Identification of novel COPD susceptibility genes using a genome-wide interaction study

Some genetic variants are associated with chronic obstructive pulmonary disease (COPD), but genetic susceptibility for lung function decline has not been studied in the general population. We investigated the genetic susceptibility-associated lung function decline with or without COPD, using data from a community-based cohort. A genome-wide interaction study was conducted to identify the association between genetic variants and pulmonary function, and the way variants relate to lung impairment in accordance with smoking status and amount was examined. We further used a linear mixed model to examine the association and interaction to time effect. We found annual mean FEV ₁ declines of 41.7 mL for men and 33.4 mL for women, and the annual rate of decline in FEV ₁ was the fastest for current smokers. We also found a previously identified locus near FAM13 , the most significant SNPs from the results of two likelihood ratio tests for FEV ₁ /FVC. These selected SNPs were located in the upstream region of FAM13 on chromosome 4 and had similar minor allele frequencies (MAFs). Furthermore, we found that certain SNPs tended to have lower FEV ₁ /FVC values, and lung function decreased much faster with time interactions. The SNP most associated with lung function decline was the rs75679995 SNP on chromosome 7, and those SNPs located within the TAD of the DNAH11 region and the eQTL of rs9991425 revealed a higher expression of MFAP3L and AADAT genes. This is the first gene–time interaction study of lung function decline as a risk factor for COPD in the Korean population. In addition to replicating previously known signals for FAM13A , we identified two novel genomic regions ( DNAH11, AADAT ) involved in this gene–environmental interaction.