Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema

Abstract

Rationale: chronic obstructive pulmonary disease (COPD), characterized by airflow limitation, is a disorder with high phenotypic and genetic heterogeneity. Pulmonary emphysema is a major but variable component of COPD; familial data suggest that different components of COPD, such as emphysema, may be influenced by specific genetic factors.

Objectives: to identify genetic determinants of emphysema assessed through high-resolution chest computed tomography in individuals with COPD.

Methods: we performed a genome-wide association study (GWAS) of emphysema determined from chest computed tomography scans with a total of 2,380 individuals with COPD in three independent cohorts of white individuals from (1) a cohort from Bergen, Norway, (2) the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and (3) the National Emphysema Treatment Trial (NETT). We tested single-nucleotide polymorphism associations with the presence or absence of emphysema determined by radiologist assessment in two of the three cohorts and a quantitative emphysema trait (percentage of lung voxels less than -950 Hounsfield units) in all three cohorts.

Measurements and main results: we identified association of a single-nucleotide polymorphism in BICD1 with the presence or absence of emphysema (P = 5.2 × 10(-7) with at least mild emphysema vs. control subjects; P = 4.8 × 10(-8) with moderate and more severe emphysema vs. control subjects).

Conclusions: our study suggests that genetic variants in BICD1 are associated with qualitative emphysema in COPD. Variants in BICD1 are associated with length of telomeres, which suggests that a mechanism linked to accelerated aging may be involved in the pathogenesis of emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT00292552).

Figure 1.

Manhattan plots of –log₁₀ P values for association analysis of emphysema radiologist scores, including cases defined as at least 5% emphysema versus chronic obstructive pulmonary disease (COPD) without emphysema control subjects in ECLIPSE, the Norway cohort, and meta-analysis (A–C), and cases defined as greater than 25% emphysema versus COPD without emphysema control subjects in ECLIPSE, the Norway cohort, and meta-analysis (D–F).

Figure 2.

Plot of –log₁₀ P values for association meta-analysis of emphysema qualitative trait for BICD1 region, (A) cases defined as at least 5% emphysema, and (B) cases defined as greater than 25% emphysema versus chronic obstructive pulmonary disease (COPD) without emphysema. “Round”: imputed; “Diamond”: typed. Color indicates r² with the most significant and typed SNP (blue diamond). Recombination rate data were based on using Build 36 coordinates, which was downloaded from HapMap.