Rare coding genetic variants may exert large effects on risk of common disease, yet their contribution to disease architecture and their utility in gene prioritization remain limited by inadequate sample sizes. Here, we performed a massive-scale rare variant association study (RVAS), analyzing over 1.1 million sequenced participants among which 130,000 had atrial fibrillation (AF). Through a multi-mask burden testing approach, we identified 15 genes significantly associated with AF through rare large-effect variation. Integrative analyses revealed strong convergence between genes implicated by rare and common variation, and highlighted instances where RVAS data may aid in GWAS prioritization. Nevertheless, several RVAS genes were not among GWAS loci ( FAM189A2 , ACTC1 , FNIP1 , FBN1 ), or were not nominated through contemporary GWAS prioritization ( KDM5B , ZFP36L2 ). Finally, we observed that ultra-rare protein-disrupting variants - concentrated in a small number of large-effect size genes - explained at least 2% of AF susceptibility across European and African ancestry groups. These findings refine the genetic architecture of AF, while highlighting the value and cost of RVAS for genomic discovery in common disease.

RATIONALE: In ever-smokers with and without chronic obstructive pulmonary disease (COPD), measures of pulmonary function and airway morphology associate with coronary artery calcification (CAC) progression, a specific feature of coronary atherosclerosis and an independent predictor of all-cause mortality. Whether these associations represent independent predictors is unknown. METHODS: Ever-smokers (n=554) (mean[SD]: 61[9] years; 44% male; 7% African American, 93% White; 49% normal spirometry; 41% COPD, 10% PRISm) from the COPDGene cohort had CAC (Agatston score) measured from chest CT scans (6.5 mSv) at phase 1 (baseline) and ∼5.5 years later. To investigate CAC initiation, the group was stratified on baseline CAC=0 or CAC>0 for analyses. Significant initiation or progression of CAC was defined as √ΔCAC>2.5. Logistic regression was performed using backwards selection, retaining variables with p-value≤0.20. Baseline covariates included age, sex, race, diagnosis or treatment for hypertension, hyperlipidemia, or diabetes, and baseline CAC. Continuous COPD phenotypes were standardized for analysis. RESULTS: Compared to those with baseline CAC>0 (n=307), those with baseline CAC=0 (n=247) were (p<0.05): younger (57[8] vs 65[8] years); more often female (54% vs 33%), African American (12% vs 3%) vs White, and current smokers (43% vs 30%); had lower smoking burden (33[26] vs 42[30] pack-years); and fewer had COPD (28% vs 51%). Among those with baseline CAC=0, 37% (n=91) initiated CAC between baseline and follow-up, which was independently predicted by lower FEV1 %predicted and FVC, or greater wall area percent, airway wall thickness, and small airway dimensions (Pi10 SRWA), but not PRM %gas trapping (p=0.48), or PRM %emphysema (p=0.49) (Table). Of those with baseline CAC>0, 81% (n=250) had CAC progression, but this was not independently predicted by spirometric or anatomic characteristics of COPD (p>0.21). CONCLUSIONS: Among ever-smokers with and without COPD, pulmonary obstruction and airway inflammatory morphology were independent predictors of CAC initiation in those with baseline CAC=0. The lack of association of pulmonary phenotypes with CAC progression in the CAC>0 group may be due to low statistical power resulting from unequal group sizes (57 non-progressors vs 250 progressors). The initiation of CAC from 0 to >0 may be driven by factors different than those resulting in CAC progression among those with existing CAC. The degree to which CAC initiation and progression represents a stabilization of non-calcified plaque warrants further investigation necessitating contrast-enhanced imaging. Nevertheless, pulmonary obstruction and airway inflammatory morphology remained independent predictors of CAC initiation after adjustment for covariates.

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. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.

Rationale: The impact of respiratory exacerbation on chronic obstructive pulmonary disease (COPD) is well established. The effects of respiratory exacerbations in people with cigarette smoking but normal spirometry are unknown. Objectives: To assess the association of respiratory exacerbations with lung function decline and mortality in people with normal spirometry and current or former cigarette smoking history. Methods: We analyzed data from COPDGene study participants with ⩾10 pack-years of cigarette smoking and normal spirometry at enrollment (Visit 1) defined as post-bronchodilator FEV1/FVC greater than or equal to the lower limit of normal and FEV1 greater than or equal to the lower limit of normal. We examined whether respiratory exacerbations occurring between Visit 1 and the 5-year follow-up visit (Visit 2) were associated with FEV1 decline and all-cause mortality. Measurements and Main Results: Among 2,939 participants with cigarette smoking history and normal lung function at Visit 1, each additional exacerbation between Visits 1 and 2 was associated with a 2.96 ml/yr FEV1 decline (95% confidence interval [CI], 1.81 to 4.12; P < 0.001) at Visit 2. Experiencing one or more severe exacerbations between Visits 1 and 2 was associated with 14.6 ml/yr FEV1 decline relative to those with no severe exacerbations (95% CI, 8.56 to 20.6; P < 0.001). Individuals with one or more severe exacerbations between Visits 1 and 2 had increased mortality compared with those with no severe exacerbations (17.1% vs. 9.8%; adjusted hazard ratio, 1.97; 95% CI, 1.40 to 2.77; P < 0.001). Conclusions: Respiratory exacerbations in people with cigarette smoking but normal spirometry were associated with lung function decline. Experiencing a severe respiratory exacerbation was associated with increased mortality.

Importance:Individuals at risk for chronic obstructive pulmonary disease (COPD) but without spirometric airflow obstruction can have respiratory symptoms and structural lung disease on chest computed tomography. Current guidelines recommend COPD diagnostic schemas that do not incorporate imaging abnormalities. Objective:To determine whether a multidimensional COPD diagnostic schema that includes respiratory symptoms and computed tomographic imaging abnormalities identifies additional individuals with disease. Design, Setting, and Participants:This cohort study included 2 longitudinal cohorts: the Genetic Epidemiology of COPD (COPDGene), which enrolled 10 305 participants between November 9, 2007, and April 15, 2011, with longitudinal follow-up through August 31, 2022; and the Canadian Cohort Obstructive Lung Disease (CanCOLD), which enrolled 1561 participants between November 26, 2009, and July 15, 2015, with follow-up through December 31, 2023. Exposure:Exposure included the new multidimensional COPD diagnostic schema, defined by (1) major diagnostic category: presence of the major criterion (airflow obstruction based on postbronchodilator forced expiratory volume in the first second of expiration [FEV1]/forced vital capacity ratio <0.70) and at least 1 of 5 minor criteria (emphysema or bronchial wall thickening on computed tomography, dyspnea, poor respiratory quality of life, and chronic bronchitis); or (2) minor diagnostic category: presence of least 3 of 5 minor criteria (which must include emphysema and bronchial wall thickening for individuals with respiratory symptoms potentially due to other causes). Main Outcomes and Measures:All-cause mortality, respiratory cause-specific mortality, exacerbations, and annualized change in FEV1. Results:Among 9416 adults in COPDGene (mean [SD] age at enrollment, 59.6 [9.0] years; 5035 [53.5%] were men; 3071 [32.6%] were Black; 6345 (67.4%) were White; 4943 [52.5%] currently smoked), 811 of 5250 individuals (15.4%) without airflow obstruction were newly classified as having COPD by minor diagnostic category, and 282 of 4166 individuals (6.8%) with airflow obstruction were classified as not having COPD. Reclassified individuals with a new COPD diagnosis had greater all-cause mortality (adjusted hazard ratio, 1.98; 95% CI, 1.67-2.35; P < .001) and respiratory-specific mortality (adjusted hazard ratio, 3.58; 95% CI, 1.56-8.20; P = .003), more exacerbations (adjusted incidence rate ratio, 2.09; 95% CI, 1.79-2.44; P < .001), and more rapid FEV1 decline (adjusted β = -7.7 mL/y; 95% CI, -13.2 to -2.3; P = .006) compared with individuals classified as not having COPD. Among individuals with airflow obstruction on spirometry, those no longer classified as having COPD based on this new diagnostic schema had outcomes similar to those without airflow obstruction. Among 1341 adults in CanCOLD, individuals newly classified as having COPD experienced more exacerbations (adjusted incidence rate ratio, 2.09; 95% CI, 1.25-3.51; P < .001). Conclusions and Relevance:A new COPD diagnostic schema integrating respiratory symptoms, respiratory quality of life, spirometry, and structural lung abnormalities on computed tomographic imaging newly classified some individuals as having COPD. These individuals had an increased risk of all-cause and respiratory-related death, frequent exacerbations, and rapid lung function decline compared with individuals classified as not having COPD. Some individuals with airflow obstruction without respiratory symptoms or evidence of structural lung disease were no longer classified as having COPD.

Background:Little information is available on iron with diabetes risk among African Americans, a population where both anemia and elevated ferritin are common. We tested whether plasma proteomic measurements of ferritin and transferrin were associated with increased diabetes risk in a cohort of current and former African American (NHB) and Non-Hispanic White (NHW) smokers. Methods:NHB and NHW participants from the COPDGene study who were free of diabetes (n = 4693) at baseline were followed for incident diabetes. The SomaScan was used to determine the relative amounts of natural log-transformed ferritin, transferrin, and hepcidin. Findings:During an average of 5.6 years of follow-up, diabetes incidence was 7.9%. Ferritin at follow-up was higher in NHB than NHW participants (p = <0.0001). Ferritin at follow-up was associated with increased diabetes risk (OR = 1.36, 95% CI = 1.08-1.70), while transferrin was associated with decreased risk (OR = 0.25, 95% CI = 0.08-0.77) controlling for age, sex, BMI, smoking pack-years, hepcidin, CRP, and Il-6. Race-specifically, increased risk associated with higher ferritin levels among NHB (OR = 1.56, 95% CI = 1.13-2.16) but not NHW (OR = 1.22, 95% CI = 0.89-1.68) participants. Sex-specifically, ferritin's relationship was similar among NHB men and women and NHW women (ORs ranging from 1.41-1.59); but not NHW men (OR = 0.98, 95% CI = 0.64-1.49). Similarly, transferrin ORs non-significantly ranged from 0.19-0.30 for NHB men and women and NHW women, but was significant for NHW men (OR = 0.07, 95% CI = 0.01-0.63). Interpretation:Higher body iron stores is associated with increased diabetes risk among both NHB and NHW people. Unsuspected elevated iron stores may increase diabetes risk in NHB patients and should be monitored.

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10−14) and among males (p = 1.0 × 10−9), but the signal was not genome-wide significant among females (p = 6.4 × 10−6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10−8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10−7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10−7) than former smokers (p = 7.5 × 10−3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10−8) and current smokers (p = 1.7 × 10−7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Background Cardiovascular disease (CVD) is the most important comorbidity in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations not only contribute to COPD progression but may also elevate the risk of CVD. This study aimed to determine whether COPD exacerbations increase the risk of subsequent CVD events using up to 15 years of prospective longitudinal follow‐up data from the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. Methods and Results The COPDGene study is a large, multicenter, longitudinal investigation of COPD, including subjects at enrollment aged 45 to 80 years with a minimum of 10 pack‐years of smoking history. Cox proportional hazards models and Kaplan‐Meier survival curves were used to assess the risk of a composite end point of CVD based on the COPD exacerbation rate. Frequent exacerbators exhibited a higher cumulative incidence of composite CVD end points than infrequent exacerbators, irrespective of the presence of CVD at baseline. After adjusting for covariates, frequent exacerbators still maintained higher hazard ratios (HRs) than the infrequent exacerbator group (without CVD: HR, 1.81 [95% CI, 1.47–2.22]; with CVD: HR, 1.92 [95% CI, 1.51–2.44]). This observation remained consistently significant in moderate to severe COPD subjects and the preserved ratio impaired spirometry population. In the mild COPD population, frequent exacerbators showed a trend toward more CVD events. Conclusions COPD exacerbations are associated with an increased risk of subsequent cardiovascular events in subjects with and without preexisting CVD. Patients with COPD experiencing frequent exacerbations may necessitate careful monitoring and additional management for subsequent potential CVD. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00608764.

The genome-wide association studies (GWAS) typically use linear or logistic regression models to identify associations between phenotypes (traits) and genotypes (genetic variants) of interest. However, the use of regression with the additive assumption has potential limitations. First, the normality assumption of residuals is the one that is rarely seen in practice, and deviation from normality increases the Type-I error rate. Second, building a model based on such an assumption ignores genetic structures, like, dominant, recessive, and protective-risk cases. Ignoring genetic variants may result in spurious conclusions about the associations between a variant and a trait. We propose an assumption-free model built upon data-consistent inversion (DCI), which is a recently developed measure-theoretic framework utilized for uncertainty quantification. This proposed DCI-derived model builds a nonparametric distribution on model inputs that propagates to the distribution of observed data without the required normality assumption of residuals in the regression model. This characteristic enables the proposed DCI-derived model to cover all genetic variants without emphasizing on additivity of the classic-GWAS model. Simulations and a replication GWAS with data from the COPDGene demonstrate the ability of this model to control the Type-I error rate at least as well as the classic-GWAS (additive linear model) approach while having similar or greater power to discover variants in different genetic modes of transmission.

Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components). In secondary analyses, we adjusted for age, sex, current smoking status, genetic ancestry (via principal components), income, education, and living status (urban vs. rural). In addition, we examined sex-stratified mediation models and sex-moderated mediation models. For both analyses, we adjusted for age, current smoking status, and genetic ancestry (via principal components). In the UK Biobank, rs6424532 [LOC105378800] had a statistically significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 4.0 × 10−4) among all participants and a marginally significant indirect effect among females (p = 0.02) and males (p = 4.0 × 10−3). Moreover, rs10501696 [GRM5] had a marginally significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 0.01) among all participants and a significant indirect effect among females (p = 2.2 × 10−3). In the secondary analyses, the sex-moderated indirect effect was marginally significant for rs10501696 [GRM5] on broad depression through the log of pack-years of cigarette smoking (p = 0.01). In the COPDGene study, the effect of an SNP (rs10501696) in GRM5 on depressive symptoms and medication was mediated by log of pack-years (p = 0.02); however, no SNPs had a sex-moderated mediated effect on depressive symptoms. In the UK Biobank, we found SNPs in two genes [LOC105378800, GRM5] with an indirect effect on broad depression through the log of pack-years of cigarette smoking. In addition, the indirect effect for GRM5 on broad depression through smoking may be moderated by sex. These results suggest that genetic regions associated with broad depression may be mediated by cigarette smoking and this relationship may be moderated by sex.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

INTRODUCTION:Diabetes and dementia are diseases of high healthcare burden worldwide. Individuals with diabetes have 1.4 to 2.2 times higher risk of dementia. Our objective was to evaluate evidence of causality between these two common diseases.METHODS:We conducted a one-sample Mendelian randomization (MR) analysis in the U.S. Department of Veterans Affairs Million Veteran program. The study included 334,672 participants ≥65 years of age with type 2 diabetes and dementia case-control status and genotype data.RESULTS:For each standard deviation increase in genetically-predicted diabetes, we found increased odds of three dementia diagnoses in non-Hispanic White participants (all-cause: OR=1.07[1.05-1.08], P =3.40E-18; vascular: OR=1.11[1.07-1.15], P =3.63E-09, Alzheimer's: OR=1.06[1.02-1.09], P =6.84E-04) and non-Hispanic Black participants (all-cause: OR=1.06[1.02-1.10], P =3.66E-03, vascular: OR=1.11[1.04-1.19], P =2.20E-03, Alzheimer's: OR=1.12 [1.02-1.23], P =1.60E-02) but not in Hispanic participants (all P >.05).DISCUSSION:We found evidence of causality between diabetes and dementia using a one-sample MR study, with access to individual level data, overcoming limitations of prior studies utilizing two-sample MR techniques.

Background:Abnormal lung volumes representing air trapping identify the subset of smokers with preserved spirometry who develop spirometric chronic obstructive pulmonary disease (COPD) and adverse outcomes. However, how lung volumes evolve in early COPD as airflow obstruction develops remains unclear. Methods:To establish how lung volumes change with the development of spirometric COPD, we examined lung volumes from the pulmonary function data (seated posture) available in the U.S. Department of Veterans Affairs electronic health records (n=71,356) and lung volumes measured by computed tomography (supine posture) available from the COPD Genetic Epidemiology (COPDGene®) study (n=7969) and the SubPopulations and InterMediate Outcome Measures In COPD Study (SPIROMICS) (n=2552) cohorts, and studied their cross-sectional distributions and longitudinal changes across the airflow obstruction spectrum. Patients with preserved ratio-impaired spirometry (PRISm) were excluded from this analysis. Results:Lung volumes from all 3 cohorts showed similar patterns of distributions and longitudinal changes with worsening airflow obstruction. The distributions for total lung capacity (TLC), vital capacity (VC), and inspiratory capacity (IC) and their patterns of change were nonlinear and included different phases. When stratified by airflow obstruction using Global initiative for chronic Obstructive Lung Disease (GOLD) stages, patients with GOLD 1 (mild) COPD had larger lung volumes (TLC, VC, IC) compared to patients with GOLD 0 (smokers with preserved spirometry) or GOLD 2 (moderate) disease. In longitudinal follow-up of baseline GOLD 0 patients who progressed to spirometric COPD, those with an initially higher TLC and VC developed mild obstruction (GOLD 1) while those with an initially lower TLC and VC developed moderate obstruction (GOLD 2). Conclusions:In COPD, TLC, and VC have biphasic distributions, change in nonlinear fashions as obstruction worsens, and could differentiate those GOLD 0 patients at risk for more rapid spirometric disease progression.

Rationale: Cigarette smoking contributes to risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in COPDGene into normal spirometry, Preserved Ratio Impaired Spirometry (PRISm), GOLD 1-2 and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after review of death certificates, medical records and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional-hazards models. Results: Over 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5±9.0 years; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ≥7. St. George's Respiratory Questionnaire score ≥25 was associated with higher mortality in all groups: HR 1.48 [1.20-1.84] normal spirometry; HR 1.40 [1.05-1.87] PRISm; HR 1.80 [1.49-2.17] GOLD 1-2; HR 1.65 [1.26-2.17] GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification and a potential drug target for vascular calcific disease. de Vries, Conomos, Singh and Nicholson et al. identify two additional loci associated with coronary artery calcification (ARSE and MMP16) via a genome-wide association study in 22,400 participants from multiple ancestral groups and prove that ARSE is a mediator of vascular smooth muscle cell calcification and phenotype switching.

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by pathologic changes in the airways, lung parenchyma, and persistent inflammation, but the links between lung structural changes and blood transcriptome patterns have not been fully described. Objectives: The objective of this study was to identify novel relationships between lung structural changes measured by chest computed tomography (CT) and blood transcriptome patterns measured by blood RNA sequencing (RNA-seq). Methods: CT scan images and blood RNA-seq gene expression from 1223 participants in the COPD Genetic Epidemiology (COPDGene (R)) study were jointly analyzed using deep learning to identify shared aspects of inflammation and lung structural changes that we labeled image-expression axes (IEAs). We related IEAs to COPD-related measurements and prospective health outcomes through regression and Cox proportional hazards models and tested them for biological pathway enrichment. Results: We identified 2 distinct IEAs: IEAemph which captures an emphysema-predominant process with a strong positive correlation to CT emphysema and a negative correlation to forced expiratory volume in 1 second and body mass index (BMI); and IEAairway which captures an airway-predominant process with a positive correlation to BMI and airway wall thickness and a negative correlation to emphysema. Pathway enrichment analysis identified 29 and 13 pathways significantly associated with IEAemph and IEAairway, respectively (adjusted p<0.001). Conclusions: Integration of CT scans and blood RNA-seq data identified 2 IEAs that capture distinct inflammatory processes associated with emphysema and airway-predominant COPD.