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Background  Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.    Methods  We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV 1 ) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV 1  by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.    Results  The overall meta-analysis produced suggestive evidence for association at the novel  IL16/STARD5/TMC3  locus on chromosome 15 ( P   =  5.71 × 10 -7 ). In addition, meta-analysis using the five cohorts with ≥3 FEV 1  measurements per participant identified the novel  ME3  locus on chromosome 11 ( P   =  2.18 × 10 -8 ) at genome-wide significance. Neither locus was associated with FEV 1  decline in two additional cohort studies. We confirmed gene expression of  IL16 ,  STARD5 , and  ME3  in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV 1  decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.    Conclusions  In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV 1  that harbor candidate genes with biologically plausible functional links to lung function.

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function