Author(s): Qiao D.; Ameli A.; Sharma A.; Hersh C.P.; Morrow J.; Hobbs B.D.; Cho M.H.; Laird N.; Lange C.; Chen H.; Prokopenko D.; Parker M.M.; Kho A.; Beaty T.H.; Crapo J.D.; Barnes K.; Nickerson D.; Bamshad M.; Lomas D.A.; Liu Y.; Spitz M.; Agusti A.; Make B.J.; Calverley P.M.; Donner C.F.; Wouters E.; Vestbo J.; Pare P.D.; Levy R.D.; Rennard S.I.; Tal-Singer R.; Silverman E.K.
Source: American Journal of Respiratory and Critical Care Medicine; 2018; vol. 197
Publication Date: 2018
Publication Type(s): Conference Abstract
Available at American Journal of Respiratory and Critical Care Medicine – from Edge Hill Aintree LIRC (lib302411) Local Print Collection [location] : Edge Hill Aintree LIRC.
Abstract:Introduction: Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence chronic obstructive pulmonary disease (COPD) susceptibility. To identify additional rare coding variants in patients with COPD, we utilized an extreme-phenotype study design and conducted whole exome sequencing analysis in multiple cohorts of individuals with severe COPD. Methods: We sequenced a total of 2,543 subjects from two family-based studies (the Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). All cases in the COPDGene study were clinically severe, with forced expiratory volume in one second (FEV1) < 50% predicted; the mean FEV1 across all cases in the family-based studies was 41.9% predicted. Controls were smokers with normal spirometry. We conducted two complementary analyses: 1) a gene-based segregation method (GESE) in the family studies, and 2) rare variant association tests (single variant, genes, and pathways) in the case-control and family-based studies. We sought evidence for overlap between case-control and family-based data using network analysis methods. Also, we closely examined candidate loci associated with COPD or lung function using both association testing and filtering approach. Results: Using GESE in the family-based data, we identified rare variants in TBC1D10A and RFPL1 segregating in multiple pedigrees, but failed to find suggestive evidence of replication in the case-control data. Similarly, we were unable to find significant single variants, genes, or pathways that replicated. We found no significant overlap of top association results in case-control and family studies; however, the significant close proximity of the genes with p-values < 0.01 in the protein-protein interaction network (p=0.014) indicated their involvement in similar biological processes or pathways important for COPD. The resulting network component was significantly enriched in the transforming growth factor beta receptor binding and cilia-related pathways. We did find individual subjects with homozygous high risk genotypes for rare Mendelian syndromes previously reported to include emphysema as a component in their syndrome definition, including cutis laxa and Niemann-Pick Disease Type C. Conclusions: In an exome sequencing study of severe COPD from multiple cohorts, we did not identify novel individual rare variants or genes of strong effect; however, network analysis suggested that additional coding variants below conventional significance thresholds may contribute to COPD susceptibility. These results highlight the potential of network analysis to gain insight into genetic association studies, and likely reflect heterogeneity of genetic risk along with limitations of statistical power and functional annotation.