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 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 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 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 Investigating causality in associations between education and smoking: A two-sample Mendelian randomization study

2017 ◽  
Author(s):  
Suzanne H. Gage ◽  
Jack Bowden ◽  
George Davey Smith ◽  
Marcus R. Munafo
Keyword(s):  
Smoking Cessation ◽  
Educational Attainment ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Smoking Initiation ◽  
Self Report ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Increased Risk ◽  
Higher Educational Attainment

AbstractBackgroundLower educational attainment is associated with increased rates of smoking, but ascertaining causality is challenging. We used two-sample Mendelian randomization (MR) analyses of summary statistics to examine whether educational attainment is causally related to smoking.Methods and FindingsWe used summary statistics from genome-wide association studies of educational attainment and a range of smoking phenotypes (smoking initiation, cigarettes per day, cotinine levels and smoking cessation). Various complementary MR techniques (inverse-variance weighted regression, MR Egger, weighted-median regression) were used to test the robustness of our results. We found broadly consistent evidence across these techniques that higher educational attainment leads to reduced likelihood of smoking initiation, reduced heaviness of smoking among smokers (as measured via self-report and cotinine levels), and greater likelihood of smoking cessation among smokers.ConclusionsOur findings indicate a causal association between low educational attainment and increased risk of smoking, and may explain the observational associations between educational attainment and adverse health outcomes such as risk of coronary heart disease.

scholarly journals Educational attainment reduces the risk of suicide attempt among individuals with and without psychiatric disorders independent of cognition: a multivariable Mendelian randomization study with more than 815,000 participants

2019 ◽  
Author(s):  
Daniel B. Rosoff ◽  
Zachary A. Kaminsky ◽  
Falk W. Lohoff
Keyword(s):  
Mental Disorders ◽  
Suicide Attempt ◽  
Educational Attainment ◽  
Household Income ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Point Estimate ◽  
Genome Wide Association Studies ◽  
Causal Nature ◽  
Comorbid Mental Disorders

ABSTRACTBackgroundRates of suicidal ideation, attempts and completions are increasing and identifying causal risk factors continues to be a public health priority. Observational literature has shown that educational attainment (EA) and cognitive performance (CP) can influence suicide attempt risk; however, due to residual confounding and reverse causation, the causal nature of these relationships is unknown.MethodsWe perform a multivariable two-sample Mendelian randomization (MR) analysis to disentangle the effects of EA and CP on suicide attempt risk. We use summary statistics from recent genome-wide association studies (GWAS) of EA, CP, household income versus suicide attempt risk in individuals with and without mental disorders, with more than 815,000 combined study participants.ResultsWe found evidence that both EA and CP significantly reduced the risk of suicide attempt when considered separately in single variable MR (SVMR) (Model 1 EA odds ratio (OR), 0.524, 95% CI, 0.412-0.666, P = 1.07⨯10−7; CP OR, 0.714, 95% CI, 0.577-0.885, P = 0.002). When simultaneously analyzing EA,CA, and adjusting for household income but not comorbid mental disorders (Model 1), we found evidence that the direct effect of EA, independent of CP, on suicide attempt risk was greater than the total effect estimated by SVMR, with EA, independent of CP, significantly reducing the risk of suicide attempt by almost 66% (95% CI, 43%-79%); however, the effect of CP was no longer significant independent of EA (Model 1 EA OR, 0.342, 95% CI, 0.206-0.568, P = 1.61×10−4; CP OR, 1.182, 95% CI, 0.842-1.659, P = 0.333). Further, when accounting for comorbid mental disorders (Model 2), these results did not significantly change: we found EA significantly reduced the risk of suicide attempt by 55% (35%-68%), a lower point estimate but still within the 95% confidence interval of Model 1; the effect of CP was still not significant (Model 2 EA OR, 0.450, 95% CI, 0.314-0.644, P < 1.00×10−4; CP OR, 1.143, 95% CI, 0.803-1.627, P = 0.475).ConclusionsOur results show that even after accounting for comorbid mental disorders and adjusting for household income, EA, but not CP, is a causal risk factor in suicide attempt. These findings could have important implications for health policy and prevention programs aimed at reducing the increasing rates of suicide.

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 Educational attainment reduces the risk of suicide attempt among individuals with and without psychiatric disorders independent of cognition: a bidirectional and multivariable Mendelian randomization study with more than 815,000 participants

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniel B. Rosoff ◽  
Zachary A. Kaminsky ◽  
Andrew M. McIntosh ◽  
George Davey Smith ◽  
Falk W. Lohoff
Keyword(s):  
Suicide Attempt ◽  
Educational Attainment ◽  
Psychiatric Disorders ◽  
Mendelian Randomization ◽  
Association Studies ◽  
The United States ◽  
European Ancestry ◽  
Independent Effect ◽  
Genome Wide Association Studies ◽  
Causal Nature

Abstract Rates of suicidal behavior are increasing in the United States and identifying causal risk factors continues to be a public health priority. Observational literature has shown that educational attainment (EA) and cognitive performance (CP) influence suicide attempt risk; however, the causal nature of these relationships is unknown. Using summary statistics from genome-wide association studies (GWAS) of EA, CP, and suicide attempt risk with > 815,000 combined white participants of European ancestry, we performed multivariable Mendelian randomization (MR) to disentangle the effects of EA and CP on attempted suicide. In single-variable MR (SVMR), EA and CP appeared to reduce suicide attempt risk (EA odds ratio (OR) per standard deviation (SD) increase in EA (4.2 years), 0.524, 95% CI, 0.412–0.666, P = 1.07 × 10−7; CP OR per SD increase in standardized score, 0.714, 95% CI, 0.577–0.885, P = 0.002). Conversely, bidirectional analyses found no effect of a suicide attempt on EA or CP. Using various multivariable MR (MVMR) models, EA seems to be the predominant risk factor for suicide attempt risk with the independent effect (OR, 0.342, 95% CI, 0.206–0.568, P = 1.61 × 10−4), while CP had no effect (OR, 1.182, 95% CI, 0.842–1.659, P = 0.333). In additional MVMR analyses accounting simultaneously for potential behavioral and psychiatric mediators (tobacco smoking; alcohol consumption; and self-reported nerves, tension, anxiety, or depression), the effect of EA was little changed (OR, 0.541, 95% CI, 0.421–0.696, P = 3.33 × 10−6). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our results show that even after accounting for psychiatric disorders and behavioral mediators, EA, but not CP, may causally influence suicide attempt risk among white individuals of European ancestry, which could have important implications for health policy and programs aimed at reducing the increasing rates of suicide. Future work is necessary to examine the EA–suicide relationship populations of different ethnicities.

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&amp;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 A comprehensive evaluation of methods for Mendelian randomization using realistic simulations and an analysis of 38 biomarkers for risk of type 2 diabetes

2021 ◽  
Author(s):  
Guanghao Qi ◽  
Nilanjan Chatterjee
Keyword(s):  
Type 2 Diabetes ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Real Data ◽  
Causal Effects ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Simulation Studies ◽  
Sample Sizes

Abstract Background Previous studies have often evaluated methods for Mendelian randomization (MR) analysis based on simulations that do not adequately reflect the data-generating mechanisms in genome-wide association studies (GWAS) and there are often discrepancies in the performance of MR methods in simulations and real data sets. Methods We use a simulation framework that generates data on full GWAS for two traits under a realistic model for effect-size distribution coherent with the heritability, co-heritability and polygenicity typically observed for complex traits. We further use recent data generated from GWAS of 38 biomarkers in the UK Biobank and performed down sampling to investigate trends in estimates of causal effects of these biomarkers on the risk of type 2 diabetes (T2D). Results Simulation studies show that weighted mode and MRMix are the only two methods that maintain the correct type I error rate in a diverse set of scenarios. Between the two methods, MRMix tends to be more powerful for larger GWAS whereas the opposite is true for smaller sample sizes. Among the other methods, random-effect IVW (inverse-variance weighted method), MR-Robust and MR-RAPS (robust adjust profile score) tend to perform best in maintaining a low mean-squared error when the InSIDE assumption is satisfied, but can produce large bias when InSIDE is violated. In real-data analysis, some biomarkers showed major heterogeneity in estimates of their causal effects on the risk of T2D across the different methods and estimates from many methods trended in one direction with increasing sample size with patterns similar to those observed in simulation studies. Conclusion The relative performance of different MR methods depends heavily on the sample sizes of the underlying GWAS, the proportion of valid instruments and the validity of the InSIDE assumption. Down-sampling analysis can be used in large GWAS for the possible detection of bias in the MR methods.

scholarly journals Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

2021 ◽  
Vol 22 (11) ◽  
pp. 6083
Author(s):  
Aintzane Rueda-Martínez ◽  
Aiara Garitazelaia ◽  
Ariadna Cilleros-Portet ◽  
Sergi Marí ◽  
Rebeca Arauzo ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Clear Cell ◽  
Association Studies ◽  
Epidemiological Data ◽  
Epidemiological Studies ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Genomic Analyses ◽  
Gynecological Disorder ◽  
Robust Evidence

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.

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