Genetic Determinants of Pulmonary Artery Size in over 50,000 Subjects with and without COPD

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.