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

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.

To characterize the genetic architecture of PA size across COPD-enriched and population-based cohorts.

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.

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.

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.