scholarly journals Genetically informed precision drug repurposing for lung function and implications for respiratory infection

2020 ◽  
Author(s):  
William R. Reay ◽  
Sahar I. El Shair ◽  
Michael P. Geaghan ◽  
Carlos Riveros ◽  
Elizabeth G. Holliday ◽  
...  
Keyword(s):  
Lung Function ◽  
Drug Targets ◽  
Causal Effect ◽  
Association Studies ◽  
Drug Repurposing ◽  
Human Adenovirus ◽  
Mendelian Randomisation ◽  
Polygenic Scores ◽  
Impaired Lung Function ◽  
Human Proteins

ABSTRACTImpaired lung function is associated with significant morbidity and mortality. Restrictive and obstructive lung disorders are a large contributor to decreased lung function, as well as the acute impact of infection. Measures of pulmonary function are heritable, and thus, we sought to utilise genomics to propose novel drug repurposing candidates which could improve respiratory outcomes. Lung function measures were found to be genetically correlated with metabolic and hormone traits which could be pharmacologically modulated, with a causal effect of increased fasting glucose on diminished lung function supported by latent causal variable models and Mendelian randomisation. We developed polygenic scores for lung function specifically within pathways with known drug targets to prioritise individuals who may benefit from particular drug repurposing opportunities, accompanied by transcriptome-wide association studies to identify drug-gene interactions with potential lung function increasing modes of action. These drug repurposing candidates were further considered relative to the host-viral interactome of three viruses with associated respiratory pathology (SARS-CoV2, influenza, and human adenovirus). We uncovered an enrichment amongst glycaemic pathways of human proteins which putatively interact with virally expressed SARS-CoV2 proteins, suggesting that antihyperglycaemic agents may have a positive effect both on lung function and SARS-CoV2 progression.

scholarly journals Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
William R Reay ◽  
Sahar I El Shair ◽  
Michael P Geaghan ◽  
Carlos Riveros ◽  
Elizabeth G Holliday ◽  
...  
Keyword(s):  
Lung Function ◽  
Drug Targets ◽  
Fasting Glucose ◽  
Drug Repurposing ◽  
Gene Interactions ◽  
Improve Lung Function ◽  
Polygenic Scores ◽  
Modifiable Factor ◽  
Respiratory Outcomes ◽  
Novel Drug

Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug–gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.

scholarly journals Genetic correlation and causal relationships between cardio-metabolic traits and Lung function Impairment

2020 ◽  
Author(s):  
Matthias Wielscher ◽  
Andre FS Amaral ◽  
Diana van der Plaat ◽  
Louise V Wain ◽  
Sylvain Sebert ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Lung Function ◽  
Genetic Correlation ◽  
Large Scale ◽  
Causal Effect ◽  
Association Studies ◽  
Metabolic Health ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Metabolic Traits

Background: Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods We performed three analyses: 1) cardio-metabolic health to lung function association tests in NFBC1966, 2) cross trait LD score regression to compare genetic backgrounds and 3) Mendelian Randomization (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from UK Biobank data or published large-scale genome-wide association studies (N > 82,000). Results We observed negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR) we found associations between Type 2 Diabetes instruments and FVC as well as FEV1/FVC. BMI instruments were associated to all lung function traits and CRP instruments to FVC. These genetic association provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Conclusions: The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being mediated by CRP. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

scholarly journals Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Matthias Wielscher ◽  
Andre F. S. Amaral ◽  
Diana van der Plaat ◽  
Louise V. Wain ◽  
Sylvain Sebert ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Lung Function ◽  
Genetic Correlation ◽  
Causal Effect ◽  
Association Studies ◽  
Metabolic Health ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Metabolic Traits

Abstract Background Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000). Results We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Conclusions The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

scholarly journals Genomics-driven drug discovery based on disease-susceptibility genes

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Kyuto Sonehara ◽  
Yukinori Okada
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Disease Susceptibility ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Drug Repurposing ◽  
Susceptibility Genes ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Disease Associations

AbstractGenome-wide association studies have identified numerous disease-susceptibility genes. As knowledge of gene–disease associations accumulates, it is becoming increasingly important to translate this knowledge into clinical practice. This challenge involves finding effective drug targets and estimating their potential side effects, which often results in failure of promising clinical trials. Here, we review recent advances and future perspectives in genetics-led drug discovery, with a focus on drug repurposing, Mendelian randomization, and the use of multifaceted omics data.

scholarly journals Pulmonary function and risk of Alzheimer dementia: two-sample Mendelian randomization study

2020 ◽  
Author(s):  
Tom C. Russ ◽  
Sarah E. Harris ◽  
G. David Batty
Keyword(s):  
Pulmonary Function ◽  
Causal Effect ◽  
Association Studies ◽  
Forced Expiratory Volume ◽  
Health Concern ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Global Public Health ◽  
Alzheimer Dementia ◽  
Dementia Risk

ABSTRACTDementia is a major global public health concern and in addition to recognised risk factors there is emerging evidence that poorer pulmonary function is linked with subsequent dementia risk. However, it is unclear if this observed association is causal or whether it might result from confounding. Therefore, we present the first two-sample Mendelian randomisation study of the association between pulmonary function and Alzheimer dementia using the most recent genome-wide association studies to produce instrumental variables for both. We found no evidence of a causal effect of reduced Forced Expiratory Volume in 1 second (FEV1) or Forced Vital Capacity (FVC) on Alzheimer dementia risk (both P>0.35). However, the FEV1/FVC ratio was associated with Alzheimer dementia risk with, in fact, superior function predicting an increased dementia risk (OR 1.12, 95%CI 1.02-1.23; P=0.016) which may result from survivor bias. While we can conclude that there is no causal link between impaired pulmonary function and Alzheimer dementia, our study sheds less light on potential links with other types of dementia.

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 A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic etiology with obesity

2021 ◽  
pp. 2100199
Author(s):  
Zhaozhong Zhu ◽  
Jiachen Li ◽  
Jiahui Si ◽  
Baoshan Ma ◽  
Huwenbo Shi ◽  
...  
Keyword(s):  
Lung Function ◽  
Large Scale ◽  
Causal Effect ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genetic Etiology ◽  
Trait Analysis ◽  
Genome Wide ◽  
Shared Genetic

Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, the knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWAS in other populations are lacking.We included 100 285 subjects from China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS were performed on FEV1, FVC, FEV1/FVC in CKB. We then performed genome-wide cross-trait analysis between the lung function and obesity traits (body mass index [BMI], BMI-adjusted waist-to-hip ratio, and BMI-adjusted waist circumference) to investigate the shared genetic effects in CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in CKB and its interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with CKB using 457 756 subjects from UK Biobank (UKB) for replication and investigation of ancestry specific effect.We identified 9 genome-wide significant novel loci for FEV1, 6 for FVC and 3 for FEV1/FVC in CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important pathways, including cell proliferation, embryo and tissue development. Mendelian randomisation analysis suggested significant negative causal effect of BMI on FEV1 and on FVC in both CKB and UKB. Lung function PRSs significantly modified the effect of change-in-BMI on change-in-lung function during an average follow-up of 8 years.This large-scale GWAS of lung function identified novel loci and shared genetic etiology between lung function and obesity. Change-in-BMI might affect change-in-lung function differently according to a subject's polygenic background. These findings may open new avenue for the development of molecular-targeted therapies for obesity and lung function improvement.

scholarly journals New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

2018 ◽  
Author(s):  
Nick Shrine ◽  
Anna L Guyatt ◽  
A Mesut Erzurumluoglu ◽  
Victoria E Jackson ◽  
Brian D Hobbs ◽  
...  
Keyword(s):  
Lung Function ◽  
Drug Targets ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
European Ancestry ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
A Genome ◽  
Disease Associations ◽  
Never Smokers

AbstractReduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

The CRP genotype, serum levels and lung function in men: the Caerphilly Prospective Study

2010 ◽  
Vol 120 (8) ◽  
pp. 347-355 ◽  
Author(s):  
Charlotte E. Bolton ◽  
Wiebke Schumacher ◽  
John R. Cockcroft ◽  
Nicholas J. Timpson ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Lung Function ◽  
Prospective Study ◽  
Causal Effect ◽  
Serum Levels ◽  
Forced Expiratory Volume ◽  
Reverse Causality ◽  
Lung Function Decline ◽  
Impaired Lung Function ◽  
Serum Crp

Systemic CRP (C-reactive protein) has been associated with impaired lung function. A causal relationship would increase the value of CRP as both a diagnostic and therapeutic tool. We assessed the association between lung function parameters, circulating CRP and CRP polymorphisms using Mendelian randomization in efforts to attribute causality to known associations. Spirometric parameters of FEV1 (forced expiratory volume in 1 s) and FVC (forced vital capacity) were determined in 2173 men participating in the Caerphilly Prospective Study. Lung function measures on 1021 participants were available at follow-up (mean, 16.8 years later). Serum CRP levels were measured at baseline, and three CRP polymorphisms were analysed. Haplotype analysis was performed. Serum CRP levels at baseline were inversely associated with contemporaneous FEV1 and FVC as well as at follow-up (P<0.001) even after adjustment for conventional confounders. Serum CRP was associated with FEV1 decline (P=0.04). All three CRP polymorphisms (rs1800947, rs1130864 and rs1205) predicted serum CRP; however, there were no clear associations of the polymorphisms or haplotypes with lung function or with lung function decline. In conclusion, serum CRP was associated with lung function cross-sectionally; however, CRP polymorphisms were not associated with lung function or decline, suggesting that the CRP–lung function relationship is due to reverse causality, an unmeasured confounding factor or only has a modest causal effect.

scholarly journals Investigating the potential effect of antihypertensive medication on psychiatric disorders: a mendelian randomisation study

2020 ◽  
Author(s):  
Solal Chauquet ◽  
Michael O’Donovan ◽  
James Walters ◽  
Naomi Wray ◽  
Sonia Shah
Keyword(s):  
Psychiatric Disorders ◽  
Drug Target ◽  
Drug Exposure ◽  
Causal Effect ◽  
Association Studies ◽  
Neuropsychiatric Symptoms ◽  
Potential Effect ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Increased Risk

ABSTRACTBackgroundThere is growing evidence from observational studies that drugs used for the prevention and treatment of CVD may cause, exacerbate, or relieve neuropsychiatric symptoms.AimUse Mendelian randomisation (MR) analysis to investigate the potential effect of different antihypertensive drugs on schizophrenia, bipolar disorder and major depressive disorder.MethodsWe conduct two sample MR using expression quantitative trait loci (eQTLs) for antihypertensive drug target genes as genetic instruments, together with summary data from published genome-wide association studies, to investigate the causal effect of changes in drug target gene expression (as proxies of drug exposure) on psychiatric disorders.ResultsA 1 standard deviation lower expression of the ACE gene in blood was associated with 4.0 mmHg (95% CI = 2.7 – 5.3) lower systolic blood pressure, but increased risk of schizophrenia (OR (95% CI) = 1.75 (1.28 – 2.38)). A concordant direction of effect was observed with ACE expression in brain tissue.ConclusionsFindings suggest an adverse effect of lower ACE expression on schizophrenia risk. This warrants further investigation to determine if lowering ACE activity for treatment of hypertension using ACE inhibitors (particularly centrally-acting drugs) may worsen symptoms in patients with schizophrenia, and whether there is any association between ACE inhibitor use and risk of (mainly late-onset) schizophrenia.

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