Novel Genes for Airway Wall Thickness Identified with Combined Genome-Wide Association and Expression Analyses

Rationale: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways.Objectives: To investigate the genetic component of AWT.Methods: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated.Measurements and Main Results: Three significant loci on chromosomes 2q (rs734556; P =  6.2 × 10−7) and 10q (rs10794108, P = 8.6 × 10−8; rs7078439, P = 2.3 × 10−7) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10−8, 7.4 × 10−8, and 7.5 × ...