Cigarette smoking and schizophrenia: Mendelian randomisation study

2020 ◽  
pp. 1-6
Author(s):  
Jianhua Chen ◽  
Ruirui Chen ◽  
Siying Xiang ◽  
Ningning Li ◽  
Chengwen Gao ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Association Studies ◽  
Smoking Initiation ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Complex Behaviour ◽  
Asian Populations ◽  
Smoking Behaviours

Background The link between schizophrenia and cigarette smoking has been well established through observational studies. However, the cause–effect relationship remains unclear. Aims We conducted Mendelian randomisation analyses to assess any causal relationship between genetic variants related to four smoking-related traits and the risk of schizophrenia. Method We performed a two-sample Mendelian randomisation using summary statistics from genome-wide association studies (GWAS) of smoking-related traits and schizophrenia (7711 cases, 18 327 controls) in East Asian populations. Single nucleotide polymorphisms (SNPs) correlated with smoking behaviours (smoking initiation, smoking cessation, age at smoking initiation and quantity of smoking) were investigated in relation to schizophrenia using the inverse-variance weighted (IVW) method. Further sensitivity analyses, including Mendelian randomisation-Egger (MR-Egger), weighted median estimates and leave-one-out analysis, were used to test the consistency of the results. Results The associated SNPs for the four smoking behaviours were not significantly associated with schizophrenia status. Pleiotropy did not inappropriately affect the results. Conclusions Cigarette smoking is a complex behaviour in people with schizophrenia. Understanding factors underlying the observed association remains important; however, our findings do not support a causal role of smoking in influencing risk of schizophrenia.

scholarly journals 586Effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation analysis

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Jian Zhao ◽  
Rachel Freathy ◽  
David Evans ◽  
Nicole Warrington ◽  
Claudia Langenberg ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Association Studies ◽  
Amino Acid Level ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Reverse Causality

Abstract Background It is suggested amino acids are critical for fetal growth, but analyses assessing causality are lacking. Mendelian randomisation (MR) can be used to examine causal effects under instrumental variable (IV) assumptions. Methods We conducted a two-sample MR study utilizing summary data from genome-wide association studies (GWAS) of amino acids (sample 1, n = 86,507) and of offspring birthweight (sample 2, combined UK Biobank and Early Growth Genetics Consortium, n = 406,063). Seventy-five independent single nucleotide polymorphisms (SNPs) robustly associated with 18 amino acids (p < 4.9 × 10-10) were used as genetic instruments. Wald ratio and inverse variance weighted methods were used in MR main analysis. Sensitivity analyses were performed to explore IV assumption violations. To explore whether there was consistency between SNP-amino acid associations in pregnancy and in the GWAS, the latter were compared to associations in the Born in Bradford cohort. Results There was evidence of positive causal effects of maternal alanine (51.9 g birthweight increase per SD increase in amino acid level, 95% CI: 24.2, 79.5), glutamine (51.3 g, 95% CI: 33.5, 69.0), glycine (10.4 g, 95% CI: 1.3, 19.6) and serine (27.1 g, 95% CI: 11.2, 43.0) on birthweight and inverse causal effects of maternal isoleucine (-109.7 g, 95% CI: -194.6, -24.9) and histidine (-41.1 g, 95% CI: -78.5, -3.7) on birthweight. Sensitivity analyses to explore reverse causality and bias due to horizontal pleiotropy supported our findings. Conclusions Some maternal circulating amino acids have causal effects on birthweight. Key messages MR can be extended to probe effects of maternal nutrition on offspring development.

scholarly journals Mendelian randomisation study of smoking exposure in relation to breast cancer risk

2021 ◽  
Author(s):  
Hanla A. Park ◽  
Sonja Neumeyer ◽  
Kyriaki Michailidou ◽  
Manjeet K. Bolla ◽  
Qin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Causal Effect ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Smoking Exposure

Abstract Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

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 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.

scholarly journals Univariable and Multivariable Two-Sample Mendelian Randomization Investigating the Effects of Leisure Sedentary Behaviors on the Risk of Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Haoxin Peng ◽  
Xiangrong Wu ◽  
Yaokai Wen ◽  
Yiyuan Ao ◽  
Yutian Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Computer Use ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Sedentary Behaviors ◽  
Watching Tv

Background:Leisure sedentary behaviors (LSB) are widespread, and observational studies have provided emerging evidence that LSB play a role in the development of lung cancer (LC). However, the causal inference between LSB and LC remains unknown.Methods: We utilized univariable (UVMR) and multivariable two-sample Mendelian randomization (MVMR) analysis to disentangle the effects of LSB on the risk of LC. MR analysis was conducted with genetic variants from genome-wide association studies of LSB (408,815 persons from UK Biobank), containing 152 single-nucleotide polymorphisms (SNPs) for television (TV) watching, 37 SNPs for computer use, and four SNPs for driving, and LC from the International Lung Cancer Consortium (11,348 cases and 15,861 controls). Multiple sensitivity analyses were further performed to verify the causality.Results: UVMR demonstrated that genetically predisposed 1.5-h increase in LSB spent on watching TV increased the odds of LC by 90% [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.44–2.50; p &lt; 0.001]. Similar trends were observed for squamous cell lung cancer (OR, 1.97; 95%CI, 1.31–2.94; p = 0.0010) and lung adenocarcinoma (OR, 1.64; 95%CI 1.12–2.39; p = 0.0110). The causal effects remained significant after adjusting for education (OR, 1.97; 95%CI, 1.44–2.68; p &lt; 0.001) and body mass index (OR, 1.86; 95%CI, 1.36–2.54; p &lt; 0.001) through MVMR approach. No association was found between prolonged LSB spent on computer use and driving and LC risk. Genetically predisposed prolonged LSB was additionally correlated with smoking (OR, 1.557; 95%CI, 1.287–1.884; p &lt; 0.001) and alcohol consumption (OR, 1.010; 95%CI, 1.004–1.016; p = 0.0016). Consistency of results across complementary sensitivity MR methods further strengthened the causality.Conclusion: Robust evidence was demonstrated for an independent, causal effect of LSB spent on watching TV in increasing the risk of LC. Further work is necessary to investigate the potential mechanisms.

scholarly journals Association between PRDM16, MEF2D, TRPM8, LRP1 gene polymorphisms and migraine susceptibility in the She ethnic population in China

2019 ◽  
Vol 42 (1) ◽  
pp. E21-E30 ◽  
Author(s):  
Xianguo Fu ◽  
Jing Yang ◽  
Xiaoyang Wu ◽  
Qifang Lin ◽  
Yuli Zeng ◽  
...  
Keyword(s):  
Association Studies ◽  
Direct Sequencing ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Han Chinese ◽  
Small Sample ◽  
Genome Wide Association Studies ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Asian Populations

Background: The prevalence of migraines in the She population, a minority in China, is significantly higher than that in Han Chinese and other Asian populations. Two single nucleotide polymorphisms (SNPs) have been found to be associated with migraine susceptibility in the She population. Purpose: This study investigated four SNPs, identified in genome-wide association studies, within migraine-susceptible loci in Han Chinese for their association with migraine susceptibility in the She population. Methods: Two-hundred unrelated migraine patients and 200 healthy controls were recruited. The SNPs examined included rs2651899 (PRDM16 ), rs2274316 (MEF2D ), rs7577262 (TRPM8) and rs11172113 (LRP1). Genotyping of the SNPs was performed by allele-specific polymerase chain reaction and direct sequencing. Results: No significant differences between the participants with migraines and controls (participants without migraines) were demonstrated in genotypes, alleles and allele carriage frequencies for the four SNPs. A subgroup analysis found that migraine with aura had a lower frequency of C allele positivity in rs2651899 than in healthy controls (59.6% vs. 74.5%, respectively; P < 0.034). Univariate analyses indicated that no genotype of the four SNPs had a significant association with migraines. Males had a lower risk of migraines, and advanced age was a significant risk factor for migraines in females. Conclusion: The SNPs in four migraine susceptible loci in Han Chinese were not risk factors for migraines in a relatively small sample of the She population.

scholarly journals Personality, lifestyle and job satisfaction: causal association between neuroticism and job satisfaction using Mendelian randomisation in the UK biobank cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Gull Rukh ◽  
Junhua Dang ◽  
Gaia Olivo ◽  
Diana-Maria Ciuculete ◽  
Mathias Rask-Andersen ◽  
...  
Keyword(s):  
Physical Activity ◽  
Job Satisfaction ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Single Variable ◽  
Causal Association ◽  
Uk Biobank ◽  
The Uk

AbstractJob-related stress has been associated with poor health outcomes but little is known about the causal nature of these findings. We employed Mendelian randomisation (MR) approach to investigate the causal effect of neuroticism, education, and physical activity on job satisfaction. Trait-specific genetic risk score (GRS) based on recent genome wide association studies were used as instrumental variables (IV) using the UK Biobank cohort (N = 315,536). Both single variable and multivariable MR analyses were used to determine the effect of each trait on job satisfaction. We observed a clear evidence of a causal association between neuroticism and job satisfaction. In single variable MR, one standard deviation (1 SD) higher genetically determined neuroticism score (4.07 units) was associated with −0.31 units lower job satisfaction (95% confidence interval (CI): −0.38 to −0.24; P = 9.5 × 10−20). The causal associations remained significant after performing sensitivity analyses by excluding invalid genetic variants from GRSNeuroticism (β(95%CI): −0.28(−0.35 to −0.21); P = 3.4 x 10−15). Education (0.02; −0.08 to 0.12; 0.67) and physical activity (0.08; −0.34 to 0.50; 0.70) did not show any evidence for causal association with job satisfaction. When genetic instruments for neuroticism, education and physical activity were included together, the association of neuroticism score with job satisfaction was reduced by only −0.01 units, suggesting an independent inverse causal association between neuroticism score (P = 2.7 x 10−17) and job satisfaction. Our findings show an independent causal association between neuroticism score and job satisfaction. Physically active lifestyle may help to increase job satisfaction despite presence of high neuroticism scores. Our study highlights the importance of considering the confounding effect of negative personality traits for studies on job satisfaction.

scholarly journals The relationship between cognitive function, Alzheimer's disease and sleep duration: A Mendelian randomisation study

2020 ◽  
Author(s):  
Antoine Salzmann ◽  
Nishi Chaturvedi ◽  
Victoria Garfield
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Reaction Time ◽  
Cognitive Function ◽  
Sleep Duration ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
The Relationship

Objective: Sleep duration is associated with cognitive function and dementia. MR evidence to date, points towards a causal relationship in this direction. However, whether cognitive function or dementia may also cause problematic sleep duration remains unclear. Methods: We conducted summary-level Mendelian Randomisation (MR) analyses to estimate the causal association between general cognitive function, 'g' (177 SNPs), reaction time (44 SNPs), Alzheimer's disease (AD) (29 SNPs), and self-reported and objective sleep duration. Sensitivity analyses included: MR-Egger, Weighted median estimator and leave-one-out analyses. We used data from recently published cognitive function, AD and sleep duration genome wide association studies. Results: MR results showed that AD was associated with longer, (Beta=0.14, 95% CI=0.04;0.24), whilst 'g', and reaction time were associated with shorter (Beta=-0.06, 95% CI=-0.11;-0.01 and Beta=-0.15, 95% CI=-0.29;-0.01, respectively), objective sleep duration. No association was observed between our exposures and self-reported sleep duration. Interpretation: These results suggest a causative relationship between AD, 'g', reaction time and objective sleep duration, where AD is associated with longer sleep duration and 'g' and reaction time are associated with shorter sleep. This study furthers our understanding of the relationship between brain health and sleep duration and sheds light on the causal nature of these associations.

scholarly journals GWAS-Top Polymorphisms Associated With Late-Onset Alzheimer Disease in Brazil: Pointing Out Possible New Culprits Among Non-Coding RNAs

2021 ◽  
Vol 8 ◽  
Author(s):  
Gabriela Canalli Kretzschmar ◽  
Nina Moura Alencar ◽  
Saritha Suellen Lopes da Silva ◽  
Carla Daniela Sulzbach ◽  
Caroline Grisbach Meissner ◽  
...  
Keyword(s):  
Large Scale ◽  
Late Onset ◽  
Association Studies ◽  
Brazilian Population ◽  
Functional Explanation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Bioinformatic Tools ◽  
Asian Populations ◽  
Functional Investigation

Several genome-wide association studies (GWAS) have been carried out with late-onset Alzheimer’s disease (LOAD), mainly in European and Asian populations. Different polymorphisms were associated, but several of them without a functional explanation. GWAS are fundamental for identifying loci associated with diseases, although they often do not point to causal polymorphisms. In this sense, functional investigations are a fundamental tool for discovering causality, although the failure of this validation does not necessarily indicate a non-causality. Furthermore, the allele frequency of associated genetic variants may vary widely between populations, requiring replication of these associations in other ethnicities. In this sense, our study sought to replicate in 150 AD patients and 114 elderly controls from the South Brazilian population 18 single-nucleotide polymorphisms (SNPs) associated with AD in European GWAS, with further functional investigation using bioinformatic tools for the associated SNPs. Of the 18 SNPs investigated, only four were associated in our population: rs769449 (APOE), rs10838725 (CELF1), rs6733839, and rs744373 (BIN1–CYP27C1). We identified 54 variants in linkage disequilibrium (LD) with the associated SNPs, most of which act as expression or splicing quantitative trait loci (eQTLs/sQTLs) in genes previously associated with AD or with a possible functional role in the disease, such as CELF1, MADD, MYBPC3, NR1H3, NUP160, SPI1, and TOMM40. Interestingly, eight of these variants are located within long non-coding RNA (lncRNA) genes that have not been previously investigated regarding AD. Some of these polymorphisms can result in changes in these lncRNAs’ secondary structures, leading to either loss or gain of microRNA (miRNA)-binding sites, deregulating downstream pathways. Our pioneering work not only replicated LOAD association with polymorphisms not yet associated in the Brazilian population but also identified six possible lncRNAs that may interfere in LOAD development. The results lead us to emphasize the importance of functional exploration of associations found in large-scale association studies in different populations to base personalized and inclusive medicine in the future.

scholarly journals Type 2 Diabetes and Glycemic Traits Are Not Causal Factors of Osteoarthritis: A Two-Sample Mendelian Randomization Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiyong Cui ◽  
Hui Feng ◽  
Baichuan He ◽  
Yong Xing ◽  
Zhaorui Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Knee Oa ◽  
Increased Risk

BackgroundIt remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA).MethodsHere, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identified single-nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG), and 2-h postprandial glucose (2hGlu) from genome-wide association studies (GWAS). We used the MR inverse variance weighted (IVW), the MR–Egger method, the weighted median (WM), and the Robust Adjusted Profile Score (MR.RAPS) to reveal the associations of T2D, FG, and 2hGlu with hip and knee OA risks. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.ResultsWe did not find statistically significant causal effects of genetically increased T2D risk, FG, and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR–Egger OR = 1.1708, 95% CI 0.9469–1.4476, p = 0.1547). It was confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR–Egger, intercept = −0.0105, p = 0.1367). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR–Egger Q = 30.1362, I2 &lt; 0.0001, p = 0.6104).ConclusionOur MR study did not support causal effects of a genetically increased T2D risk, FG, and 2hGlu on hip and knee OA risk.

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