
Author(s):  
Hannah M Sallis ◽  
George Davey Smith ◽  
Marcus R Munafò
Keyword(s):  
Personality Traits ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Smoking Initiation ◽  
Smoking Prevention ◽  
Cigarette Consumption ◽  
Genome Wide Association Studies ◽  
Self Medication ◽  
Prevention Programmes ◽  
Causal Nature

AbstractBackgroundDespite the well-documented association between smoking and personality traits such as neuroticism and extraversion, little is known about the potential causal nature of these findings. If it were possible to unpick the association between personality and smoking, it may be possible to develop more targeted smoking cessation programmes that could lead to both improved uptake and efficacy.MethodsRecent genome-wide association studies (GWAS) have identified variants robustly associated with both smoking phenotypes and personality traits. Here we use publicly available GWAS summary statistics in addition to data from UK Biobank to investigate the link between smoking and personality. We first estimated genetic overlap between traits using LD score regression and then applied both one- and two-sample Mendelian randomization methods to unpick the nature of this relationship.ResultsWe found clear evidence of a modest genetic correlation between smoking behaviours and both neuroticism and extraversion, suggesting shared genetic aetiology. We found some evidence to suggest an association between neuroticism and increased smoking initiation. We also found some evidence that personality traits appear to be causally linked to certain smoking phenotypes: higher neuroticism and heavier cigarette consumption, and higher extraversion and increased odds of smoking initiation. The latter finding could lead to more targeted smoking prevention programmes.ConclusionThe association between neuroticism and cigarette consumption lends support to the self-medication hypothesis, while the association between extraversion and smoking initiation could lead to more targeted smoking prevention programmes.

scholarly journals The effect of smoking on multiple sclerosis: a mendelian randomization study

2020 ◽  
Author(s):  
Ruth E Mitchell ◽  
Kirsty Bates ◽  
Robyn E Wootton ◽  
Adil Harroud ◽  
J. Brent Richards ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Meta Analysis ◽  
Smoking Initiation ◽  
Smoking Behaviour ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Smoking Duration

AbstractThe causes of multiple sclerosis (MS) remain unknown. Smoking has been associated with MS in observational studies and is often thought of as an environmental risk factor. We used two-sample Mendelian Randomization (MR) to examined whether this association is causal using genetic variants identified in genome-wide association studies (GWAS) as associated with smoking. We assessed both smoking initiation and lifetime smoking behaviour (which captures smoking duration, heaviness and cessation). There was very limited evidence for a meaningful effect of smoking on MS susceptibility was measured using summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) meta-analysis, including 14,802 cases and 26,703 controls. There was no clear evidence for an effect of smoking on the risk of developing MS (smoking initiation: odds ratio [OR] 1.03, 95% confidence interval [CI] 0.92-1.61; lifetime smoking: OR 1.10, 95% CI 0.87-1.40). These findings suggest that smoking does not have a detrimental consequence on MS susceptibility. Further work is needed to determine the causal effect of smoking on MS progression.

scholarly journals Is disrupted sleep a risk factor for Alzheimer’s disease? Evidence from a two-sample Mendelian randomization analysis

2020 ◽  
Author(s):  
Emma L Anderson ◽  
Rebecca C Richmond ◽  
Samuel E Jones ◽  
Gibran Hemani ◽  
Kaitlin H Wade ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Daytime Sleepiness ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Self Report ◽  
Genome Wide Association Studies ◽  
Tentative Evidence

Abstract Background It is established that Alzheimer’s disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD. Methods We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk. Results Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50–0.99). Some other sleep traits (accelerometer-measured ‘eveningness’ and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated. Conclusions Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.

scholarly journals Little evidence for an effect of smoking on multiple sclerosis risk: A Mendelian Randomization study

PLoS Biology ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. e3000973
Author(s):  
Ruth E. Mitchell ◽  
Kirsty Bates ◽  
Robyn E. Wootton ◽  
Adil Harroud ◽  
J. Brent Richards ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Meta Analysis ◽  
Smoking Initiation ◽  
Smoking Behaviour ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Smoking Duration

The causes of multiple sclerosis (MS) remain unknown. Smoking has been associated with MS in observational studies and is often thought of as an environmental risk factor. We used two-sample Mendelian randomization (MR) to examine whether this association is causal using genetic variants identified in genome-wide association studies (GWASs) as associated with smoking. We assessed both smoking initiation and lifetime smoking behaviour (which captures smoking duration, heaviness, and cessation). There was very limited evidence for a meaningful effect of smoking on MS susceptibility as measured using summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) meta-analysis, including 14,802 cases and 26,703 controls. There was no clear evidence for an effect of smoking on the risk of developing MS (smoking initiation: odds ratio [OR] 1.03, 95% confidence interval [CI] 0.92–1.61; lifetime smoking: OR 1.10, 95% CI 0.87–1.40). These findings suggest that smoking does not have a detrimental consequence on MS susceptibility. Further work is needed to determine the causal effect of smoking on MS progression.

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 Cigarette smoking and personality: interrogating causality using Mendelian randomisation

2018 ◽  
Vol 49 (13) ◽  
pp. 2197-2205 ◽  
Author(s):  
Hannah M. Sallis ◽  
George Davey Smith ◽  
Marcus R. Munafò
Keyword(s):  
Personality Traits ◽  
Association Studies ◽  
Smoking Initiation ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Individual Level ◽  
Causal Pathways ◽  
Genome Wide ◽  
Level Data ◽  
Causal Nature

AbstractBackgroundDespite the well-documented association between smoking and personality traits such as neuroticism and extraversion, little is known about the potential causal nature of these findings. If it were possible to unpick the association between personality and smoking, it may be possible to develop tailored smoking interventions that could lead to both improved uptake and efficacy.MethodsRecent genome-wide association studies (GWAS) have identified variants robustly associated with both smoking phenotypes and personality traits. Here we use publicly available GWAS summary statistics in addition to individual-level data from UK Biobank to investigate the link between smoking and personality. We first estimate genetic overlap between traits using LD score regression and then use bidirectional Mendelian randomisation methods to unpick the nature of this relationship.ResultsWe found clear evidence of a modest genetic correlation between smoking behaviours and both neuroticism and extraversion. We found some evidence that personality traits are causally linked to certain smoking phenotypes: among current smokers each additional neuroticism risk allele was associated with smoking an additional 0.07 cigarettes per day (95% CI 0.02–0.12, p = 0.009), and each additional extraversion effect allele was associated with an elevated odds of smoking initiation (OR 1.015, 95% CI 1.01–1.02, p = 9.6 × 10−7).ConclusionWe found some evidence for specific causal pathways from personality to smoking phenotypes, and weaker evidence of an association from smoking initiation to personality. These findings could be used to inform future smoking interventions or to tailor existing schemes.

scholarly journals A Novel Method for Mendelian Randomization Analyses With Pleiotropy and Linkage Disequilibrium in Genetic Variants From Individual Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuquan Wang ◽  
Tingting Li ◽  
Liwan Fu ◽  
Siqian Yang ◽  
Yue-Qing Hu
Keyword(s):  
Linkage Disequilibrium ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Random Effect ◽  
Pleiotropic Effect ◽  
Genome Wide Association Studies ◽  
The Novel ◽  
Novel Method

Mendelian randomization makes use of genetic variants as instrumental variables to eliminate the influence induced by unknown confounders on causal estimation in epidemiology studies. However, with the soaring genetic variants identified in genome-wide association studies, the pleiotropy, and linkage disequilibrium in genetic variants are unavoidable and may produce severe bias in causal inference. In this study, by modeling the pleiotropic effect as a normally distributed random effect, we propose a novel mixed-effects regression model-based method PLDMR, pleiotropy and linkage disequilibrium adaptive Mendelian randomization, which takes linkage disequilibrium into account and also corrects for the pleiotropic effect in causal effect estimation and statistical inference. We conduct voluminous simulation studies to evaluate the performance of the proposed and existing methods. Simulation results illustrate the validity and advantage of the novel method, especially in the case of linkage disequilibrium and directional pleiotropic effects, compared with other methods. In addition, by applying this novel method to the data on Atherosclerosis Risk in Communications Study, we conclude that body mass index has a significant causal effect on and thus might be a potential risk factor of systolic blood pressure. The novel method is implemented in R and the corresponding R code is provided for free download.

scholarly journals bGWAS: an R package to perform Bayesian genome wide association studies

2020 ◽  
Vol 36 (15) ◽  
pp. 4374-4376
Author(s):  
Ninon Mounier ◽  
Zoltán Kutalik
Keyword(s):  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
R Package ◽  
Genome Wide Association ◽  
Supplementary Information ◽  
Genome Wide Association Studies ◽  
Biological Mechanisms ◽  
Genome Wide ◽  
Related Risk

Abstract Summary Increasing sample size is not the only strategy to improve discovery in Genome Wide Association Studies (GWASs) and we propose here an approach that leverages published studies of related traits to improve inference. Our Bayesian GWAS method derives informative prior effects by leveraging GWASs of related risk factors and their causal effect estimates on the focal trait using multivariable Mendelian randomization. These prior effects are combined with the observed effects to yield Bayes Factors, posterior and direct effects. The approach not only increases power, but also has the potential to dissect direct and indirect biological mechanisms. Availability and implementation bGWAS package is freely available under a GPL-2 License, and can be accessed, alongside with user guides and tutorials, from https://github.com/n-mounier/bGWAS. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study

2019 ◽  
Vol 50 (14) ◽  
pp. 2435-2443 ◽  
Author(s):  
Robyn E. Wootton ◽  
Rebecca C. Richmond ◽  
Bobby G. Stuijfzand ◽  
Rebecca B. Lawn ◽  
Hannah M. Sallis ◽  
...  
Keyword(s):  
Causal Effect ◽  
Association Studies ◽  
Smoking Initiation ◽  
Smoking Behaviour ◽  
Positive Control ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Weak Evidence ◽  
Smoking Duration ◽  
The Uk

AbstractBackgroundSmoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).MethodsWe conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium.ResultsThere was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67–3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71–2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking (β = 0.091, 95% CI 0.027–0.155, p = 0.005) but evidence was mixed for schizophrenia (β = 0.022, 95% CI 0.005–0.038, p = 0.009) with very weak evidence for an effect on smoking initiation.ConclusionsThese findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.

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