Background: Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality, is significantly influenced by genetic factors. Despite more than 200 loci discovered by large-scale genome-wide association studies, identified loci explain only a small portion of the heritability of pulmonary function and COPD.
Methods: After sample and variant quality control, we performed whole genome sequence (WGS) analysis of pulmonary function (FEV1, FVC and FEV1/FVC) and COPD disease status of 39,644 multi-ethnic samples in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We performed single variant analysis using the Scalable and Accurate Implementation of GEneralized mixed model (SAIGE) implemented on the ENCORE platform.
Results: Using a genome-wide significance level of 5×10-9, we identified 18 genome-wide significant regions (within 2Mb) including 1,520 variants in the multi-ethnic data. In the ancestry-stratified analysis, we identified 11 genetic regions in the European- and 1 in the African-ancestry samples, respectively. In total, we identified 20 distinct regions with 1,532 variants; 10 of these regions were previously identified in the Freeze5b data in the TOPMed program including fewer samples. These newer regions were near EPHA6, GRK7, LAMA5, MGC57346-CRHR1, RHOBTB3, SCRT2 and SLC52A3. Some of these regions have been previously associated with a range of traits including blood protein measurements, body height, and others. Our analyses complement the large-scale GWAS studies with a focus on low-frequency variants, and indicates that new genetic regions could be discovered with larger sample size of whole genome sequencing data.