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.

scholarly journals Genetic associations and architecture of asthma-chronic obstructive pulmonary disease overlap

2020 ◽  
Author(s):  
C. John ◽  
A.L. Guyatt ◽  
N. Shrine ◽  
R. Packer ◽  
T.A. Olafsdottir ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
European Ancestry ◽  
Chronic Obstructive ◽  
Genetic Associations ◽  
Obstructive Pulmonary Disease ◽  
Genome Wide ◽  
A Genome ◽  
Stage 1

AbstractSome individuals have characteristics of both asthma and COPD (asthma-COPD overlap, ACO), and evidence suggests they experience worse outcomes than those with either condition alone. Improved knowledge of the genetic architecture would contribute to understanding whether determinants of risk in this group differ from those in COPD or asthma.We conducted a genome-wide association study in 8,068 cases and 40,360 controls of European ancestry from UK Biobank (stage 1). After excluding variants only associated with asthma or COPD we selected 31 variants for further investigation in 12 additional cohorts (stage 2), and discovered eight novel signals for ACO in a meta-analysis of stage 1 and 2 studies.Our signals include an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function, and suggest a spectrum of shared and distinct genetic influences in asthma, COPD and ACO. A number of signals may represent loci that predispose to serious long-term consequences in people with asthma.

scholarly journals Integrative Omics Reveal Novel Protein Targets For Chronic Obstructive Pulmonary Disease Biomarker Discovery

2021 ◽  
Author(s):  
Ana I Hernandez Cordero ◽  
Stephen Milne ◽  
Chen Xi Yang ◽  
Xuan Li ◽  
Henry Shi ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Lung Function ◽  
Pulmonary Disease ◽  
Biomarker Discovery ◽  
Association Studies ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Obstructive Pulmonary Disease ◽  
Integrative Omics

AbstractBackgroundLarge genome-wide association studies (GWAS) and other genetic studies have revealed genetic loci that are associated with chronic obstructive pulmonary disease (COPD). However, the proteins responsible for COPD pathogenesis remain elusive. We used integrative-omics by combining genetics of lung function and COPD with genetics of proteome to identify proteins underlying lung function variation and COPD risk.MethodsWe used summary statistics from the GWAS of human plasma proteome from the INTERVAL cohort (n=3,301) and integrated these data with lung function GWAS results from the UK Biobank cohorts (n=400,102) and COPD GWAS results from the ICGC cohort (35,735 cases and 222,076 controls). We performed in parallel: a proteome-wide Bayesian colocalization, and a proteome-wide Mendelian Randomization (MR) analyses. Next, we selected proteins that colocalized with lung function and/or COPD risk and explored their causal association with lung function and/or COPD using MR analysis (P<0.05).ResultsWe found 537, 607, and 250 proteins that colocalized with force expiratory volume in one second (FEV1), FEV1/forced vital capacity (FVC), or COPD risk, respectively. Of these, 1,051 were unique proteins. The sRAGE protein demonstrated the strongest colocalization with FEV1/FVC and COPD risk, while QSOX2, FAM3D and F177A proteins had the strongest associations with FEV1. Of these, 37 proteins that colocalized with lung function and/or COPD, also had a significant causal association. These included proteins such as PDE4D, QSOX2 and RGAP1, amongst others.ConclusionIntegrative-omics reveals new proteins related to lung function. These proteins may play important roles in the pathogenesis of COPD.

scholarly journals Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations

2018 ◽  
Author(s):  
Phuwanat Sakornsakolpat ◽  
Dmitry Prokopenko ◽  
Maxime Lamontagne ◽  
Nicola F. Reeve ◽  
Anna L. Guyatt ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Lung Function ◽  
Pulmonary Disease ◽  
Genetic Risk ◽  
Chronic Obstructive ◽  
Alveolar Type ◽  
Imaging Features ◽  
Cell Type ◽  
Obstructive Pulmonary Disease ◽  
A Genome

SummaryChronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5×10−8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

scholarly journals Global biobank analyses provide lessons for computing polygenic risk scores across diverse cohorts

2021 ◽  
Author(s):  
Ying Wang ◽  
Shinichi Namba ◽  
Esteban Lopera ◽  
Sini Kerminen ◽  
Kristin Tsuo ◽  
...  
Keyword(s):  
Best Practices ◽  
Prediction Accuracy ◽  
Disease Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
Risk Scores ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Polygenic Risk

SummaryWith the increasing availability of biobank-scale datasets that incorporate both genomic data and electronic health records, many associations between genetic variants and phenotypes of interest have been discovered. Polygenic risk scores (PRS), which are being widely explored in precision medicine, use the results of association studies to predict the genetic component of disease risk by accumulating risk alleles weighted by their effect sizes. However, limited studies have thoroughly investigated best practices for PRS in global populations across different diseases. In this study, we utilize data from the Global-Biobank Meta-analysis Initiative (GBMI), which consists of individuals from diverse ancestries and across continents, to explore methodological considerations and PRS prediction performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRS using heuristic (pruning and thresholding, P+T) and Bayesian (PRS-CS) methods. We found that the genetic architecture, such as SNP-based heritability and polygenicity, varied greatly among endpoints. For both PRS construction methods, using a European ancestry LD reference panel resulted in comparable or higher prediction accuracy compared to several other non-European based panels; this is largely attributable to European descent populations still comprising the majority of GBMI participants. PRS-CS overall outperformed the classic P+T method, especially for endpoints with higher SNP-based heritability. For example, substantial improvements are observed in East-Asian ancestry (EAS) using PRS-CS compared to P+T for heart failure (HF) and chronic obstructive pulmonary disease (COPD). Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma which has known variation in disease prevalence across global populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using the GBMI and highlight the importance of best practices for PRS in the biobank-scale genomics era.

scholarly journals Meta-analysis of exome array data identifies six novel genetic loci for lung function

2018 ◽  
Vol 3 ◽  
pp. 4 ◽  
Author(s):  
Victoria E. Jackson ◽  
Jeanne C. Latourelle ◽  
Louise V. Wain ◽  
Albert V. Smith ◽  
Megan L. Grove ◽  
...  
Keyword(s):  
Lung Function ◽  
Pulmonary Disease ◽  
Meta Analysis ◽  
African Ancestry ◽  
Regulation Of Gene Expression ◽  
Forced Expiratory Volume ◽  
European Ancestry ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Array Data

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

Respiratory traits and coal workers’ pneumoconiosis: Mendelian randomisation and association analysis

2020 ◽  
pp. oemed-2020-106610
Author(s):  
Ting Wang ◽  
Wenqing Sun ◽  
Hongyan Wu ◽  
Yuxin Cheng ◽  
Yan Li ◽  
...  
Keyword(s):  
Lung Function ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Enrichment Analysis ◽  
Normal Lung ◽  
Mendelian Randomisation ◽  
Chronic Obstructive ◽  
Susceptibility Loci ◽  
Genetic Associations ◽  
Obstructive Pulmonary Disease

ObjectivesSusceptibility loci of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease were also significantly associated with the predisposition of coal worker’s pneumoconiosis (CWP) in recent studies. However, only a few genes and loci were targeted in previous studies.MethodsTo systematically evaluate the genetic associations between CWP and other respiratory traits, we reviewed the reported genome-wide association study loci of five respiratory traits and then conducted a Mendelian randomisation study and a two-stage genetic association study.ResultsInterestingly, we found that for each SD unit, higher lung function was associated with a 66% lower risk of CWP (OR=0.34, 95% CI: 0.15 to 0.77, p=0.010) using conventional Mendelian randomisation analysis (inverse variance weighted method). Moreover, we found susceptibility loci of interstitial lung disease (rs2609255, OR=1.29, p=1.61×10−4) and lung function (rs4651005, OR=1.39, p=1.62×10−3; rs985256, OR=0.73, p=8.24×10−4 and rs6539952, OR=1.28, p=4.32×10−4) were also significantly associated with the risk of CWP. Functional annotation showed these variants were significantly associated with the expression of FAM13A (rs2609255, p=7.4 ×10−4), ANGPTL1 (rs4651005, p=5.4 ×10−7), SPATS2L (rs985256, p=1.1 ×10−5) and RP11-463O9.9 (rs6539952, p=7.1 ×10−6) in normal lung tissues, which were related to autophagy pathway simultaneously according to enrichment analysis.ConclusionsThese results provided a deeper understanding of the genetic predisposition basis of CWP.

scholarly journals The effects of marijuana smoking on lung function in older people

2019 ◽  
Vol 54 (6) ◽  
pp. 1900826 ◽  
Author(s):  
Wan C. Tan ◽  
Jean Bourbeau ◽  
Shawn D. Aaron ◽  
James C. Hogg ◽  
François Maltais ◽  
...  
Keyword(s):  
Lung Function ◽  
Population Based ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Long Term Effects ◽  
Obstructive Pulmonary Disease ◽  
Before And After ◽  
Rate Of Decline ◽  
Never Smokers

BackgroundPrevious studies have associated marijuana exposure with increased respiratory symptoms and chronic bronchitis among long-term cannabis smokers. The long-term effects of smoked marijuana on lung function remain unclear.MethodsWe determined the association of marijuana smoking with the risk of spirometrically defined chronic obstructive pulmonary disease (COPD) (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio <0.7) in 5291 population-based individuals and the rate of decline in FEV1 in a subset of 1285 males and females, aged ≥40 years, who self-reported use (or non-use) of marijuana and tobacco cigarettes and performed spirometry before and after inhaled bronchodilator on multiple occasions. Analysis for the decline in FEV1 was performed using random mixed effects regression models adjusted for age, sex and body mass index. Heavy tobacco smoking and marijunana smoking was defined as >20 pack-years and >20 joint-years, respectively.Results∼20% of participants had been or were current marijuana smokers with most having smoked tobacco cigarettes in addition (83%). Among heavy marijuana users, the risk of COPD was significantly increased (adjusted OR 2.45, 95% CI 1.55–3.88). Compared to never-smokers of marijuana and tobacco, heavy marijuana smokers and heavy tobacco smokers experienced a faster decline in FEV1 by 29.5 mL·year−1 (p=0.0007) and 21.1 mL·year−1 (p<0.0001), respectively. Those who smoked both substances experienced a decline of 32.31 mL·year−1 (p<0.0001).InterpretationHeavy marijuana smoking increases the risk of COPD and accelerates FEV1 decline in concomitant tobacco smokers beyond that observed with tobacco alone.

scholarly journals Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xutong Zhao ◽  
◽  
Dandi Qiao ◽  
Chaojie Yang ◽  
Silva Kasela ◽  
...  
Keyword(s):  
Lung Function ◽  
Genome Sequence ◽  
Molecular Mechanisms ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Chronic Obstructive ◽  
Whole Genome ◽  
Obstructive Pulmonary Disease ◽  
Family Based ◽  
The Uk

Abstract Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

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