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

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.

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

Genome Medicine ◽

10.1186/s13073-021-00914-x ◽

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.

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

European Respiratory Journal ◽

10.1183/13993003.00199-2021 ◽

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.

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

10.1101/2020.12.15.20248279 ◽

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.

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No Causal Association Between Adiponectin and the Risk of Rheumatoid Arthritis: A Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.670282 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hanzhu Chen ◽

Shuai Mi ◽

Jiahao Zhu ◽

Weidong Jin ◽

Yasong Li ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Genetic Correlation ◽

Causal Relationship ◽

Large Scale ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

Reverse Direction ◽

Genome Wide Association Studies

Background: Accumulating evidence from observational studies suggested that circulating adiponectin levels are associated with the risk of rheumatoid arthritis (RA), but the causality remains unknown. We aimed to assess the causal relationship of adiponectin with RA risk.Methods: Based on summary statistics from large-scale genome-wide association studies (GWAS), we quantified the genetic correlation between adiponectin and RA. Then bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship. Twenty single-nucleotide polymorphisms (SNPs) associated with adiponectin were selected as instrumental variables from a recent GWAS (n = 67,739). We applied theses SNPs to a large-scale GWAS for RA (14,361 cases and 43,923 controls) with replication using RA data from the FinnGen consortium (6,236 cases and 147,221 controls) and the UK Biobank (5,201 cases and 457,732 controls). The inverse-variance weighted (IVW) and multiple pleiotropy-robust methods were used for two-sample MR analyses.Results: Our analyses showed no significant genetic correlation between circulating adiponectin levels and RA [rG = 0.127, 95% confidence interval (CI): –0.012 to 0.266, P = 0.074]. In MR analyses, genetically predicted adiponectin levels were not significantly associated with the RA risk (odds ratio: 0.98, 95% CI: 0.88–1.09, P = 0.669). In the reverse direction analysis, there is little evidence supporting an association of genetic susceptibility to RA with adiponectin (β: 0.007, 95% CI: –0.003 to 0.018, P = 0.177). Replication analyses and sensitivity analyses using different models yielded consistent results.Conclusions: Our findings provided no evidence to support the causal effect of adiponectin levels on RA risk and of RA on circulating adiponectin levels.

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

10.1101/2020.07.28.20163352 ◽

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.

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Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study

Psychological Medicine ◽

10.1017/s0033291719002678 ◽

2019 ◽

Vol 50 (14) ◽

pp. 2435-2443 ◽

Cited By ~ 29

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.

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

10.1101/2020.06.25.20139816 ◽

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.

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Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

PLoS ONE ◽

10.1371/journal.pone.0100776 ◽

2014 ◽

Vol 9 (7) ◽

pp. e100776 ◽

Cited By ~ 41

Author(s):

Wenbo Tang ◽

Matthew Kowgier ◽

Daan W. Loth ◽

María Soler Artigas ◽

Bonnie R. Joubert ◽

...

Keyword(s):

Lung Function ◽

Large Scale ◽

Association Studies ◽

Genome Wide Association ◽

Longitudinal Change ◽

Genome Wide Association Studies ◽

Adult Lung ◽

Genome Wide ◽

Meta Analyses

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

10.1101/2020.03.19.20039412 ◽

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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A comprehensive gene-centric pleiotropic association analysis for 14 psychiatric disorders with GWAS summary statistics

BMC Medicine ◽

10.1186/s12916-021-02186-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Haojie Lu ◽

Jiahao Qiao ◽

Zhonghe Shao ◽

Ting Wang ◽

Shuiping Huang ◽

...

Keyword(s):

Psychiatric Disorders ◽

Genetic Correlation ◽

Large Scale ◽

Association Studies ◽

Single Gene ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Nucleotide Polymorphisms ◽

Entire Genome ◽

Gene Level

Abstract Background Recent genome-wide association studies (GWASs) have revealed the polygenic nature of psychiatric disorders and discovered a few of single-nucleotide polymorphisms (SNPs) associated with multiple psychiatric disorders. However, the extent and pattern of pleiotropy among distinct psychiatric disorders remain not completely clear. Methods We analyzed 14 psychiatric disorders using summary statistics available from the largest GWASs by far. We first applied the cross-trait linkage disequilibrium score regression (LDSC) to estimate genetic correlation between disorders. Then, we performed a gene-based pleiotropy analysis by first aggregating a set of SNP-level associations into a single gene-level association signal using MAGMA. From a methodological perspective, we viewed the identification of pleiotropic associations across the entire genome as a high-dimensional problem of composite null hypothesis testing and utilized a novel method called PLACO for pleiotropy mapping. We ultimately implemented functional analysis for identified pleiotropic genes and used Mendelian randomization for detecting causal association between these disorders. Results We confirmed extensive genetic correlation among psychiatric disorders, based on which these disorders can be grouped into three diverse categories. We detected a large number of pleiotropic genes including 5884 associations and 2424 unique genes and found that differentially expressed pleiotropic genes were significantly enriched in pancreas, liver, heart, and brain, and that the biological process of these genes was remarkably enriched in regulating neurodevelopment, neurogenesis, and neuron differentiation, offering substantial evidence supporting the validity of identified pleiotropic loci. We further demonstrated that among all the identified pleiotropic genes there were 342 unique ones linked with 6353 drugs with drug-gene interaction which can be classified into distinct types including inhibitor, agonist, blocker, antagonist, and modulator. We also revealed causal associations among psychiatric disorders, indicating that genetic overlap and causality commonly drove the observed co-existence of these disorders. Conclusions Our study is among the first large-scale effort to characterize gene-level pleiotropy among a greatly expanded set of psychiatric disorders and provides important insight into shared genetic etiology underlying these disorders. The findings would inform psychiatric nosology, identify potential neurobiological mechanisms predisposing to specific clinical presentations, and pave the way to effective drug targets for clinical treatment.

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