Multi-Trait Polygenic Scores for COPD and COPD Exacerbations Implicate Druggable Proteins.

Objectives: To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting.

Design: Prospective cohort studies.

Setting: Genetic Epidemiology of COPD (COPDGene; 2007-present), Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE; 2005-2008), Mass General Brigham Biobank (MGBB; 2010-present), All of Us (2016-present), and UK Biobank (UKB; 2006-present).

Overlap between COPD genetic association results and transcriptional quantitative trait loci.

Genome-wide association studies (GWAS) have identified multiple genetic loci associated with chronic obstructive pulmonary disease (COPD). Here, we identify SNPs that are associated with alternative splicing (sQTL) and gene expression (eQTLs) to identify functions for COPD associated genetic variants. RNA sequencing on whole blood from 3743 subjects in the COPDGene Study and from lung tissue of 1241 subjects from the Lung Tissue Research Consortium (LTRC) was analyzed.

Mosaic Loss of Y chromosome associates with lung function, emphysema and epigenetic aging.

Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mutation, but its relationship with pulmonary health remains undercharacterized. Leveraging mLOY assessment in over 12,000 men, including 5,097 from the COPDGene Study and 7,235 from six additional cohorts in Trans-Omics for Precision Medicine program, we investigated its association with respiratory outcomes and epigenetic aging. Cross-sectionally, mLOY was associated with airflow obstruction with prevalence increasing with age, particularly in men with a former smoking history.

Visual and Quantitative Interstitial Lung Abnormality Progression in COPDGene.

Rationale: Interstitial lung abnormalities (ILA) are visually identified changes on chest computed tomography (CT) scans that may represent early/mild pulmonary fibrosis. Quantitative interstitial abnormalities (QIA) measure potential parenchymal lung injury on chest CT scans using an automated algorithm. It is not known if combining these visual and quantitative assessments improves prediction of imaging progression.

miRNA-mRNA network analysis identifies PAX5 as a potential regulator of adaptive immune response in COPD.

Micro-ribonucleic acids (miRNAs) are key post-transcriptional regulators of the immune system and may play a role in Chronic Obstructive Pulmonary Disease (COPD). In this paper, we constructed subject-specific miRNA-mRNA regulatory networks using bulk and deconvoluted whole blood RNA-sequencing, whole blood miRNA-sequencing, and B-cell receptor-sequencing data from up to 570 miRNAs, 11,859 mRNAs, and 3,190 participants in the COPDGene study. Analysis of whole blood networks revealed two subnetworks of miRNA-mRNA interactions significantly (FDR<0.

Towards early detection and disease interception of COPD across the lifespan.

COPD is "a heterogeneous lung condition characterized by chronic respiratory symptoms due to abnormalities of the airways and/or alveoli that cause persistent, often progressive, airflow obstruction". COPD has been traditionally associated with tobacco smoking and accelerated lung function decline. However, our understanding of the pathogenesis of COPD has changed significantly over the past few years due to the recognition that different lung function trajectories starting in early life and progressing across the lifespan are also important pathways to COPD.

Deep Learning of Suboptimal Spirometry to Predict Respiratory Outcomes and Mortality.

Importance: Obtaining spirometry requires repeated testing and using the maximal values based on quality control criteria. Whether the suboptimal efforts are useful for the prediction of respiratory outcomes is not clear.

Objective: To determine whether a machine learning model could predict respiratory outcomes and mortality based on suboptimal spirometry.

Interstitial Lung Abnormalities, Coronary Heart Disease, and Mortality.

Background: Interstitial lung abnormalities (ILA) share common risk factors with coronary heart disease (CHD), including increased age and cigarette smoking, however the relationship between ILA and CHD has not been well described.

Methods: Participants from the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease study (COPDGene) and Age Gene/Environment Susceptibility (AGES)-Reykjavik studies with ILA assessment, clinical CHD, and coronary artery calcium (CAC) data were included. In both cohorts, CHD was defined by clinical history and additionally by CAC>100.

Ancestry Calibration of Polygenic Risk Scores Improves Risk Stratification and Effect Estimation in African American Adults.

Polygenic risk score (PRS) distributions vary across populations, complicating PRS risk assessment. We evaluated the impact of PRS calibration according to individualized genetic ancestry estimates on PRS performance using two large multi-ethnic PRS for type 2 diabetes (T2D) (PRS) and height (PRS), in 8,841 African American (AA) individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. We calibrated each participant's score as a function of estimated genetic similarity to the Yoruba (GSYRI) cohort in the 1000 Genomes Project.

Proteomic biomarkers of emphysema-predominant and non-emphysema-predominant chronic obstructive pulmonary disease.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a complex and heterogeneous disease. Emphysema-predominant and non-emphysema predominant COPD are two major disease subtypes capturing important aspects of COPD heterogeneity. Molecular differences between these COPD subtypes are unknown.

Omic Risk Scores are Associated with COPD-related Traits Across Three Cohorts.

Background: Chronic obstructive pulmonary disease (COPD) exhibits marked heterogeneity in lung function decline, mortality, exacerbations, and other disease-related outcomes. Omic risk scores (ORS) estimate the cumulative contribution of omics, such as the transcriptome, proteome, and metabolome, to a particular trait. This study evaluates the predictive value of ORS for COPD-related traits in both smoking-enriched and general population cohorts.

B-cell immune repertoire sequencing in tobacco cigarette smoking, vaping, and chronic obstructive pulmonary disease in the COPDGene cohort.

Rationale: Cigarette smoking (CS) impairs B-cell function and antibody production, increasing infection risk. The impact of e-cigarette use ('vaping') and combined CS and vaping ('dual-use') on B-cell activity is unclear.

Objective: To examine B-cell receptor sequencing (BCR-seq) profiles associated with CS, vaping, and dual-use.

Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.

Background: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

Methods: Computationally predicted damaging or loss-of-function (REVEL > 0.

Polygenic risk scores for rheumatoid arthritis and idiopathic pulmonary fibrosis and associations with RA, interstitial lung abnormalities, and quantitative interstitial abnormalities among smokers.

Objective: Genome-wide association studies (GWAS) facilitate construction of polygenic risk scores (PRSs) for rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). We investigated associations of RA and IPF PRSs with RA and high-resolution chest computed tomography (HRCT) parenchymal lung abnormalities.

Methods: Participants in COPDGene, a prospective multicenter cohort of current/former smokers, had chest HRCT at study enrollment.

Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B.

Cross-cohort analysis of expression and splicing quantitative trait loci in TOPMed.

Most genetic variants associated with complex traits and diseases occur in non-coding genomic regions and are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterize 14,324 ancestrally diverse RNA-sequencing samples from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and integrate whole genome sequencing data to perform and expression and splicing quantitative trait locus (-/trans-e/sQTL) analyses in six tissues and cell types, most notably whole blood (N=6,454) and lung (N=1,291). We show this dataset enables greater detection of secondary cis-e/sQTL signals than was achieved in previous studies, and that secondary cis-eQTL and primary trans-eQTL signal discovery is not saturated even though eGene discovery is.

Identifying chronic obstructive pulmonary disease subtypes using multi-trait genetics.

Background: Chronic Obstructive Pulmonary Disease (COPD) has a broad spectrum of clinical characteristics. The aetiology of these differences is not well understood. The objective of this study is to assess whether respiratory genetic variants cluster by phenotype and associate with COPD heterogeneity.

Characterisation of a COPD-associated nephronectin () functional splicing genetic variant in human lung tissue long-read sequencing.

Background: Identification of COPD disease-causing genes is an important tool for understanding why COPD develops, who is at highest COPD risk and how new COPD treatments can be developed. Previous COPD genetic studies have identified a highly significant genetic association near (nephronectin), a gene involved in tissue repair, but the biological mechanisms underlying this association are unknown.

Methods: Splicing quantitative trait locus (sQTL) analysis was performed to identify common genetic variants that alter RNA splicing in lung tissues.

The Association of Interstitial Lung Abnormalities and Preserved Ratio Impaired Spirometry With Mortality.

Background: Preserved ratio impaired spirometry (PRISm) findings are heterogeneous and include restrictive lung disease. Interstitial lung abnormalities (ILAs) may represent early interstitial lung disease. The relationship between PRISm and ILAs is not well understood.

Missing Regulation Between Genetic Association and Transcriptional Abundance for Hypercholesterolemia Genes.

Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease, and it plays a causal role in the development of atherosclerosis. Genome-wide association studies (GWASs) have successfully identified hundreds of genetic variants associated with LDL-C. Most of these risk loci fall in non-coding regions of the genome, and it is unclear how these non-coding variants affect circulating lipid levels.

Polygenic Risk Score Added to Conventional Case Finding to Identify Undiagnosed Chronic Obstructive Pulmonary Disease.

Importance: Chronic obstructive pulmonary disease (COPD) is often undiagnosed. Although genetic risk plays a significant role in COPD susceptibility, its utility in guiding spirometry testing and identifying undiagnosed cases is unclear.

Objective: To determine whether a COPD polygenic risk score (PRS) enhances the identification of undiagnosed COPD beyond a case-finding questionnaire (eg, the Lung Function Questionnaire) using conventional risk factors and respiratory symptoms.