The findings of a study conducted in patients with chronic obstructive pulmonary disease (COPD), published in the American Journal of Respiratory Cell and Molecular Biology, support the value of whole-genome sequencing (WGS), particularly for rare or poorly imputed variants, in unique populations.
Genome-wide association studies (GWAS) have identified common variants associated with risk for COPD, but much of the genetic contribution to COPD remains unknown. Rare variants may contribute to some of the genetic risk. In contrast to GWAS, WGS includes important noncoding regions and also improves coverage of coding regions.
Dmitry Prokopenko, PhD, from the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues hypothesized that performing WGS in individuals with severe COPD and in smoking control patients with normal pulmonary function would allow them to identify novel genetic determinants of COPD. A total of 821 cases of severe and very severe COPD and 973 control patients from the COPDGene and Boston Early-Onset COPD studies were sequenced. The researchers included 2 study populations (non-Hispanic whites and African Americans) and performed an association analysis of these individuals to assess the effect of common and rare sequenced variants on risk for severe COPD. The variants were compared in the same participants from 2 data sources: sequenced and imputed.
Top-ranked associations included TNS1, which has been previously associated with lung function but not COPD. The results confirmed associations between variants near HHIP and CHRNA3 genes as affecting risk for severe COPD, and there was a suggestive association in African Americans upstream of SERPINA6 and near SERPINA1. Variants of SERPINA1 are known to cause alpha-1 antitrypsin deficiency. However, the investigators were unable to find conclusive evidence for rare variants in or near SERPINA1.
The researchers found a small but not insignificant number of common variants and most rare variants that could not be identified using existing imputation panels. This issue is even more significant in African Americans, who may harbor different genetic variants. GWAS relies on existing imputation panels, but African Americans are poorly represented on these panels.
The researchers noted that their study underscores the importance of having large sample sizes in sequencing studies and the necessity of improving tools for functional annotation of the noncoding genomic regions to permit optimal use of WGS data and discern new associations with COPD. They suggested that with the decreasing costs associated with sequencing, WGS may eventually eliminate the need for genotyping and imputation.
Prokopenko D, Sakornsakolpat P, Loehlein Fier H, et al. Whole genome sequencing in severe chronic obstructive pulmonary disease [published June 27, 2018]. Am J Respir Cell Mol Biol. doi:10.1165/rcmb.2018-0088OC