Identification of Novel COPD Susceptibility Genes: A Genome-wide Interaction Study

Abstract

Abstract Background: Variants of some genes are associated with chronic obstructive pulmonary disease (COPD). However, genetic susceptibility for lung function decline in the general population remains unclear. Here, we investigated the genetic susceptibility associated with lung function decline with or without COPD by analyzing a community. Methods: A genome-wide interaction study was performed to identify the association between genetic variants and pulmonary function and examine their impact on lung impairment in terms of smoking status. We analyzed the association between genetic variants and lung function using a linear mixed model for association and interaction-to-time effects. Results: We observed 8,554 participants for 12 years. The annual mean FEV1 declines were 41.7 mL (in men) and 33.4 mL (in women); the annual rate of FEV1 decline was the fastest for current smokers. A locus upstream of FAM13 on chromosome 4, which harbored the most significant single-nucleotide polymorphisms (SNPs), was previously identified from two likelihood ratio tests for FEV1/FVC; these SNPs had similar minor allele frequencies. Additionally, certain SNPs showed lower FEV1/FVC values. The rs75679995 SNP on chromosome 7 showed the highest association with lung function decline; the SNPs located within the DNAH11 region TAD and rs9991425 eQTL were associated with higher MFAP3L and AADAT expression. Conclusion: This is the first gene-time interaction study of lung function decline as a risk factor for COPD in a community-based population. We replicated previously known signals for FAM13A and identified two novel genomic regions (DNAH11 and AADAT) involved in these gene-environment interactions.