Genetic Determinants of Pulmonary Artery Size in over 50,000 Subjects with and without COPD
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT Rationale Pulmonary artery (PA) enlargement is a non-invasive imaging biomarker associated with pulmonary hypertension and mortality in COPD; however, its genetic determinants remain incompletely understood. Objectives To characterize the genetic architecture of PA size across COPD-enriched and population-based cohorts. Methods We performed genome-wide association analyses of PA diameter using whole-genome sequencing in COPDGene (n=9,418) and ECLIPSE (n=1,859), and imputed-genotype data from the UK Biobank (n=37,073). We replicated lead variants in the Framingham Heart Study (FHS; n=3,289), incorporated all four studies into a joint meta-analysis, and identified independent signals through conditional analyses. Candidate effector genes were prioritized using coding variant annotation, colocalization, and integrative regulatory evidence. Measurements and Main Results We identified 44 independent genome-wide significant PA diameter signals within 39 loci, including 8 variants replicated in FHS, novel associations near FRMD4B , SLC20A2 , BORCS7-ASMT , and KCNRG , and 5 signals in conditional analysis including multiple signals at ANO1 . Genetic effects were concordant across imaging modalities and cohorts of differing COPD burden. Effector-gene prioritization nominated ABCC8 , PDGFD , HMCN1 , CCNE1 , and TBX20 , implicating pathways in vascular remodeling, developmental regulation, smooth muscle and endothelial function, ion-channel signaling, and extracellular matrix organization. Colocalization with pulse pressure GWAS demonstrated substantial shared causal variation between pulmonary and systemic vascular biology. Conclusions In this largest genetic study of pulmonary vascular imaging to date, PA diameter exhibits a polygenic architecture consistent across imaging modalities and cohorts of differing COPD burden. The prioritized effector genes bridge rare-variant pulmonary hypertension biology with common-variant systemic vascular biology.
Source: medRxiv
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G1052645489, G1356451498, G2096685756, Rare variants and NHLBI traits in deeply phenotyped cohorts, G232264632, G2417563097, G3078883119, Rare variants and NHLBI traits in deeply phenotyped cohorts, (2 of 2) Genetic Epidemiology of COPD, G5163278296, G5258357286, (2 of 2) Genetic Epidemiology of COPD, Matrikines and COPD-PH, G631129105, G6615318374, (1 of 2) Genetic Epidemiology of COPD, G7519571385, Integrative genomic, transcriptomic and proteomic studies of pulmonary function and COPD, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, G8354759825, G9000091268, G9000180696, G9000228787, Uncovering the genetically-driven differential susceptibility to chronic obstructive pulmonary disease and pulmonary fibrosis, Imaging and multi-omics analyses to identify molecular subtypes of distinct emphysema patterns, Genetic and Genomic Characterization of the Occurrence and Progression of Interstitial Lung Abnormalities, Identifying Subtypes of COPD Using Metabolomic and Genomic Approaches, G993448119
OpenAlex ID: W7167331657