Whole-Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease.
Genome-wide association studies have identified common variants associated with chronic obstructive pulmonary disease (COPD). Whole-genome sequencing (WGS) offers comprehensive coverage of the entire genome, as compared with genotyping arrays or exome sequencing. We hypothesized that WGS in subjects with severe COPD and smoking control subjects with normal pulmonary function would allow us to identify novel genetic determinants of COPD. We sequenced 821 patients with severe COPD and 973 control subjects from the COPDGene and Boston Early-Onset COPD studies, including both non-Hispanic white and African American individuals. We performed single-variant and grouped-variant analyses, and in addition, we assessed the overlap of variants between sequencing- and array-based imputation. Our most significantly associated variant was in a known region near HHIP (combined P = 1.6 × 10-9); additional variants approaching genome-wide significance included previously described regions in CHRNA5, TNS1, and SERPINA6/SERPINA1 (the latter in African American individuals). None of our associations were clearly driven by rare variants, and we found minimal evidence of replication of genes identified by previously reported smaller sequencing studies. With WGS, we identified more than 20 million new variants, not seen with imputation, including more than 10,000 of potential importance in previously identified COPD genome-wide association study regions. WGS in severe COPD identifies a large number of potentially important functional variants, with the strongest associations being in known COPD risk loci, including HHIP and SERPINA1. Larger sample sizes will be needed to identify associated variants in novel regions of the genome.
['Prokopenko|Dmitry|D|0000-0002-1844-5652', 'Sakornsakolpat|Phuwanat|P|0000-0002-4308-0974', 'Fier|Heide Loehlein|HL|', 'Qiao|Dandi|D|', 'Parker|Margaret M|MM|', 'McDonald|Merry-Lynn N|MN|', 'Manichaikul|Ani|A|', 'Rich|Stephen S|SS|', 'Barr|R Graham|RG|', 'Williams|Christopher J|CJ|', 'Brantly|Mark L|ML|', 'Lange|Christoph|C|', 'Beaty|Terri H|TH|', 'Crapo|James D|JD|', 'Silverman|Edwin K|EK|', 'Cho|Michael H|MH|0000-0002-4907-1657']
D001741:African Americans D000368:Aged D016022:Case-Control Studies D015331:Cohort Studies D005260:Female D020022:Genetic Predisposition to Disease D055106:Genome-Wide Association Study D006801:Humans D008168:Lung D008297:Male D008875:Middle Aged D020641:Polymorphism, Single Nucleotide D029424:Pulmonary Disease, Chronic Obstructive D012720:Severity of Illness Index D044465:Whites D000073336:Whole Genome Sequencing
whole-genome sequencing chronic obstructive pulmonary disease association studies