scholarly journals Genetic evidence for a causative effect of airflow obstruction on left ventricular filling: a Mendelian randomisation study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lars Harbaum ◽  
Jan K. Hennigs ◽  
Marcel Simon ◽  
Tim Oqueka ◽  
Henrik Watz ◽  
...  
Keyword(s):  
General Population ◽  
Genetic Variants ◽  
Airflow Obstruction ◽  
Left Ventricular ◽  
Sensitivity Analyses ◽  
Weighted Regression ◽  
Mendelian Randomisation ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Inverse Variance

Abstract Background Observational studies on the general population have suggested that airflow obstruction associates with left ventricular (LV) filling. To limit the influence of environmental risk factors/exposures, we used a Mendelian randomisation (MR) approach based on common genetic variations and tested whether a causative relation between airflow obstruction and LV filling can be detected. Methods We used summary statistics from large genome-wide association studies (GWAS) on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) measured by spirometry and the LV end-diastolic volume (LVEDV) as assessed by cardiac magnetic resonance imaging. The primary MR was based on an inverse variance weighted regression. Various complementary MR methods and subsets of the instrument variables were used to assess the plausibility of the findings. Results We obtained consistent evidence in our primary MR analysis and subsequent sensitivity analyses that reducing airflow obstruction leads to increased inflow to the LV (odds ratio [OR] from inverse variance weighted regression 1.05, 95% confidence interval [CI] 1.01–1.09, P = 0.0172). Sensitivity analyses indicated a certain extent of negative horizontal pleiotropy and the estimate from biased-corrected MR-Egger was adjusted upward (OR 1.2, 95% CI 1.09–1.31, P < 0.001). Prioritisation of single genetic variants revealed rs995758, rs2070600 and rs7733410 as major contributors to the MR result. Conclusion Our findings indicate a causal relationship between airflow obstruction and LV filling in the general population providing genetic context to observational associations. The results suggest that targeting (even subclinical) airflow obstruction can lead to direct cardiac improvements, demonstrated by an increase in LVEDV. Functional annotation of single genetic variants contributing most to the causal effect estimate could help to prioritise biological underpinnings.

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 Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study

2020 ◽  
Author(s):  
Charlie N. Saunders ◽  
◽  
Alex J. Cornish ◽  
Ben Kinnersley ◽  
Philip J. Law ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mendelian Randomisation ◽  
Published Data ◽  
Genome Wide Association Studies ◽  
Standard Deviation Increase ◽  
Inverse Variance ◽  
Profile Score

Abstract Background The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for glioma risk factors. Methods We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weighted (IVW-RE) model, with robust adjusted profile score (MR-RAPS), weighted median and mode-based estimates computed to assess the robustness of findings. Odds ratios per one standard deviation increase in each phenotype were calculated for all glioma, glioblastoma (GBM) and non-GBM tumours. Results No significant associations (P < 1.58 × 10−4) were observed between phenotypes and glioma under the IVW-RE model. Suggestive associations (1.58 × 10−4 < P < 0.05) were observed between leukocyte telomere length (LTL) with all glioma (ORSD = 3.91, P = 9.24 × 10−3) and GBM (ORSD = 4.86, P = 3.23 × 10−2), but the association was primarily driven by the TERT variant rs2736100. Serum low-density lipoprotein cholesterol and plasma HbA1C showed suggestive associations with glioma (ORSD = 1.11, P = 1.39 × 10−2 and ORSD = 1.28, P = 1.73 × 10−2, respectively), both associations being reliant on single genetic variants. Conclusions Our study provides further insight into the aetiological basis of glioma for which published data have been mixed.

scholarly journals Relationship between smoking and ALS: Mendelian randomisation interrogation of causality

2020 ◽  
Vol 91 (12) ◽  
pp. 1312-1315
Author(s):  
Sarah Opie-Martin ◽  
Robyn E Wootton ◽  
Ashley Budu-Aggrey ◽  
Aleksey Shatunov ◽  
Ashley R Jones ◽  
...  
Keyword(s):  
Association Studies ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Reverse Causality ◽  
Genome Wide ◽  
Inverse Variance ◽  
A Genome

ObjectiveSmoking has been widely studied as a susceptibility factor for amyotrophic lateral sclerosis (ALS), but results are conflicting and at risk of confounding bias. We used the results of recently published large genome-wide association studies and Mendelian randomisation methods to reduce confounding to assess the relationship between smoking and ALS.MethodsTwo genome-wide association studies investigating lifetime smoking (n=463 003) and ever smoking (n=1 232 091) were identified and used to define instrumental variables for smoking. A genome-wide association study of ALS (20 806 cases; 59 804 controls) was used as the outcome for inverse variance weighted Mendelian randomisation, and four other Mendelian randomisation methods, to test whether smoking is causal for ALS. Analyses were bidirectional to assess reverse causality.ResultsThere was no strong evidence for a causal or reverse causal relationship between smoking and ALS. The results of Mendelian randomisation using the inverse variance weighted method were: lifetime smoking OR 0.94 (95% CI 0.74 to 1.19), p value 0.59; ever smoking OR 1.10 (95% CI 1 to 1.23), p value 0.05.ConclusionsUsing multiple methods, large sample sizes and sensitivity analyses, we find no evidence with Mendelian randomisation techniques that smoking causes ALS. Other smoking phenotypes, such as current smoking, may be suitable for future Mendelian randomisation studies

scholarly journals Genetically increased circulating FUT3 level leads to reduced risk of Idiopathic Pulmonary Fibrosis: a Mendelian Randomisation Study

2021 ◽  
pp. 2003979
Author(s):  
Tomoko Nakanishi ◽  
Agustin Cerani ◽  
Vincenzo Forgetta ◽  
Sirui Zhou ◽  
Richard J. Allen ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Protective Effects ◽  
Inverse Variance ◽  
Genetic Signal ◽  
Reduced Risk

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments we used genetic determinants of circulating proteins which reside cis to the encoded gene (cis-SNPs), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalization analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.MR analyses of 834 proteins found that a one sd increase in circulating FUT3 and FUT5 was associated with a reduced risk of IPF (OR: 0.81, 95%CI: 0.74–0.88, p=6.3×10−7, and OR: 0.76, 95%CI: 0.68–0.86, p=1.1×10−5). Sensitivity analyses including multiple-cis SNPs provided similar estimates both for FUT3 (inverse variance weighted [IVW] OR: 0.84, 95%CI: 0.78–0.91, p=9.8×10−6, MR-Egger OR: 0.69, 95%CI: 0.50–0.97, p=0.03) and FUT5 (IVW OR: 0.84, 95%CI: 0.77–0.92, p=1.4×10−4, MR-Egger OR: 0.59, 95%CI: 0.38–0.90, p=0.01) FUT3 and FUT5 signals colocalized with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%. Further transcriptomic investigations supported the protective effects of FUT3 for IPF.An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.

scholarly journals Are psychiatric disorders risk factors for COVID-19 susceptibility and severity? a two-sample, bidirectional, univariable and multivariable Mendelian Randomization study

2020 ◽  
Author(s):  
Jurjen J. Luykx ◽  
Bochao D. Lin
Keyword(s):  
Bipolar Disorder ◽  
Psychiatric Disorders ◽  
Observational Studies ◽  
Mendelian Randomization ◽  
Neuropsychiatric Disorders ◽  
Sensitivity Analyses ◽  
Effect Estimate ◽  
Genome Wide Association Studies ◽  
Genetic Liability ◽  
Increased Risk

AbstractImportanceObservational studies have suggested bidirectional associations between psychiatric disorders and COVID-19 phenotypes, but results of such studies are inconsistent. Mendelian Randomization (MR) may overcome limitations of observational studies, e.g. unmeasured confounding and uncertainties about cause and effect.ObjectiveTo elucidate associations between neuropsychiatric disorders and COVID-19 susceptibility and severity.MethodIn November, 2020, we applied a two-sample, bidirectional, univariable and multivariable MR design to genetic data from genome-wide association studies (GWASs) of neuropsychiatric disorders and COVID-19 phenotypes (released on 20 Oct. 2020). Our study population consisted of almost 2 million participants with either a (neuro)psychiatric disorder or data on COVID-19 status. Outcomes and exposures were anxiety, anxiety-and-stress related disorders, major depressive disorder, schizophrenia, bipolar disorder, schizophrenia-bipolar disorder combined (BIP-SCZ), and Alzheimer’s dementia on the one hand; and self-reported, confirmed, hospitalized, and very severe COVID-19 on the other.ResultsIn single-variable MR analysis the most significant and only Bonferroni-corrected significant result was found for BIP-SCZ (a combined anxiety of bipolar disorder and schizophrenia as cases vs. controls): the effect estimate was consistent with increased risk of COVID-19 (OR = 1.17, 95% CI, 1.06-1.28; p = 0.0012). Nominally significant univariable results were in line with slightly elevated risks of COVID-19 for genetic liabilities to bipolar disorder and schizophrenia. No COVID-19 phenotype consistently increased risk of (neuro)psychiatric disorders. In multivariable MR, bipolar disorder was the only phenotype showing a Bonferroni-corrected significant effect on a COVID-19 phenotype, namely severe COVID-19 (OR = 1.293; 95% CI, 1.095-1.527; p = 0.003). All sensitivity analyses confirmed the results.ConclusionsGenetic liability to bipolar disorder slightly increases COVID-19 susceptibility and severity. The contribution of bipolar disorder to these COVID-19 phenotypes was smaller than the odds ratios estimated by observational studies. Strength of association and direction of effect for genetic liability to schizophrenia were similar, albeit less significant. We found no consistent evidence of reverse effects, i.e. of genetic liability to COVID-19 on psychiatric disorders.

scholarly journals Novel Rare Genetic Variants Associated with Airflow Obstruction in the General Population

2020 ◽  
Vol 201 (4) ◽  
pp. 485-488 ◽  
Author(s):  
Maaike de Vries ◽  
Diana A. van der Plaat ◽  
Ivana Nedeljkovic ◽  
K. Joeri van der Velde ◽  
Najaf Amin ◽  
...  
Keyword(s):  
General Population ◽  
Genetic Variants ◽  
Airflow Obstruction ◽  
Rare Genetic Variants

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 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 Does smoking cause lower educational attainment and general cognitive ability? Triangulation of causal evidence using multiple study designs

2020 ◽  
pp. 1-9
Author(s):  
Suzanne H. Gage ◽  
Hannah M. Sallis ◽  
Glenda Lassi ◽  
Robyn E. Wootton ◽  
Claire Mokrysz ◽  
...  
Keyword(s):  
Educational Attainment ◽  
Cognitive Ability ◽  
Fluid Intelligence ◽  
Causal Effect ◽  
Smoking Initiation ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
General Cognitive Ability ◽  
Inverse Variance ◽  
Lower Educational Attainment

Abstract Background Observational studies have found associations between smoking and both poorer cognitive ability and lower educational attainment; however, evaluating causality is challenging. We used two complementary methods to explore this. Methods We conducted observational analyses of up to 12 004 participants in a cohort study (Study One) and Mendelian randomisation (MR) analyses using summary and cohort data (Study Two). Outcome measures were cognitive ability at age 15 and educational attainment at age 16 (Study One), and educational attainment and fluid intelligence (Study Two). Results Study One: heaviness of smoking at age 15 was associated with lower cognitive ability at age 15 and lower educational attainment at age 16. Adjustment for potential confounders partially attenuated findings (e.g. fully adjusted cognitive ability β −0.736, 95% CI −1.238 to −0.233, p = 0.004; fully adjusted educational attainment β −1.254, 95% CI −1.597 to −0.911, p < 0.001). Study Two: MR indicated that both smoking initiation and lifetime smoking predict lower educational attainment (e.g. smoking initiation to educational attainment inverse-variance weighted MR β −0.197, 95% CI −0.223 to −0.171, p = 1.78 × 10−49). Educational attainment results were robust to sensitivity analyses, while analyses of general cognitive ability were less so. Conclusion We find some evidence of a causal effect of smoking on lower educational attainment, but not cognitive ability. Triangulation of evidence across observational and MR methods is a strength, but the genetic variants associated with smoking initiation may be pleiotropic, suggesting caution in interpreting these results. The nature of this pleiotropy warrants further study.

scholarly journals Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Shah ◽  
◽  
Albert Henry ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiac Development ◽  
Association Studies ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractHeart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

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