scholarly journals Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

2020 ◽  
Author(s):  
Joao Fadista ◽  
Luke M. Kraven ◽  
Juha Karjalainen ◽  
Shea J. Andrews ◽  
Frank Geller ◽  
...  
Keyword(s):  
Risk Factors ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Genetic Correlation ◽  
Risk Allele ◽  
Causal Effect ◽  
Association Studies ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Increased Risk

Background. Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. Methods. We performed a Mendelian randomisation (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5x10-8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative. The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. Findings. We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0.31 [95% CI 0.04-0.57], P = 0.023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1.05, [95% CI 0.92-1.20], P = 0.43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1.21, [95% CI 1.06-1.38], P = 4.24x10-3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0.86, [95% CI 0.73-1.00], P = 2.99x10-2) . Interpretation. The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors.

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.

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 The role of obesity in female reproductive conditions: A Mendelian Randomisation Study

2021 ◽  
Author(s):  
Samvida S. Venkatesh ◽  
Teresa Ferreira ◽  
Stefania Benonisdottir ◽  
Nilufer Rahmioglu ◽  
Christian M. Becker ◽  
...  
Keyword(s):  
Causal Effect ◽  
Association Studies ◽  
Overweight And Obesity ◽  
Additive Models ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Reproductive Disorders ◽  
Metabolic Hormones ◽  
Genetic Components ◽  
Increased Risk

Background: Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Methods and Findings: We estimated observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive conditions using logistic regression, generalised additive models, and Mendelian randomisation (two-sample, non-linear, and multivariable) applied to data from UK Biobank and publicly available genome-wide association studies (GWAS). Body mass index (BMI), waist-hip ratio (WHR), and WHR adjusted for BMI (WHRadjBMI) were observationally (odds ratios (ORs) = 1.02 - 1.87 per 1 S.D. obesity trait) and causally (ORs = 1.06 - 2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Causal effect estimates of WHR and WHRadjBMI, but not BMI, were attenuated compared to their observational counterparts. Genetically predicted visceral adipose tissue mass was causal for the development of HMB, PCOS, and pre-eclampsia (ORs = 1.01 - 3.38). Increased waist circumference also posed a higher causal risk (ORs = 1.16 - 1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06 - 1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% - 50% of the total causal effect of obesity on pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. Conclusions: In this first systematic, large-scale, genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions, we found that common indices of overall and central obesity increased risk of reproductive disorders to heterogenous extents, mediated by metabolic hormones. Our results suggest exploring the mechanisms mediating the causal effects of overweight and obesity on gynaecological health to identify targets for disease prevention and treatment.

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 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 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 Evaluating the effects of alcohol and tobacco use on cardiovascular disease using multivariable Mendelian randomization

2019 ◽  
Author(s):  
Daniel B. Rosoff ◽  
George Davey Smith ◽  
Nehal Mehta ◽  
Toni-Kim Clarke ◽  
Falk W. Lohoff
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Alcohol Use ◽  
Tobacco Use ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Cvd Risk ◽  
Increased Risk

ABSTRACTAlcohol and tobacco use, two major modifiable risk factors for cardiovascular disease (CVD), are often consumed together. Using large publicly available genome-wide association studies (results from > 940,000 participants), we conducted two-sample multivariable Mendelian randomization (MR) to simultaneously assess the independent effects of alcohol and tobacco use on CVD risk factors and events. We found genetic instruments associated with increased alcohol use, controlling for tobacco use, associated with increased high-density-lipoprotein-cholesterol (HDL-C), decreased triglycerides, but not with coronary heart disease (CHD), myocardial infarction (MI), nor stroke; and instruments for increased tobacco use, controlling for alcohol use, associated with decreased HDL-C, increased triglycerides, and increased risk of CHD and MI. Exploratory analysis found associations with HDL-C, LDL-C, and intermediate-density-lipoprotein metabolites. Consistency of results across complementary methods accommodating different MR assumptions strengthened causal inference, providing strong genetic evidence for the causal effects of modifiable lifestyle risk factors on CVD risk.

scholarly journals Genetic overlap between idiopathic pulmonary fibrosis and COVID−19

2021 ◽  
Author(s):  
Richard J Allen ◽  
Beatriz Guillen-Guio ◽  
Emma Croot ◽  
Luke M Kraven ◽  
Samuel Moss ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Biological Processes ◽  
Genetic Loci ◽  
Genome Wide ◽  
Genetic Overlap ◽  
Causal Variants ◽  
Shared Genetic

AbstractGenome-wide association studies (GWAS) of coronavirus disease 2019 (COVID-19) and idiopathic pulmonary fibrosis (IPF) have identified genetic loci associated with both traits, suggesting possible shared biological mechanisms. Using updated GWAS of COVID-19 and IPF, we evaluated the genetic overlap between these two diseases and identified four genetic loci (including one novel) with likely shared causal variants between severe COVID-19 and IPF. Although there was a positive genetic correlation between COVID-19 and IPF, two of these four shared genetic loci had an opposite direction of effect. IPF-associated genetic variants related to telomere dysfunction and spindle assembly showed no association with COVID-19 phenotypes. Together, these results suggest there are both shared and distinct biological processes driving IPF and severe COVID-19 phenotypes.

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 Causal Inference for Heritable Phenotypic Risk Factors Using Heterogeneous Genetic Instruments

2020 ◽  
Author(s):  
Jingshu Wang ◽  
Qingyuan Zhao ◽  
Jack Bowden ◽  
Gilbran Hemani ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Risk Factors ◽  
Complex Traits ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Genome Wide ◽  
Genetic Instruments

Over a decade of genome-wide association studies have led to the finding that significant genetic associations tend to spread across the genome for complex traits. The extreme polygenicity where "all genes affect every complex trait" complicates Mendelian Randomization studies, where natural genetic variations are used as instruments to infer the causal effect of heritable risk factors. We reexamine the assumptions of existing Mendelian Randomization methods and show how they need to be clarified to allow for pervasive horizontal pleiotropy and heterogeneous effect sizes. We propose a comprehensive framework GRAPPLE (Genome-wide mR Analysis under Pervasive PLEiotropy) to analyze the causal effect of target risk factors with heterogeneous genetic instruments and identify possible pleiotropic patterns from data. By using summary statistics from genome-wide association studies, GRAPPLE can efficiently use both strong and weak genetic instruments, detect the existence of multiple pleiotropic pathways, adjust for confounding risk factors, and determine the causal direction. With GRAPPLE, we analyze the effect of blood lipids, body mass index, and systolic blood pressure on 25 disease outcomes, gaining new information on their causal relationships and the potential pleiotropic pathways.

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