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.

Clearing the air: Empowering high-risk adults with digital tools for smoking cessation and lung cancer screening adoption.

Background: Even though lung cancer screening decreases mortality, uptake remain low. Research has focused on integrating smoking cessation into lung cancer screening programs rather than providing lung cancer screening education to eligible adults. Engaging individuals who are at high-risk for lung cancer and educating them about lung cancer screening is a critical next step.

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.

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.

Knowledge, Interest and Recommendations for Receipt of Polygenetic Risk Scores Among Adults Who Smoked Long-Term: A Descriptive Qualitative Analysis.

Objective: Researchers strive to develop more precise prediction models to understand smoking behaviors, facilitate tailored tobacco treatment and improve early detection of lung cancer, including the use of polygenic risk scores (PRS). This study aimed to better understand participants' knowledge, interest and recommendations for receipt of PRS information. Its specific aims were to (1) describe participants' knowledge and interest in obtaining PRS in the context of smoking behaviors, tobacco treatment and/or early detection of lung cancer and (2) identify patient-reported recommendations for incorporating genetic risk information into clinical care.

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.

A generalized higher-order correlation analysis framework for multi-omics network inference.

Multiple -omics (genomics, proteomics, etc.) profiles are commonly generated to gain insight into a disease or physiological system. Constructing multi-omics networks with respect to the trait(s) of interest provides an opportunity to understand relationships between molecular features but integration is challenging due to multiple data sets with high dimensionality.

Biosurfer for systematic tracking of regulatory mechanisms leading to protein isoform diversity.

Long-read RNA-seq has shed light on transcriptomic complexity, but questions remain about the functionality of downstream protein products. We introduce Biosurfer, a computational approach for comparing protein isoforms, while systematically tracking the transcriptional, splicing, and translational variations that underlie differences in the sequences of the protein products. Using Biosurfer, we analyzed the differences in 35,082 pairs of GENCODE annotated protein isoforms, finding a majority (70%) of variable N-termini are due to the alternative transcription start sites, while only 9% arise from 5' UTR alternative splicing (AS).

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.

HHIP protein interactions in lung cells provide insight into COPD pathogenesis.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes.

Computational deconvolution of cell type-specific gene expression in COPD and IPF lungs reveals disease severity associations.

Background: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n > 1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity.

Distinct physiological, transcriptomic, and imaging characteristics of asthma-COPD overlap compared to asthma and COPD in smokers.

Background: The clinical and pathological features of asthma and chronic obstructive pulmonary disease (COPD) can converge in smokers and elderly individuals as asthma-COPD overlap (ACO). This overlap challenges the diagnosis and treatment of the distinct aetiologies underlying these conditions.

Methods: We analysed 2453 smokers (≥10 pack-years), aged 45-80 years, from the Genetic Epidemiology of COPD (COPDGene) Study, stratified as Control, Asthma, COPD, and ACO based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies.

Background: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

Methods: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets.

Partial correlation network analysis identifies coordinated gene expression within a regional cluster of COPD genome-wide association signals.

Chronic obstructive pulmonary disease (COPD) is a complex disease influenced by well-established environmental exposures (most notably, cigarette smoking) and incompletely defined genetic factors. The chromosome 4q region harbors multiple genetic risk loci for COPD, including signals near HHIP, FAM13A, GSTCD, TET2, and BTC. Leveraging RNA-Seq data from lung tissue in COPD cases and controls, we estimated the co-expression network for genes in the 4q region bounded by HHIP and BTC (~70MB), through partial correlations informed by protein-protein interactions.

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, dual-use, COPD-related outcomes, and demographic factors.

Temporal Exploration of Chronic Obstructive Pulmonary Disease Phenotypes: Insights from the COPDGene and SPIROMICS Cohorts.

Chronic obstructive pulmonary disease (COPD) exhibits considerable progression heterogeneity. We hypothesized that elastic principal graph analysis (EPGA) would identify distinct clinical phenotypes and their longitudinal relationships. Our primary objective was to create a map of COPD phenotypes and their connectivity using EPGA.